Effects of dietary RRR α-tocopherol vs all-racemic α-tocopherol on health outcomes

Effects of dietary RRR α-tocopherol vs all-racemic α-tocopherol on health outcomes Abstract Of the 8 vitamin E analogues, RRR α-tocopherol likely has the greatest effect on health outcomes. Two sources of α-tocopherol, naturally sourced RRR α-tocopherol and synthetic all-racemic α-tocopherol, are commonly consumed from foods and dietary supplements in the United States. A 2016 US Food and Drug Administration ruling substantially changed the RRR to all-racemic α-tocopherol ratio of biopotency from 1.36:1 to 2:1 for food-labeling purposes, but the correct ratio is still under debate in the literature. Few studies have directly compared the 2 α-tocopherol sources, and existing studies do not compare the efficacy of either source for preventing or treating disease in humans. To help close this gap, this review evaluates studies that investigated the effects of either RRR α-tocopherol or all-racemic α-tocopherol on health outcomes, and compares the overall findings. α-Tocopherol has been used to prevent and/or treat cancer and diseases of the central nervous system, the immune system, and the cardiovascular system, so these diseases are the focus of the review. No firm conclusions about the relative effects of the α-tocopherol sources on health outcomes can be made. Changes to α-tocopherol–relevant policies have proceeded without adequate scientific support. Additional research is needed to assemble the pieces of the α-tocopherol puzzle and to determine the RRR to all-racemic α-tocopherol ratio of biopotency for health outcomes. all-racemic α-tocopherol, health, RRR α-tocopherol, vitamin E INTRODUCTION Vitamin E, which was discovered by Katherine S. Bishop and Herbert M. Evans in the 1920s, is a lipid-soluble antioxidant that plays a crucial role in human and animal reproduction. Although the name “vitamin E” appears to refer to a single compound, there are actually 8 vitamin E analogues: 4 tocopherols (α, β, γ, and δ) and 4 tocotrienols (α, β, γ, and δ) (Figure 1). However, only α-tocopherol was used to set the recommended dietary allowance (RDA) of vitamin E for Americans.1 Humans consume 2 sources of α-tocopherol: naturally sourced α-tocopherol, which is commonly found in seed oils, and synthetic α-tocopherol, which is used to fortify food products such as ready-to-eat cereals. Figure 1 View largeDownload slide Forms of vitamin E. Abbreviation: RDA, recommended dietary allowance. Figure 1 View largeDownload slide Forms of vitamin E. Abbreviation: RDA, recommended dietary allowance. CHEMICAL STRUCTURE OF α-TOCOPHEROL Synthetic (all-racemic, or all-rac) α-tocopherol is an equimolar mix of its stereoisomers. The 3 chiral carbons of α-tocopherol (at positions 2, 4′, and 8′) can be in either an R or an S orientation, yielding 8 stereoisomers. One of the stereoisomers in all-rac α-tocopherol is 2R, 4′R, 8′R (or RRR), which is the sole stereoisomer found in nature. The other 7 stereoisomers consist of 3 2R stereoisomers (RSS, RSR, RRS) and 4 2S stereoisomers (SSS, SRR, SRS, SSR). The orientation (R or S) of the carbon at the 2-position is significant: the main α-tocopherol–binding protein in the liver, α-tocopherol transfer protein (α-TTP), has a higher affinity for RRR and the other 2R stereoisomers than for the 4 2S stereoisomers.2,3 This hepatic discrimination means that 2R stereoisomers will be preferentially packaged into very low-density lipoproteins for transport in the circulation and, consequently, will accumulate in peripheral tissues. INTAKE LEVELS OF α-TOCOPHEROL The RDA for adults is 15 mg of RRR α-tocopherol,1 but more than 88% of Americans do not meet this recommendation.4 To establish the RDA, erythrocyte hemolysis by hydrogen peroxide was used as a biomarker of vitamin E depletion and repletion.1 The use of this biomarker has been questioned,5 and there may be grounds for basing future recommendations for vitamin E intake on endpoints related to chronic disease instead.6 α-Tocopherol bioavailability is lower in cigarette smokers7,8 and individuals with metabolic syndrome,9 so certain populations may need more α-tocopherol than healthy individuals. Vitamin E deficiency is very rare, but vitamin E insufficiency may be common, given the dietary intakes reported for Americans.10 It is unknown whether marginal vitamin E deficiency leads to adverse health outcomes or to chronic disease.11 Some research suggests that the RDA is actually too high for healthy adults.12 BIOAVAILABILITY AND BIOPOTENCY OF α-TOCOPHEROL Determining the bioavailability and biopotency of synthetic and naturally sourced α-tocopherol is important for evaluating the roles of these vitamin E sources in health and disease. In the 1940s, experiments with rats showed that a dose of all-rac α-tocopheryl acetate 1.36 times the mass of a dose of naturally sourced α-tocopheryl acetate was required to prevent fetal resorption.13 Based on these studies, all-rac α-tocopheryl acetate was assigned a value of 1 IU/mg, and 1.36:1 became the accepted RRR to all-rac ratio of biopotency. International units have long been used to denote vitamin E content on food labels, but this will soon change. More recent research does not support the 1.36:1 ratio of biopotency in humans.5 Some animal and human bioavailability studies suggest a new ratio of RRR to all-rac biopotency of 2:1, as plasma and tissues accumulate about twice the amount of deuterated RRR α-tocopherol as all-rac α-tocopherol after simultaneous consumption.14–16 The preferential binding of hepatic α-TTP to the 4 2R stereoisomers over the 4 2S stereoisomers also supports the 2:1 ratio. Therefore, it has been assumed that, at doses of an equivalent mass, all-rac α-tocopherol has one-half the biopotency of RRR α-tocopherol. However, determining the RRR to all-rac α-tocopherol ratio of biopotency requires the measurement of a biological response, such as fetal resorption. The new 2:1 ratio relies solely on bioavailability data (α-tocopherol tissue concentrations) and does not reflect data on biopotency. Though there are only limited measurable clinical endpoints to study α-tocopherol biopotency,5,13 data from α-tocopherol–deficient animal models can provide insight. Future studies should explore the effects of different dose ratios of RRR to all-rac α-tocopherol on tissue accumulation and functional parameters. To eliminate competition between these 2 sources of vitamin E in the liver, a nonsimultaneous dosing regimen may be most appropriate. Still, some researchers hypothesize that there is no single ratio of biopotency for the 2 α-tocopherol sources. They assert that the bioavailability and biopotency of each source differs depending on the dosage, the type of tissue, and the duration of dosing.5,17,18 For example, RRR:SRR ratios in the brain consistently increased the longer rats were fed a diet containing mass-equivalent doses of deuterated RRR and SRR α-tocopherol (from a ratio of 1.5:1 after 4 days up to 5.3:1 after 154 days).18 The RRR:SRR ratios in other tissues changed much less than the ratios in the brain, but each tissue differed in its discrimination for RRR over time.18 These differences in availability across tissues and over time obfuscate efforts to determine the biopotency of individual α-tocopherol stereoisomers, since doing so would require the use of a precise dosing regimen and a specific tissue type. As already noted, the current unit of measurement of vitamin E on food labels (international units) will soon be replaced. Based on a May 2016 ruling, the US Food and Drug Administration (FDA) is modifying the labeling regulations for conventional foods and dietary supplements.19 Food manufacturers will be required to indicate vitamin E content in milligrams instead of international units. Furthermore, it will be assumed that 2 mg of all-rac α-tocopherol equals 1 mg of RRR α-tocopherol. This is a drastic change in the regulations, given the ongoing uncertainty over the ratio of biopotency. BIOLOGICAL BASIS FOR DIFFERENTIAL EFFECTS There is a solid biological basis for differential effects of RRR α-tocopherol and all-rac α-tocopherol on health outcomes. The body differentially distributes, metabolizes, and excretes α-tocopherol stereoisomers. As noted earlier, hepatic α-TTP has a clear preference for RRR α-tocopherol and the other 2R stereoisomers, and thus RRR α-tocopherol is preferentially taken up into tissues over SRR α-tocopherol.2,3,18,20,21 For example, the only study that quantified all 8 stereoisomers in rat brain tissue found that the 4 2R stereoisomers accumulated equally; this further demonstrates the importance of the 2-position chiral carbon for α-tocopherol availability in tissues.22 The preference of hepatic α-TTP for 2R stereoisomers suggests that 2R stereoisomers are able to perform their functions better than 2S stereoisomers. Interestingly, the 2S stereoisomers do accumulate to varying degrees in milk23 and other tissues such as the brain,18,21,22,24 presumably via chylomicron delivery. This raises 2 questions about the role of 2S stereoisomers once they reach extrahepatic tissues. First, is there competition between 2R and 2S stereoisomers within cells? And second, do 2R and 2S stereoisomers result in the same biological response? Evidence in humans, though very limited, shows preferential incorporation of RRR α-tocopherol (over all 7 other stereoisomers) into tissues of the human infant brain.24 The biological rationale for—and significance of—this is not clear, though discriminatory mechanisms in extrahepatic tissues have been proposed. For example, the blood–brain barrier may regulate the entry of α-tocopherol into the brain.18 Additionally, the α-tocopherol–binding protein α-TTP has been detected in the brains of humans25 and rats.26 Tocopherol-associated protein, which has the same lipid-binding motif as α-TTP, has also been suggested as a potential binding protein for α-tocopherol.27 Tocopherol-associated protein was detected in multiple human tissues (eg, brain, heart, lung)28 and may be a transcriptional activator.29 However, despite promising results with tocopherol-associated protein, the primary role of this protein (typically known as supernatant protein factor) is in cholesterol biosynthesis,30 which likely has little physiological relevance to α-tocopherol metabolism.31 As for excretion of vitamin E, simultaneous consumption of deuterium-labeled RRR α-tocopherol and all-rac α-tocopherol led to the preferential excretion of all-rac (as α-CEHC) over RRR in urine at a remarkably high ratio of approximately 3:1.32 This suggests that RRR is preserved over all-rac and provides evidence of the differential impact of the 2 sources of α-tocopherol. The scientific community’s understanding of vitamin E has evolved since its discovery nearly a century ago, but some aspects of vitamin E warrant further investigation. The existing research does not wholly support the FDA’s changes to the US food labeling regulations with regard to vitamin E. A change in the unit of measurement used on food labels (international units to milligrams) is appropriate, since the conversion factors for international units have not been confirmed. However, the assertion of a 2:1 ratio of biopotency between naturally sourced and synthetic α-tocopherol has not been confirmed, either. Because very few studies directly compare the effectiveness of different α-tocopherol sources for health outcomes, this review evaluates and compares studies that investigated one source or the other. It focuses on 4 areas of human health that are often associated with the effects of α-tocopherol: the central nervous system (CNS), the immune system, the cardiovascular system, and cancer. The potential mechanisms responsible for the benefits of α-tocopherol in these 4 areas are also explored briefly. Many of the reviewed studies did not use vitamin E-depleted animals—those that did are specifically noted. NEUROLOGICAL DISEASES Role of α-tocopherol in the CNS Animal studies show that α-tocopherol promotes brain health and reverses neurodegeneration by preventing oxidative stress to cell components (eg, lipids and mitochondria).33,34 Studies using the α-TTP gene knockout (Ttpa−/−) model have produced some of the most valuable findings. With age, these animals develop structural abnormalities in the cerebellum35 and spinal cord36 as well as behavioral deficits36 caused by severe α-tocopherol deficiency. The Ttpa−/− model is particularly useful because neurological tissues retain α-tocopherol, even during dietary restriction.36 This model is also relevant to humans who have ataxia with vitamin E deficiency. Individuals with this disorder have loss-of-function mutations in the α-TTP gene and experience severe neurological dysfunction.37 Management of ataxia with vitamin E deficiency includes lifelong supplemental doses of α-tocopherol, which helps normalize plasma α-tocopherol levels and may partially reverse neurological symptoms.38 Knowledge gained about the consequences of deficiency has led to increased understanding of the metabolic fate of α-tocopherol. There is conflicting evidence about the role of α-tocopherol in other neurological outcomes, such as Alzheimer’s disease (AD) and cognitive function in older adults. In epidemiological studies, high tocopherol intake is associated with decreased incidence of AD.39 Moreover, patients with AD tend to have low plasma α-tocopherol concentrations,40 and plasma α-tocopherol has been inversely associated with severity of dementia and positively associated with both abstract reasoning and retention in the Fuld Object-Memory Evaluation.41 In contrast, α-tocopherol brain concentrations were not associated with AD neuropathology in deceased humans.33 In other studies, there were no associations between plasma α-tocopherol and measures of cognitive function42 or risk of cognitive impairment43 in elderly participants. A 2017 Cochrane review concluded there is no evidence supporting the use of α-tocopherol for treatment of mild cognitive impairment, but the results of 1 trial indicate that α-tocopherol may slow the progression of AD.44 It is α-tocopherol’s antioxidant properties that are most commonly associated with neurological health and disease. Oxidative stress is a factor in many brain disorders, including AD, and thus α-tocopherol status could be a critical factor.45 Nonetheless, some research suggests that α-tocopherol has both antioxidant and nonantioxidant functions in the CNS.46 For example, α-tocopherol may regulate gene expression. Two studies showed substantial changes in the expression of genes related to myelination, synaptic function, and oxidative stress in the cortices of adult Ttpa−/− mice.47,48 Another study concluded that α-tocopherol regulates hippocampal genes involved in Parkinson disease and AD.49 Histological or behavioral indicators of neurodegeneration have not been observed in young Ttpa−/− rodents; histological markers were seen from 17 to 20 months of age,35,36 and behavioral markers were seen at 18 months of age.36 However, alterations in gene expression have been observed in younger mice. Molecular changes may therefore precede more advanced manifestations of neurodegeneration.48 Though only a handful of studies have compared the sources of α-tocopherol for their effects on neurological outcomes, work in equines has shown that RRR α-tocopherol more effectively increases serum and cerebrospinal fluid α-tocopherol concentrations than equivalent doses (international units) of all-rac α-tocopherol (Table 1).50–55 Table 1 Central nervous system, immune system, and cardiovascular health outcomes in studies that compared RRR and all-rac α-tocopherol treatments Reference  Body system  Study groupa  Treatment doses  Sample size (per group)  Dosing regimen  Dosing duration (days)  Outcomes  Overall effect of RRR vs all-rac  Pusterla et al. (2010)50  CNS  Horses  RRR α-toc: 10 000 IU (6711 mg)  4  Daily, mixed into 250 g of sweet feed  14  RRR α-toc: ↑ [α-toc]serum; 2.2- to 4.2-fold ↑ [α-toc]CSF by day 14  RRR α-toc, but not all-rac, increased serum and CSF α-toc levels  All-rac α-TA: 10 000 IU (10 000 mg)  5  All-rac α-TA: no differences in [α-toc]serum or [α-toc]CSF from day 0 to day 14  Han et al. (2010)51  Immune system  Mice  RRR α-TA: 30 mg/kg diet or 500 mg/kg diet  4  Ad libitum, added to diet  28  RRR α-TA: dose comparison—high: ↑ gene expression of signaling lymphocyte activation molecule, TNF, and others; low: ↑ gene expression of IL-3 and others. α-toc source comparison—RRR: ↑ gene expression of lymphocyte activation molecule, TNFSF9, and others  Differences in spleen T lymphocyte gene transcription between α-toc doses and α-toc sources following ex vivo stimulation  All-rac α-TA: 30 mg/kg diet or 500mg/kg diet  4  All-rac α-TA: dose comparison—high: ↑ gene expression of IL-2 and others; low: ↑ gene expression of IGF-1 and others  Horn et al. (2010)52  Immune system  Cattle  RRR α-TA: 1000 IU (735 mg)  50  Daily, corn-based supplement  –b  RRR α-TA: ↑ [α-toc]serum; no differences in calf [IgG]serum or leukocyte CD14 and CD18 protein expressions compared with control. Source comparison—no overall difference in response to OVA challenge  No differences in immune response in suckling calves between α-toc sources  All-rac α-TA: 1000 IU (1000 mg)  50  All-rac α-TA: ↑ [α-toc]serum; no differences in calf [IgG]serum or leukocyte CD14 and CD18 protein expressions compared with control  Amazan et al. (2014)53  Immune system  Pigs  RRR α-TA: 150 mg or 50 mg  12  Daily, in water  c  RRR α-TA: dose comparison—high: ↑ [α-toc]serum and ↑ [IgA]serum  Higher α-toc serum levels in piglets from sows fed RRR α-toc compared with piglets from sows fed all-rac α-toc; no differences in immunoglobulin levels  All-rac α-TA: 150 mg  12  Daily, in feed  Source comparison—RRR: ↑ [α-toc]serum; no differences in [IgA]serum, [IgG]serum, or [IgM]serum  Reaven & Witztum (1993)54  CV system  Humans  RRR α-TA: 800 mg  7  Twice daily, α-TA capsules  56  RRR α-TA: ↑ [α-toc]LDL; ≈ 30% ↑ lag time of LDL oxidation after 28 and 56 days of supplementation; ↓ TBARS; ↓ macrophage degradation of LDL  No differences in LDL α-toc levels, susceptibility to lipid peroxidation of LDL, or other outcomes between α-toc sources  All-rac α-TA: 800 mg  8  All-rac α-TA: ↑ [α-toc]LDL; ≈ 30% ↑ lag time of LDL oxidation after 28 and 56 days of supplementation; ↓ TBARS; ↓ macrophage degradation of LDL  Devaraj et al. (1997)55  CV system  Humans  RRR α-TA: 100 IU (73.5 mg); 200 IU (147 mg); 400 IU (294 mg); or 800 IU (588 mg)  9–10  Daily, α-TA or placebo (soybean oil) capsules  56  RRR α-TA: dose comparison—↑ [α-toc]plasma and ↑ [α-toc]LDL with increasing dose; no differences in plasma lipid, lipoprotein, or fatty acid levels across doses or over time; prolongation of lag phase of oxidation with doses ≥ 400 IU  No differences in oxidative susceptibility of LDL or plasma α-toc concentrations between α-toc sources at any dose        All-rac α-TA: 100 IU (100 mg); 200 IU (200 mg); 400 IU (400 mg); or 800 IU (800 mg)  9–10      All-rac α-TA: dose comparison—↑ [α-toc]plasma and ↑ [α-toc]LDL with increasing dose; no differences in plasma lipid, lipoprotein, or fatty acid levels across doses or over time; prolongation of lag phase of oxidation with doses ≥ 400 IU    Reference  Body system  Study groupa  Treatment doses  Sample size (per group)  Dosing regimen  Dosing duration (days)  Outcomes  Overall effect of RRR vs all-rac  Pusterla et al. (2010)50  CNS  Horses  RRR α-toc: 10 000 IU (6711 mg)  4  Daily, mixed into 250 g of sweet feed  14  RRR α-toc: ↑ [α-toc]serum; 2.2- to 4.2-fold ↑ [α-toc]CSF by day 14  RRR α-toc, but not all-rac, increased serum and CSF α-toc levels  All-rac α-TA: 10 000 IU (10 000 mg)  5  All-rac α-TA: no differences in [α-toc]serum or [α-toc]CSF from day 0 to day 14  Han et al. (2010)51  Immune system  Mice  RRR α-TA: 30 mg/kg diet or 500 mg/kg diet  4  Ad libitum, added to diet  28  RRR α-TA: dose comparison—high: ↑ gene expression of signaling lymphocyte activation molecule, TNF, and others; low: ↑ gene expression of IL-3 and others. α-toc source comparison—RRR: ↑ gene expression of lymphocyte activation molecule, TNFSF9, and others  Differences in spleen T lymphocyte gene transcription between α-toc doses and α-toc sources following ex vivo stimulation  All-rac α-TA: 30 mg/kg diet or 500mg/kg diet  4  All-rac α-TA: dose comparison—high: ↑ gene expression of IL-2 and others; low: ↑ gene expression of IGF-1 and others  Horn et al. (2010)52  Immune system  Cattle  RRR α-TA: 1000 IU (735 mg)  50  Daily, corn-based supplement  –b  RRR α-TA: ↑ [α-toc]serum; no differences in calf [IgG]serum or leukocyte CD14 and CD18 protein expressions compared with control. Source comparison—no overall difference in response to OVA challenge  No differences in immune response in suckling calves between α-toc sources  All-rac α-TA: 1000 IU (1000 mg)  50  All-rac α-TA: ↑ [α-toc]serum; no differences in calf [IgG]serum or leukocyte CD14 and CD18 protein expressions compared with control  Amazan et al. (2014)53  Immune system  Pigs  RRR α-TA: 150 mg or 50 mg  12  Daily, in water  c  RRR α-TA: dose comparison—high: ↑ [α-toc]serum and ↑ [IgA]serum  Higher α-toc serum levels in piglets from sows fed RRR α-toc compared with piglets from sows fed all-rac α-toc; no differences in immunoglobulin levels  All-rac α-TA: 150 mg  12  Daily, in feed  Source comparison—RRR: ↑ [α-toc]serum; no differences in [IgA]serum, [IgG]serum, or [IgM]serum  Reaven & Witztum (1993)54  CV system  Humans  RRR α-TA: 800 mg  7  Twice daily, α-TA capsules  56  RRR α-TA: ↑ [α-toc]LDL; ≈ 30% ↑ lag time of LDL oxidation after 28 and 56 days of supplementation; ↓ TBARS; ↓ macrophage degradation of LDL  No differences in LDL α-toc levels, susceptibility to lipid peroxidation of LDL, or other outcomes between α-toc sources  All-rac α-TA: 800 mg  8  All-rac α-TA: ↑ [α-toc]LDL; ≈ 30% ↑ lag time of LDL oxidation after 28 and 56 days of supplementation; ↓ TBARS; ↓ macrophage degradation of LDL  Devaraj et al. (1997)55  CV system  Humans  RRR α-TA: 100 IU (73.5 mg); 200 IU (147 mg); 400 IU (294 mg); or 800 IU (588 mg)  9–10  Daily, α-TA or placebo (soybean oil) capsules  56  RRR α-TA: dose comparison—↑ [α-toc]plasma and ↑ [α-toc]LDL with increasing dose; no differences in plasma lipid, lipoprotein, or fatty acid levels across doses or over time; prolongation of lag phase of oxidation with doses ≥ 400 IU  No differences in oxidative susceptibility of LDL or plasma α-toc concentrations between α-toc sources at any dose        All-rac α-TA: 100 IU (100 mg); 200 IU (200 mg); 400 IU (400 mg); or 800 IU (800 mg)  9–10      All-rac α-TA: dose comparison—↑ [α-toc]plasma and ↑ [α-toc]LDL with increasing dose; no differences in plasma lipid, lipoprotein, or fatty acid levels across doses or over time; prolongation of lag phase of oxidation with doses ≥ 400 IU    Abbreviations and symbols: α-TA, α-tocopheryl acetate; α-toc, α-tocopherol; CSF, cerebrospinal fluid; CV, cardiovascular; IgA, immunoglobulin A; IgG, immunoglobulin G; IGF-1, insulin-like growth factor 1; IgM, immunoglobulin M; IL-2, mouse interleukin 2; IL-3, mouse interleukin 3; LDL, low-density lipoprotein; OVA, ovalbumin; TBARS, thiobarbituric acid-reactive substances; TNF, mouse tumor necrosis factor; TNFSF9, mouse tumor necrosis factor (ligand) superfamily, member 9; ↑, increased; ↓, decreased. a Animal groups were not vitamin E depleted prior to the study. b Dams were supplemented at ≈ 6 weeks prepartum until the beginning of breeding season; outcomes were measured in their suckling calves. c Sows were fed either all-rac α-TA or one of two RRR α-TA doses beginning 84 days prepartum and through lactation; after weaning, piglets were fed 3.33 mg of all-rac α-TA per day until 42 days of age. Neurological studies investigating RRR α-tocopherol Most CNS-related studies with RRR α-tocopherol have used rodent models. For example, a daily dose of RRR α-tocopherol delayed the neurological symptoms of ataxia with vitamin E deficiency and decreased lipid peroxidation in Ttpa−/− mice.36 An RRR α-tocopherol–supplemented diet also attenuated development of the tau pathology (a key component of Parkinson disease) in a transgenic mouse model that overexpresses a human tau isoform.56 Studies have also used RRR α-tocopherol to treat induced seizures57 and permanent cerebral brain injuries58 in otherwise healthy, vitamin E–sufficient rats. In both cases, RRR α-tocopherol reduced unfavorable hippocampal microglia activation.57,58 Treatment also significantly decreased markers related to oxidative stress57 and prevented pyramidal cell death.58 Using a mouse model of AD and vitamin E deficiency (Ttpa−/− + APPsw), RRR α-tocopherol supplementation reduced plasma amyloid β levels59 and amyloid plaque areas in the cortex and hippocampus.60 Supplementation normalized performance in the Morris water maze but did not improve performance in other behavioral tasks, such as a contextual fear conditioning test.60 Some animal research does not support a benefit of RRR α-tocopherol for CNS function.61 Additionally, very few CNS-related trials in humans have studied the effect of RRR α-tocopherol. In a long-term trial of RRR α-tocopherol supplementation in healthy older women, no significant cognitive benefits after multiple assessments were observed.62 Neurological studies investigating all-rac α-tocopherol Rats fed an α-tocopherol–deficient diet for 38 weeks followed by an all-rac α-tocopherol repletion diet for 20 weeks had less functional neural deterioration than rats fed an α-tocopherol–deficient diet throughout the study.63 Their electrophysiological parameters were also more similar to those of controls.63 The diet of the control group contained low levels of RRR α-tocopherol, indicating that repletion with all-rac α-tocopherol may be sufficient to restore the normal neural function observed in animals fed RRR α-tocopherol. A second rodent study investigated long-term potentiation in the dentate gyrus (hippocampus) of aged and young rats fed a diet supplemented with all-rac α-tocopherol.64 Long-term potentiation is the long-lasting strengthening of synapses, and it is one cellular mechanism used to explain learning and memory.64 While aged control mice (consuming a diet containing standard α-tocopherol levels) exhibited reduced long-term potentiation and increased lipid peroxidation, aged rats fed all-rac α-tocopherol–supplemented diets showed sustained long-term potentiation and reduced lipid peroxidation, similar to findings in young rats.64 This suggests that all-rac α-tocopherol helped prevent age-related oxidative stress in the hippocampus. In a third animal study, transgenic mice were used to investigate apoE4, an apolipoprotein E isoform involved in CNS lipoprotein metabolism and implicated as an independent risk factor for AD. All-rac α-tocopherol supplementation did not affect most of the AD-related endpoints.65 In 2 randomized, placebo-controlled human trials, daily supplementation with high-doses synthetic α-tocopherol delayed AD progression in individuals with mild to moderately severe AD.66,67 RRR α-tocopherol vs all-rac α-tocopherol: conclusions for neurological outcomes Some studies (both animal and human) did not specify whether RRR or all-rac α-tocopherol was used, which severely limits the comparability of results across studies. Despite the known consequences of low α-tocopherol status, the relative effect of RRR vs all-rac α-tocopherol in CNS health is not clear; none of the CNS studies aimed to show the ratio of biopotency between the 2 sources. Most research in animals showed some benefits from both RRR and all-rac α-tocopherol for the doses used. In 2 studies conducted in AD patients, all-rac α-tocopherol supplementation resulted in positive outcomes. Several human trials have used poorly defined vitamin E supplements that contain multiple tocopherol analogues; these studies were not included in this review. IMMUNE RESPONSE Role of α-tocopherol in the immune system The role of α-tocopherol in the immune system has been studied through the lens of allergic airway disease and lung function. Following ovalbumin sensitization, Ttpa−/− mice displayed a reduced immune response in the lung, demonstrating a need for α-tocopherol.68 Furthermore, higher serum α-tocopherol is related to favorable spirometric markers in young adults,69 and α-tocopherol may improve or reverse the functional decline of T cells that occurs with aging.70 The best-known function of α-tocopherol (ie, antioxidant) may be linked to immune-related outcomes. Some studies suggest that antioxidant intake is inversely associated with asthma prevalence.71 A second relevant function of α-tocopherol in the immune system involves signal transduction pathways. In endothelial cells, α-tocopherol inhibits protein kinase C α, thereby inhibiting the recruitment of leukocytes72,73 and altering the inflammatory immune response. It may also regulate the expression of immune-related genes in the heart74 as well as a group of genes related to inflammation.75 A few immunological studies have explicitly compared all-rac α-tocopherol with RRR α-tocopherol (Table 1).51–53 One ex vivo study used T lymphocytes from spleens of aged adult wild-type mice. The animals were fed diets with high or low levels of either RRR or all-rac α-tocopherol. After 4 weeks of treatment, it was shown that both the dose and the source of α-tocopherol influenced gene transcription.51 Distinct gene expression profiles were observed, even when the high dose of all-rac α-tocopherol (500 mg per kilogram of diet) was compared with the low dose of RRR α-tocopherol (30 mg per kilogram of diet).51 This suggests that the 2 α-tocopherol sources interact differently with their cellular targets and are not equivalent, even when all-rac α-tocopherol doses are well above the hypothesized 2:1 ratio of biopotency. In another study, calves suckling cows whose diets were supplemented with either RRR α-tocopherol or all-rac α-tocopherol had higher serum α-tocopherol levels than controls, but there were no differences in immune function in calves after an ovalbumin challenge.52 A third study found that piglets of sows fed RRR α-tocopherol had higher serum α-tocopherol levels than piglets of sows fed all-rac α-tocopherol.53 However, serum immunoglobulin levels in the piglets did not differ between groups.53 Immune-response studies investigating RRR α-tocopherol Some studies have assessed the effect of RRR α-tocopherol and age on immune outcomes. Linker for Activation of T cells is necessary for T-cell activation, and changes in phosphorylation signifies an altered response.76 Phosphorylation of Linker for Activation of T cells was significantly reduced in spleen CD4+ T cells of aged control mice, but RRR α-tocopherol treatment normalized phosphorylation.76 RRR α-tocopherol may reduce allergic responses and lung inflammation. Rodent dams were fed an RRR α-tocopherol–supplemented diet, and then their pups were sensitized with ovalbumin to induce an immune response. The pups had significantly lower eosinophil recruitment and inflammation in their lung tissue compared with the pups of dams fed a standard diet.77 In the lungs of pups in the treatment group, there were also significant decreases in the expression of genes encoding allergen-induced proteins (eg, interleukin [IL]-4 and IL-33).77 In contrast, a different rodent study showed that short-term (10-day) pretreatment with RRR α-tocopherol was ineffective in preventing the effects of an antigen challenge.78 Only a few human studies have examined the effects of RRR α-tocopherol supplementation on immune system outcomes. Research in asthmatics has yielded conflicting results: Supplemental doses of RRR α-tocopherol significantly decreased airway oxidative stress in 1 study79 but had no measurable impact on asthma control in another.80 However, the former study was small and was not randomized or placebo controlled. Immune-response studies investigating all-rac α-tocopherol T-cell function becomes impaired with age, but this was partially remedied by α-tocopherol in rodent studies. Feeding aged mice a diet containing high-dose all-rac α-tocopherol triggered changes in the transcription of genes important for the immune response: α-tocopherol led to induced expression of IL-2 and repressed expression of IL-4 in the animals’ splenic T cells.81 In another study examining T-helper 1 cytokine production, old influenza-infected mice were fed a diet containing high-dose all-rac α-tocopherol.82 Splenocytes from these mice had higher production of some cytokines, eg, IL-2 and interferon-γ, but not of others, eg, IL-6 and IL-1β.82 Production of prostaglandin E2 (PGE2) was also significantly reduced in macrophages of these mice.82 Since PGE2 levels increase with age and may reduce the normal T-helper 1 response, α-tocopherol may enhance T-helper 1 cell function by decreasing PGE2.82 Numerous gene transcripts in lung tissue were either up- or downregulated in male and female mice fed diets supplemented with low-dose or high-dose all-rac α-tocopherol.83 Despite similar levels of α-tocopherol in lung between sexes fed the high all-rac diet, substantially more genes were affected by α-tocopherol treatment in females than in males (≈ 500 vs ≈ 80).83 Of particular interest was a cluster of 13 functionally related cytoskeleton genes that were all induced by an α-tocopherol–supplemented diet.83 Though these findings lack statistical power, this research provides a starting point for future studies assessing the impact of sex and α-tocopherol on gene expression in lung tissue. In a trial with healthy older adults, daily supplementation with all-rac α-tocopherol improved multiple measures; in particular, participants had significantly decreased plasma lipid peroxide concentrations and enhanced cell-mediated immunity.84 De la Fuente et al.,85 Meydani et al.,86 and Lee et al.87 also found that supplemental doses of all-rac α-tocopherol positively affected immune outcomes in older adults. Effects on airway disease have been studied as well. Participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study who received daily synthetic 2-ambo α-tocopherol (which is 50% RRR and 50% SRR) supplements showed no differences in the development of chronic obstructive pulmonary disease symptoms, such as chronic bronchitis and dyspnea.88 RRR α-tocopherol vs all-rac α-tocopherol: conclusions for immune response outcomes In human and animal studies, RRR α-tocopherol and all-rac α-tocopherol have resulted in both positive and null effects on immune-related outcomes. The human studies often provided very high daily doses of all-rac α-tocopherol, so it is possible that supplements provided sufficient amounts of RRR or other 2R stereoisomers to produce beneficial effects. Using biomarkers of immune function to establish recommendations for α-tocopherol intake could be a worthwhile approach. Older adults may benefit most from the effect of α-tocopherol on immune function and inflammation. CARDIOVASCULAR DISEASES Role of α-tocopherol in the cardiovascular system The development of cardiovascular diseases (CVDs), such as atherosclerosis, is intricately linked to the oxidation of low-density lipoprotein (LDL) particles and its consequences.89,90 Hence, vitamin E, which can inhibit this oxidation, has been used to prevent and treat negative CVD outcomes. Epidemiological studies have supported an inverse relationship between vitamin E intake and risk of coronary heart disease in both women91 and men.92 An inverse association between plasma α-tocopherol levels and mortality due to ischemic heart disease in men from 16 European study populations was also reported.93 In animal models, atherosclerosis-prone, vitamin E–deficient mice (Ttpa−/− Apoe−/−) had significantly larger aortic lesions (in the arch and thorax) than atherosclerosis-prone mice without a genetic predisposition for vitamin E deficiency (Ttpa+/+ Apoe−/−).94 The double knockout mice also showed increased lipid peroxidation in the proximal aorta.94 This compelling study showed that adequate vitamin E status may prevent oxidative damage and formation of atherosclerotic lesions. Gene regulation by α-tocopherol has been demonstrated in the heart, which could be an additional mechanism by which α-tocopherol prevents unfavorable cardiovascular outcomes. Genes related to proper immune response, lipid metabolism, and inflammation were dysregulated in hearts of Ttpa−/− mice.74 Other nonantioxidant roles are possible for α-tocopherol in the CV system, as α-tocopherol has been shown to inhibit vascular smooth muscle cell proliferation through a protein kinase C–dependent mechanism,95,96 to inhibit platelet aggregation,97–99 and to modulate the inflammatory response via changes in monocyte function.100 Results from human studies evaluating the effect of α-tocopherol on the cardiovascular system are inconsistent. One meta-analysis found that vitamin E supplementation positively affected flow-mediated vasodilation (which serves as a marker of endothelial function and CVD risk).101 In contrast, a separate meta-analysis concluded that α-tocopherol supplementation did not help prevent strokes.102 Both meta-analyses included studies that used RRR or all-rac α-tocopherol, and neither distinguished between the α-tocopherol sources in their analyses. This highlights the challenge of evaluating the health effects of individual sources of α-tocopherol. Very few studies have directly compared the effect of different α-tocopherol sources on cardiovascular health, and the 2 described below were conducted decades ago (Table 1).54,55 In 1, participants received very high daily doses (1600 mg/d) of either RRR α-tocopherol or all-rac α-tocopherol for 8 weeks; afterward, their lipid levels and the susceptibility of isolated lipoproteins to oxidation were measured.54 Although lag time for oxidation increased by approximately 30% in both treatment groups compared with controls, there were no differences between the 2 α-tocopherol sources for the outcomes measured.54 Devaraj et al.55 provided participants with 100 IU, 200 IU, 400 IU, or 800 IU of either RRR α-tocopherol or all-rac α-tocopherol for 8 weeks (8 treatment groups). As dose increased, total plasma α-tocopherol concentrations also increased (measured at week 8); this was true for both α-tocopherol sources.55 There were no significant differences in total plasma α-tocopherol levels between the RRR and all-rac α-tocopherol groups at any dose. This is not surprising, since even the lowest dose (100 IU) is high relative to the typical dietary intake. This study did not quantify individual α-tocopherol stereoisomers in the plasma, but future studies that compare RRR and all-rac α-tocopherol should consider doing so. Devaraj et al.55 also measured the susceptibility of isolated lipoproteins to oxidation. Only at doses ≥400 IU was there a prolonged lag phase of oxidation, and there were no differences between the 2 α-tocopherol sources.55 Lipoprotein oxidation may be a useful functional measurement, given its role in atherosclerosis. To investigate the ratio of biopotency of RRR to all-rac α-tocopherol, lower doses of α-tocopherol (closer to amounts normally consumed in the diet) are likely needed. Both studies included only healthy participants, so it is unclear whether similar results would be seen in populations with CVD. Cardiovascular studies investigating RRR α-tocopherol In adult Apoe−/− mice fed a high-fat diet, an RRR α-tocopherol intervention significantly decreased lesion size in the aortic root but did not affect a marker of oxidative stress or improve the resistance of plasma lipids to oxidation when exposed to peroxyl radicals.103 RRR α-tocopherol improved CVD-related endpoints in several human studies. In an ex vivo experiment, RRR α-tocopherol supplements drastically inhibited platelet adhesion in study participants,104 and researchers later showed that cosupplementation with RRR α-tocopherol and aspirin (a platelet antiaggregating agent) may help prevent ischemic events in patients with ischemic cerebrovascular disease.105,RRR α-tocopherol significantly reduced the risk of nonfatal myocardial infarction and cardiovascular events in patients with atherosclerosis106 and significantly reduced the risk of combined cardiovascular outcomes in hemodialysis patients.107 However, it had no effect on any cardiovascular outcomes measured in a high-risk population.108 In healthy women, RRR α-tocopherol significantly decreased cardiovascular-related deaths but did not reduce the risk of heart failure,109 myocardial infarction,110 or stroke.110 These trials indicate that α-tocopherol may be of benefit to only some populations. Cardiovascular studies investigating all-rac α-tocopherol In an atherosclerosis-prone murine model (LDL receptor–deficient mice, ie, Ldlr−/− ), mice fed a low-fat, low-cholesterol diet combined with long-term all-rac α-tocopherol supplementation initiated at an early age showed a significantly reduced area of lesion on the descending aorta and a higher survival rate when compared with mice not given all-rac α-tocopherol.111 Several studies have investigated synthetic α-tocopherol to treat or prevent cardiovascular disease in human populations with varying health statuses (eg, smokers, patients with CVD or diabetes, patients with a history of other conditions), but most have reported null results.112–116 In fact, α-tocopherol significantly increased the risk of hemorrhagic stroke in 1 study.116 Fewer studies have been conducted in healthy populations, but 1 study reported that all-rac α-tocopherol reduced LDL levels and lowered LDL susceptibility to oxidation.117 RRR α-tocopherol vs all-rac α-tocopherol: conclusions for cardiovascular outcomes Epidemiological studies have shown that the consumption of α-tocopherol from foods may provide some benefit to the cardiovascular system. The effectiveness of an α-tocopherol intervention may depend on the cardiovascular health status at the time the intervention is initiated. RRR α-tocopherol intake may improve cardiovascular outcomes in atherosclerosis-susceptible animal models and in humans with preexisting conditions, but not in healthy individuals or those at high risk for cardiovascular events. All-rac α-tocopherol has been beneficial in some animal studies, but most human research suggests no benefit to the cardiovascular system. Some potentially valuable research did not identify which α-tocopherol source was used. This was the case for 2 animal studies in which supplementary α-tocopherol reduced lesion areas in aortas of atherosclerosis-susceptible mice.118,119 The contradictory results reported in the literature for the 2 different α-tocopherol sources may stem from the wide-ranging dosing regimens used: every study used a different amount, frequency, and duration of dosing. CANCER Role of α-tocopherol in cancer To categorize the complex underpinnings of neoplastic diseases, Hanahan and Weinberg120 identified 8 hallmarks and 2 enabling characteristics of cancer. One enabling characteristic (genome instability and mutation) may be relevant to the functions of α-tocopherol. In other words, the ability of α-tocopherol to quench free radicals could prevent damage to DNA and reduce the risk of cancer development. Oxidative stress may indeed be linked to carcinogenesis, since it damages cell components.121 However, α-tocopherol has not been shown to prevent DNA damage via antioxidant action in humans, and it is unclear whether an antioxidant mechanism could result in clinically relevant health benefits.122–124 In vitro, α-tocopherol inhibits vascular endothelial growth factor released from human breast cancer cells,125 so α-tocopherol could theoretically influence another cancer hallmark, ie, angiogenesis.120 Nevertheless, the existing literature does not support this relationship. In preclinical studies, α-tocopherol and α-tocopherol derivatives have been ineffective in preventing tumor formation in the colon, and results have been inconsistent in lung, prostate, and mammary gland studies.126 Studies assessing α-tocopherol intake from food sources or supplements and cancer risk have not shown an unequivocal benefit from increased consumption, though there may be some benefit for particular types of cancer and specific patient populations.127–129 High vitamin E intake significantly decreased pancreatic cancer risk,130 colon cancer risk,131 and bladder cancer mortality.132 A significant inverse association between serum α-tocopherol and advanced and aggressive prostate cancer risk has also been reported.133 On the contrary, vitamin E supplementation was not associated with colorectal cancer risk,134 colon cancer mortality,135 or stomach cancer mortality.136 On the whole, the literature does not support a beneficial role for α-tocopherol in the treatment or prevention of cancer. Nevertheless, because of the proposed link between antioxidants and cancer, and because α-tocopherol has been administered in relevant human trials, the results of interventions with RRR α-tocopherol and all-rac α-tocopherol will be briefly summarized. Cancer studies investigating RRR α-tocopherol In a large, long-term trial, supplementation with RRR α-tocopherol had no significant effect on the incidence of total cancer, breast cancer, lung cancer, colon cancer, or cancer deaths,110 nor did it significantly reduce the incidence of total cancer, organ-specific cancer, or cancer deaths in a second trial with high-risk volunteers.137 Daily antioxidant supplements, which included RRR α-tocopherol, also did not reduce adenoma incidence in patients with previously removed adenomas.138 Cancer studies investigating all-rac α-tocopherol Debatably the most optimistic findings for cancer outcomes came from a trial in smokers, in which supplementation with synthetic α-tocopherol reduced colorectal cancer incidence,139 prostate cancer incidence,139 and prostate cancer mortality.140 Conversely, there was no effect of all-rac α-tocopherol on incidence of prostate cancer, total cancer, cancer at other sites or on cancer mortality in other randomized, placebo-controlled studies.141,142 In 1 of these studies, all-rac α-tocopherol supplementation actually nonsignificantly increased prostate cancer incidence.141 RRRα-tocopherol vs all-rac α-tocopherol: conclusions for cancer outcomes Cancer-related benefits from α-tocopherol consumption have been observed in some epidemiological studies, but the majority of clinical trials of α-tocopherol supplementation do not confirm these findings. It is conceivable that diets containing antioxidant-rich foods, eg, fruits and vegetables, could be beneficial but that supplements are not. Despite a plausible basis for cancer-related benefits, it seems that neither α-tocopherol source affects cancer outcomes. CONCLUSION The effects of α-tocopherol on nonalcoholic steatohepatitis,143,144 eye disorders,145,146 and other health conditions have been studied previously, but this review focused on 4 of the more well-known areas of disease associated with vitamin E. Comparing studies that investigated the sources of α-tocopherol revealed many limitations, such as differences in population characteristics (vitamin E status, sex, age, health status), dose and dosing frequency of α-tocopherol, study size and duration, and the wide array of different endpoints considered. There is stronger evidence for a beneficial role of α-tocopherol in some health outcomes (eg, neurological function) than in others (eg, cancer), but unfortunately, a number of studies neglected to disclose which α-tocopherol source was investigated. In 2000, Hoppe and Krennrich5 called on researchers to discover novel in vivo biomarkers for α-tocopherol status and new methods for assessing the ratio of RRR to all-rac biopotency.5 Almost 2 decades later, their optimistic call for action is still unrealized. Language used in the recent FDA ruling presumes a scientific consensus on the relative bioavailability and biopotency of the different α-tocopherol sources, and yet it is not possible to ascertain this essential information from the existing research. Studies have also failed to compare the effectiveness of RRR vs all-rac α-tocopherol for the selected health outcomes. In general, animal research has shown that both sources of α-tocopherol produce beneficial effects, while human trials have been less conclusive. Significant questions remain unanswered. These require more targeted research that directly compares relevant dose levels of RRR and all-rac α-tocopherol in relation to human diseases. Key questions include the following: (1) What factors beyond hepatic α-TTP determine the accumulation of particular stereoisomers in tissues, and how does the preferential accumulation of stereoisomers affect human health? (2) What is the appropriate RRR to all-rac ratio of biopotency? (3) What human-relevant biochemical markers could be established for measuring α-tocopherol sufficiency? (4) How do age and health status affect the metabolism of RRR and all-rac α-tocopherol? (5) What are the implications for the food and supplement industries? These questions and others must be addressed to develop optimal policies and set α-tocopherol intake recommendations. Acknowledgments Author contributions. K.M.Ranard wrote the first draft. Both K.M. Ranard and J.W. Erdman revised the manuscript and approved the final draft. Funding/support. This work was supported by a US Department of Agriculture (USDA) National Institute of Food and Agriculture (NIFA) Hatch grant (no. ILLU-698–915) and the Division of Nutritional Sciences Vision 20/20 Grant Program at the University of Illinois at Urbana-Champaign. Declaration of interest. The authors have no relevant interests to declare. References 1 Institute of Medicine, Food and Nutrition Board, Panel on Dietary Antioxidants and Related Compounds. Vitamin E. In: Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids . Washington, DC: National Academy Press; 2000: 186– 283. 2 Traber MG, Burton GW, Ingold KU, et al.   RRR- and SRR-α-tocopherols are secreted without discrimination in human chylomicrons, but RRR-α-tocopherol is preferentially secreted in very low density lipoproteins. J Lipid Res . 1990; 31: 675– 685. Google Scholar PubMed  3 Traber MG, Ramakrishnan R, Kayden HJ. Human plasma vitamin E kinetics demonstrate rapid recycling of plasma RRR-alpha-tocopherol. Proc Natl Acad Sci USA.  1994; 91: 10005– 10008. http://dx.doi.org/10.1073/pnas.91.21.10005 Google Scholar CrossRef Search ADS   4 2015 Dietary Guidelines Advisory Committee. Scientific Report of the 2015 Dietary Guidelines Advisory Committee. Washington, DC: US Dept of Agriculture, Dept of Health and Human Services. https://health.gov/dietaryguidelines/2015-scientific-report/PDFs/Scientific-Report-of-the-2015-Dietary-Guidelines-Advisory-Committee.pdf. Published Feburary 2015. Accessed August 8, 2017. 5 Hoppe PP, Krennrich G. Bioavailability and potency of natural-source and all-racemic alpha-tocopherol in the human: a dispute. Eur J Nutr.  2000; 39: 183– 193. http://dx.doi.org/10.1007/s003940070010 Google Scholar CrossRef Search ADS PubMed  6 Yetley EA, MacFarlane AJ, Greene-Finestone LS, et al.   Options for basing Dietary Reference Intakes (DRIs) on chronic disease endpoints: report from a joint US-/Canadian-sponsored working group. Am J Clin Nutr.  2017; 105: 249S– 285S. Google Scholar CrossRef Search ADS PubMed  7 Bruno RS, Traber MG. Cigarette smoke alters human vitamin E requirements. J Nutr.  2005; 135: 671– 674. Google Scholar CrossRef Search ADS PubMed  8 Bruno RS, Traber MG. Vitamin E biokinetics, oxidative stress and cigarette smoking. Pathophysiology.  2006; 13: 143– 149. http://dx.doi.org/10.1016/j.pathophys.2006.05.003 Google Scholar CrossRef Search ADS PubMed  9 Mah E, Sapper TN, Chitchumroonchokchai C, et al.   α-Tocopherol bioavailability is lower in adults with metabolic syndrome regardless of dairy fat co-ingestion: a randomized, double-blind, crossover trial. Am J Clin Nutr . 2015; 102: 1070– 1080. Google Scholar CrossRef Search ADS PubMed  10 Traber MG. Vitamin E inadequacy in humans: causes and consequences. Adv Nutr.  2014; 5: 503– 514. http://dx.doi.org/10.3945/an.114.006254 Google Scholar CrossRef Search ADS PubMed  11 Traber MG., Vitamin E. In: Erdman JW, Macdonald IA, Zeisel SH, eds. Present Knowledge in Nutrition. 10th ed . Oxford, UK: Wiley-Blackwell; 2012: 214– 229. Google Scholar CrossRef Search ADS   12 Novotny JA, Fadel JG, Holstege DM, et al.   This kinetic, bioavailability, and metabolism study of RRR-α-tocopherol in healthy adults suggests lower intake requirements than previous estimates. J Nutr.  2012; 142: 2105– 2111. Google Scholar CrossRef Search ADS PubMed  13 Jensen SK, Lauridsen C. α-Tocopherol stereoisomers. Vitam Horm.  2007; 76: 281– 308. Google Scholar CrossRef Search ADS PubMed  14 Leonard SW, Terasawa Y, Farese RVJr, et al.   Incorporation of deuterated RRR- or all-rac-α-tocopherol in plasma and tissues of α-tocopherol transfer protein–null mice. Am J Clin Nutr.  2002; 75: 555– 560. Google Scholar CrossRef Search ADS PubMed  15 Burton GW, Traber MG, Acuff RV, et al.   Human plasma and tissue alpha-tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E. Am J Clin Nutr.  1998; 67: 669– 684. Google Scholar CrossRef Search ADS PubMed  16 Acuff RV, Thedford SS, Hidiroglou NN, et al.   Relative bioavailability of RRR- and all-rac-alpha-tocopheryl acetate in humans: studies using deuterated compounds. Am J Clin Nutr . 1994; 60: 397– 402. Google Scholar CrossRef Search ADS PubMed  17 Blatt DH, Pryor WA, Mata JE, et al.   Re-evaluation of the relative potency of synthetic and natural α-tocopherol: experimental and clinical observations. J Nutr Biochem . 2004; 15: 380– 395. Google Scholar CrossRef Search ADS PubMed  18 Ingold KU, Burton GW, Foster DO, et al.   Biokinetics of and discrimination between dietary RRR- and SRR-alpha-tocopherols in the male rat. Lipids . 1987; 22: 163– 172. http://dx.doi.org/10.1007/BF02537297 Google Scholar CrossRef Search ADS PubMed  19 Food labeling: revision of the Nutrition and Supplement Facts labels. College Park, MD: US Food and Drug Administration. Fed Regist. 2016;81(103):33741–33999. 20 Kaneko K, Kiyose C, Ueda T, et al.   Studies of the metabolism of α-tocopherol stereoisomers in rats using [5-methyl-14C]SRR- and RRR-α-tocopherol. J Lipid Res . 2000; 41: 357– 367. Google Scholar PubMed  21 Kiyose C, Kaneko K, Muramatsu R, et al.   Simultaneous determination of RRR- and SRR-α-tocopherols and their quinones in rat plasma and tissues by using chiral high-performance liquid chromatography. Lipids . 1999; 34: 415– 422. Google Scholar CrossRef Search ADS PubMed  22 Weiser H, Riss G, Kormann AW. Biodiscrimination of the eight α-tocopherol stereoisomers results in preferential accumulation of the four 2R forms in tissues and plasma of rats. J Nutr.  1996; 126: 2539– 2549. Google Scholar PubMed  23 Gaur S, Kuchan MJ, Lai CS, et al.   Supplementation with RRR- or all-rac-α-tocopherol differentially affects the α-tocopherol stereoisomer profile in the milk and plasma of lactating women. J Nutr.  2017; 147: 1301– 1307. Google Scholar CrossRef Search ADS PubMed  24 Kuchan MJ, Jensen SK, Johnson EJ, et al.   The naturally occurring α-tocopherol stereoisomer RRR-α-tocopherol is predominant in the human infant brain. Br J Nutr.  2016; 116: 126– 131. Google Scholar CrossRef Search ADS PubMed  25 Copp RP, Wisniewski T, Hentati F, et al.   Localization of α-tocopherol transfer protein in the brains of patients with ataxia with vitamin E deficiency and other oxidative stress related neurodegenerative disorders. Brain Res . 1999; 822: 80– 87. Google Scholar CrossRef Search ADS PubMed  26 Hosomi A, Goto K, Kondo H, et al.   Localization of α-tocopherol transfer protein in rat brain. Neurosci Lett.  1998; 256: 159– 162. Google Scholar CrossRef Search ADS PubMed  27 Zimmer S, Stocker A, Sarbolouki MN, et al.   A novel human tocopherol-associated protein: cloning, in vitro expression, and characterization. J Biol Chem.  2000; 275: 25672– 25680. http://dx.doi.org/10.1074/jbc.M000851200 Google Scholar CrossRef Search ADS PubMed  28 Zingg JM, Kempna P, Paris M, et al.   Characterization of three human sec14p-like proteins: α-tocopherol transport activity and expression pattern in tissues. Biochimie . 2008; 90: 1703– 1715. Google Scholar CrossRef Search ADS PubMed  29 Yamauchi J, Iwamoto T, Kida S, et al.   Tocopherol-associated protein is a ligand-dependent transcriptional activator. Biochem Biophys Res Commun.  2001; 285: 295– 299. http://dx.doi.org/10.1006/bbrc.2001.5162 Google Scholar CrossRef Search ADS PubMed  30 Shibata N, Arita M, Misaki Y, et al.   Supernatant protein factor, which stimulates the conversion of squalene to lanosterol, is a cytosolic squalene transfer protein and enhances cholesterol biosynthesis. Proc Natl Acad Sci USA.  2001; 98: 2244– 2249. http://dx.doi.org/10.1073/pnas.041620398 Google Scholar CrossRef Search ADS   31 Panagabko C, Morley S, Hernandez M, et al.   Ligand specificity in the CRAL-TRIO protein family. Biochemistry . 2003; 42: 6467– 6474. http://dx.doi.org/10.1021/bi034086v Google Scholar CrossRef Search ADS PubMed  32 Traber MG, Elsner A, Brigelius-Flohé R. Synthetic as compared with natural vitamin E is preferentially excreted as α-CEHC in human urine: studies using deuterated α-tocopheryl acetates. FEBS Lett . 1998; 437: 145– 148. Google Scholar CrossRef Search ADS PubMed  33 Morris MC, Schneider JA, Li H, et al.   Brain tocopherols related to Alzheimer's disease neuropathology in humans. Alzheimers Dement . 2015; 11: 32– 39. http://dx.doi.org/10.1016/j.jalz.2013.12.015 Google Scholar CrossRef Search ADS PubMed  34 Ulatowski LM, Manor D. Vitamin E and neurodegeneration. Neurobiol Dis.  2015; 84: 78– 83. http://dx.doi.org/10.1016/j.nbd.2015.04.002 Google Scholar CrossRef Search ADS PubMed  35 Ulatowski L, Parker R, Warrier G, et al.   Vitamin E is essential for Purkinje neuron integrity. Neuroscience . 2014; 260: 120– 129. http://dx.doi.org/10.1016/j.neuroscience.2013.12.001 Google Scholar CrossRef Search ADS PubMed  36 Yokota T, Igarashi K, Uchihara T, et al.   Delayed-onset ataxia in mice lacking α-tocopherol transfer protein: model for neuronal degeneration caused by chronic oxidative stress. Proc Natl Acad Sci USA.  2001; 98: 15185– 15190. Google Scholar CrossRef Search ADS   37 Ouahchi K, Arita M, Kayden H, et al.   Ataxia with isolated vitamin E deficiency is caused by mutations in the α-tocopherol transfer protein. Nat Genet.  1995; 9: 141– 145. Google Scholar CrossRef Search ADS PubMed  38 Schuelke M, Mayatepek E, Inter M, et al.   Treatment of ataxia in isolated vitamin E deficiency caused by α-tocopherol transfer protein deficiency. J Pediatr.  1999; 134: 240– 244. Google Scholar CrossRef Search ADS PubMed  39 Morris MC, Evans DA, Bienias JL, et al.   Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA . 2002; 287: 3230– 3237. http://dx.doi.org/10.1001/jama.287.24.3230 Google Scholar CrossRef Search ADS PubMed  40 Lopes Da Silva S, Vellas B, Elemans S, et al.   Plasma nutrient status of patients with Alzheimer's disease: systematic review and meta-analysis. Alzheimers Dement . 2014; 10: 485– 502. http://dx.doi.org/10.1016/j.jalz.2013.05.1771 Google Scholar CrossRef Search ADS PubMed  41 Johnson EJ, Vishwanathan R, Johnson MA, et al.   Relationship between serum and brain carotenoids, α-tocopherol, and retinol concentrations and cognitive performance in the oldest old from the Georgia Centenarian Study. J Aging Res . 2013; 2013: 951786. doi:10.1155/2013/951786 Google Scholar CrossRef Search ADS PubMed  42 Ravaglia G, Forti P, Lucicesare A, et al.   Plasma tocopherols and risk of cognitive impairment in an elderly Italian cohort. Am J Clin Nutr.  2008; 87: 1306– 1313. Google Scholar PubMed  43 Mangialasche F, Solomon A, Kareholt I, et al.   Serum levels of vitamin E forms and risk of cognitive impairment in a Finnish cohort of older adults. Exp Gerontol . 2013; 48: 1428– 1435. http://dx.doi.org/10.1016/j.exger.2013.09.006 Google Scholar CrossRef Search ADS PubMed  44 Farina N, Llewellyn D, Isaac MGEKN, et al.   Vitamin E for Alzheimer's dementia and mild cognitive impairment. Cochrane Database Syst Rev . 2017; 4: CD002854. doi:10.1002/14651858.CD002854.pub5 Google Scholar PubMed  45 Zhao Y, Zhao B. Oxidative stress and the pathogenesis of Alzheimer's disease. Oxid Med Cell Longev.  2013; 2013: 316523. doi:10.1155/2013/316523 Google Scholar PubMed  46 Gohil K, Vasu VT, Cross CE. Dietary α-tocopherol and neuromuscular health: search for optimal dose and molecular mechanisms continues! Mol Nutr Food Res . 2010; 54: 693– 709. Google Scholar CrossRef Search ADS PubMed  47 Gohil K, Godzdanker R, O'Roark E, et al.   α-Tocopherol transfer protein deficiency in mice causes multi-organ deregulation of gene networks and behavioral deficits with age. Ann N Y Acad Sci.  2004; 1031: 109– 126. Google Scholar CrossRef Search ADS PubMed  48 Gohil K, Schock BC, Chakraborty AA, et al.   Gene expression profile of oxidant stress and neurodegeneration in transgenic mice deficient in alpha-tocopherol transfer protein. Free Radic Biol Med . 2003; 35: 1343– 1354. http://dx.doi.org/10.1016/S0891-5849(03)00509-4 Google Scholar CrossRef Search ADS PubMed  49 Rota C, Rimbach G, Minihane AM, et al.   Dietary vitamin E modulates differential gene expression in the rat hippocampus: potential implications for its neuroprotective properties. Nutr Neurosci . 2005; 8: 21– 29. http://dx.doi.org/10.1080/10284150400027123 Google Scholar CrossRef Search ADS PubMed  50 Pusterla N, Puschner B, Steidl S, et al.   α-Tocopherol concentrations in equine serum and cerebrospinal fluid after vitamin E supplementation. Vet Rec.  2010; 166: 366– 368. Google Scholar CrossRef Search ADS PubMed  51 Han SN, Pang E, Zingg JM, et al.   Differential effects of natural and synthetic vitamin E on gene transcription in murine T lymphocytes. Arch Biochem Biophys.  2010; 495: 49– 55. http://dx.doi.org/10.1016/j.abb.2009.12.015 Google Scholar CrossRef Search ADS PubMed  52 Horn MJ, Van Emon ML, Gunn PJ, et al.   Effects of maternal natural (RRR alpha-tocopherol acetate) or synthetic (all-rac alpha-tocopherol acetate) vitamin E supplementation on suckling calf performance, colostrum immunoglobulin G, and immune function. J Anim Sci.  2010; 88: 3128– 3135. http://dx.doi.org/10.2527/jas.2009-2035 Google Scholar CrossRef Search ADS PubMed  53 Amazan D, Cordero G, Lopez-Bote CJ, et al.   Effects of oral micellized natural vitamin E (D-α-tocopherol) v. synthetic vitamin E (DL-α-tocopherol) in feed on α-tocopherol levels, stereoisomer distribution, oxidative stress and the immune response in piglets. Animal.  2014; 8: 410– 419. Google Scholar CrossRef Search ADS PubMed  54 Reaven PD, Witztum JL. Comparison of supplementation of RRR-alpha-tocopherol and racemic alpha-tocopherol in humans. Effects on lipid levels and lipoprotein susceptibility to oxidation. Arterioscler Thromb Vasc Biol . 1993; 13: 601– 608. Google Scholar CrossRef Search ADS   55 Devaraj S, Adams-Huet B, Fuller CJ, et al.   Dose-response comparison of RRR-α-tocopherol and all-racemic α-tocopherol on LDL oxidation. Arterioscler Thromb Vasc Biol . 1997; 17: 2273– 2279. Google Scholar CrossRef Search ADS PubMed  56 Nakashima H, Ishihara T, Yokota O, et al.   Effects of alpha-tocopherol on an animal model of tauopathies. Free Radic Biol Med.  2004; 37: 176– 186. http://dx.doi.org/10.1016/j.freeradbiomed.2004.04.037 Google Scholar CrossRef Search ADS PubMed  57 Ambrogini P, Minelli A, Galati C, et al.   Post-seizure α-tocopherol treatment decreases neuroinflammation and neuronal degeneration induced by status epilepticus in rat hippocampus. Mol Neurobiol.  2014; 50: 246– 256. Google Scholar CrossRef Search ADS PubMed  58 Annahazi A, Mracsko E, Sule Z, et al.   Pre-treatment and post-treatment with alpha-tocopherol attenuates hippocampal neuronal damage in experimental cerebral hypoperfusion. Eur J Pharmacol . 2007; 571: 120– 128. http://dx.doi.org/10.1016/j.ejphar.2007.05.048 Google Scholar CrossRef Search ADS PubMed  59 Nishida Y, Ito S, Ohtsuki S, et al.   Depletion of vitamin E increases amyloid β accumulation by decreasing its clearances from brain and blood in a mouse model of Alzheimer disease. J Biol Chem.  2009; 284: 33400– 33408. Google Scholar CrossRef Search ADS PubMed  60 Nishida Y, Yokota T, Takahashi T, et al.   Deletion of vitamin E enhances phenotype of Alzheimer disease model mouse. Biochem Biophys Res Commun.  2006; 350: 530– 536. http://dx.doi.org/10.1016/j.bbrc.2006.09.083 Google Scholar CrossRef Search ADS PubMed  61 Gaedicke S, Zhang X, Huebbe P, et al.   Dietary vitamin E, brain redox status and expression of Alzheimer's disease–relevant genes in rats. Br J Nutr.  2009; 102: 398– 406. http://dx.doi.org/10.1017/S000711450819122X Google Scholar CrossRef Search ADS PubMed  62 Kang JH, Cook N, Manson J, et al.   A randomized trial of vitamin E supplementation and cognitive function in women. Arch Intern Med.  2006; 166: 2462– 2468. http://dx.doi.org/10.1001/archinte.166.22.2462 Google Scholar CrossRef Search ADS PubMed  63 Hayton SM, Kriss T, Wade A, et al.   Effects on neural function of repleting vitamin E–deficient rats with α-tocopherol. J Neurophysiol.  2006; 95: 2553– 2559. Google Scholar CrossRef Search ADS PubMed  64 Murray CA, Lynch MA. Dietary supplementation with vitamin E reverses the age-related deficit in long term potentiation in dentate gyrus. J Biol Chem.  1998; 273: 12161– 12168. http://dx.doi.org/10.1074/jbc.273.20.12161 Google Scholar CrossRef Search ADS PubMed  65 Huebbe P, Schaffer S, Jofre-Monseny L, et al.   Apolipoprotein E genotype and alpha-tocopherol modulate amyloid precursor protein metabolism and cell cycle regulation. Mol Nutr Food Res.  2007; 51: 1510– 1517. http://dx.doi.org/10.1002/mnfr.200700194 Google Scholar CrossRef Search ADS PubMed  66 Sano M, Ernesto C, Thomas RG, et al.   A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. N Engl J Med . 1997; 336: 1216– 1222. Google Scholar CrossRef Search ADS PubMed  67 Dysken MW, Sano M, Asthana S, et al.   Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA . 2014; 311: 33– 44. http://dx.doi.org/10.1001/jama.2013.282834 Google Scholar CrossRef Search ADS PubMed  68 Lim Y, Vasu V, Valacchi G, et al.   Severe vitamin E deficiency modulates airway allergic inflammatory responses in the murine asthma model. Free Radic Res.  2008; 42: 387– 396. http://dx.doi.org/10.1080/10715760801976600 Google Scholar CrossRef Search ADS PubMed  69 Marchese ME, Kumar R, Colangelo LA, et al.   The vitamin E isoforms α-tocopherol and γ-tocopherol have opposite associations with spirometric parameters: the CARDIA study. Respir Res.  2014; 15: 31. doi:10.1186/1465-9921-15-31 Google Scholar CrossRef Search ADS PubMed  70 Wu D, Meydani SN. Age-associated changes in immune and inflammatory responses: impact of vitamin E intervention. J Leukoc Biol.  2008; 84: 900– 914. http://dx.doi.org/10.1189/jlb.0108023 Google Scholar CrossRef Search ADS PubMed  71 Misso NL, Brooks-Wildhaber J, Ray S, et al.   Plasma concentrations of dietary and nondietary antioxidants are low in severe asthma. Eur Respir J . 2005; 26: 257– 264. http://dx.doi.org/10.1183/09031936.05.00006705 Google Scholar CrossRef Search ADS PubMed  72 Cook-Mills JM, Abdala-Valencia H, Hartert T. Two faces of vitamin E in the lung. Am J Respir Crit Care Med.  2013; 188: 279– 284. Google Scholar CrossRef Search ADS PubMed  73 Abdala-Valencia H, Berdnikovs S, Cook-Mills JM. Vitamin E isoforms differentially regulate intercellular adhesion molecule-1 activation of PKCα in human microvascular endothelial cells. PLoS One . 2012; 7:e41054. doi:10.1371/journal.pone.0041054 74 Vasu VT, Hobson B, Gohil K, et al.   Genome-wide screening of alpha-tocopherol sensitive genes in heart tissue from alpha-tocopherol transfer protein null mice (ATTP−/−). FEBS Lett.  2007; 581: 1572– 1578. Google Scholar CrossRef Search ADS PubMed  75 Azzi A, Gysin R, Kempna P, et al.   Regulation of gene expression by α-tocopherol. Biol Chem.  2004; 385: 585– 591. Google Scholar CrossRef Search ADS PubMed  76 Marko MG, Pang HJ, Ren Z, et al.   Vitamin E reverses impaired linker for activation of T cells activation in T cells from aged C57BL/6 mice. J Nutr.  2009; 139: 1192– 1197. http://dx.doi.org/10.3945/jn.108.103416 Google Scholar CrossRef Search ADS PubMed  77 Abdala-Valencia H, Berdnikovs S, Soveg FW, et al.   α-Tocopherol supplementation of allergic female mice inhibits development of CD11c+CD11b+ dendritic cells in utero and allergic inflammation in neonates. Am J Physiol Lung Cell Mol Physiol.  2014; 307: L482– L496. Google Scholar CrossRef Search ADS PubMed  78 Suchankova J, Voprsalova M, Kottova M, et al.   Effects of oral alpha-tocopherol on lung response in rat model of allergic asthma. Respirology.  2006; 11: 414– 421. http://dx.doi.org/10.1111/j.1440-1843.2006.00864.x Google Scholar CrossRef Search ADS PubMed  79 Hoskins A, Roberts JLII, Milne G, et al.   Natural source d-α-tocopheryl acetate inhibits oxidant stress and modulates atopic asthma in humans in vivo. Allergy . 2012; 67: 676– 682. Google Scholar CrossRef Search ADS PubMed  80 Pearson PJ, Lewis SA, Britton J, et al.   Vitamin E supplements in asthma: a parallel group randomised placebo controlled trial. Thorax . 2004; 59: 652– 656. http://dx.doi.org/10.1136/thx.2004.022616 Google Scholar CrossRef Search ADS PubMed  81 Han SN, Adolfsson O, Lee CK, et al.   Age and vitamin E-induced changes in gene expression profiles of T cells. J Immunol.  2006; 177: 6052– 6061. http://dx.doi.org/10.4049/jimmunol.177.9.6052 Google Scholar CrossRef Search ADS PubMed  82 Han SN, Wu D, Ha WK, et al.   Vitamin E supplementation increases T helper 1 cytokine production in old mice infected with influenza virus. Immunology . 2000; 100: 487– 493. http://dx.doi.org/10.1046/j.1365-2567.2000.00070.x Google Scholar CrossRef Search ADS PubMed  83 Oommen S, Vasu VT, Leonard SW, et al.   Genome wide responses of murine lungs to dietary α-tocopherol. Free Radic Res.  2007; 41: 98– 109. Google Scholar CrossRef Search ADS PubMed  84 Meydani SN, Barklund MP, Liu S, et al.   Vitamin E supplementation enhances cell-mediated immunity in healthy elderly subjects. Am J Clin Nutr.  1990; 52: 557– 563. Google Scholar CrossRef Search ADS PubMed  85 De la Fuente M, Hernanz A, Guayerbas N, et al.   Vitamin E ingestion improves several immune functions in elderly men and women. Free Radic Res.  2008; 42: 272– 280. http://dx.doi.org/10.1080/10715760801898838 Google Scholar CrossRef Search ADS PubMed  86 Meydani SN, Meydani M, Blumberg JB, et al.   Vitamin E supplementation and in vivo immune response in healthy elderly subjects. A randomized controlled trial. JAMA . 1997; 277: 1380– 1386. http://dx.doi.org/10.1001/jama.1997.03540410058031 Google Scholar CrossRef Search ADS PubMed  87 Lee CY, Man-Fan Wan J. Vitamin E supplementation improves cell-mediated immunity and oxidative stress of Asian men and women. J Nutr.  2000; 130: 2932– 2937. Google Scholar CrossRef Search ADS PubMed  88 Rautalahti M, Virtamo J, Haukka J, et al.   The effect of alpha-tocopherol and beta-carotene supplementation on COPD symptoms. Am J Respir Crit Care Med.  1997; 156: 1447– 1452. http://dx.doi.org/10.1164/ajrccm.156.5.96-11048 Google Scholar CrossRef Search ADS PubMed  89 Traber MG. Does vitamin E decrease heart attack risk? Summary and implications with respect to dietary recommendations. J Nutr.  2001; 131: 395S– 397S. Google Scholar CrossRef Search ADS PubMed  90 Steinberg D, Parthasarathy S, Carew TE, et al.   Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med.  1989; 320: 915– 924. Google Scholar CrossRef Search ADS PubMed  91 Stampfer MJ, Hennekens CH, Manson JE, et al.   Vitamin E consumption and the risk of coronary disease in women. N Engl J Med.  1993; 328: 1444– 1449. http://dx.doi.org/10.1056/NEJM199305203282003 Google Scholar CrossRef Search ADS PubMed  92 Rimm EB, Stampfer MJ, Ascherio A, et al.   Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med.  1993; 328: 1450– 1456. http://dx.doi.org/10.1056/NEJM199305203282004 Google Scholar CrossRef Search ADS PubMed  93 Gey KF, Puska P, Jordan P, et al.   Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Am J Clin Nutr . 1991; 53(1 suppl): 326S– 334S. Google Scholar CrossRef Search ADS   94 Terasawa Y, Ladha Z, Leonard SW, et al.   Increased atherosclerosis in hyperlipidemic mice deficient in α-tocopherol transfer protein and vitamin E. Proc Natl Acad Sci USA.  2000; 97: 13830– 13834. Google Scholar CrossRef Search ADS   95 Tasinato A, Boscoboinik D, Bartoli GM, et al.   D-α-tocopherol inhibition of vascular smooth muscle cell proliferation occurs at physiological concentrations, correlates with protein kinase C inhibition, and is independent of its antioxidant properties. Proc Natl Acad Sci USA.  1995; 92: 12190– 12194. Google Scholar CrossRef Search ADS   96 Boscoboinik D, Szewczyk A, Azzi A. α-Tocopherol (vitamin E) regulates vascular smooth muscle cell proliferation and protein kinase C activity. Arch Biochem Biophys.  1991; 286: 264– 269. Google Scholar CrossRef Search ADS PubMed  97 Freedman JE, Farhat JH, Loscalzo J, et al.   α-Tocopherol inhibits aggregation of human platelets by a protein kinase C–dependent mechanism. Circulation . 1996; 94: 2434– 2440. Google Scholar CrossRef Search ADS PubMed  98 Steiner M. Effect of alpha-tocopherol administration on platelet function in man. Thromb Haemost.  1983; 49: 73– 77. Google Scholar PubMed  99 Salonen JT, Salonen R, Seppanen K, et al.   Effects of antioxidant supplementation on platelet function: a randomized pair-matched, placebo-controlled, double-blind trial in men with low antioxidant status. Am J Clin Nutr.  1991; 53: 1222– 1229. Google Scholar CrossRef Search ADS PubMed  100 Devaraj S, Li D, Jialal I. The effects of alpha tocopherol supplementation on monocyte function. Decreased lipid oxidation, interleukin 1 beta secretion, and monocyte adhesion to endothelium. J Clin Invest.  1996; 98: 756– 763. Google Scholar CrossRef Search ADS PubMed  101 Joris PJ, Mensink RP. Effects of supplementation with the fat-soluble vitamins E and D on fasting flow-mediated vasodilation in adults: a meta-analysis of randomized controlled trials. Nutrients . 2015; 7: 1728– 1743. http://dx.doi.org/10.3390/nu7031728 Google Scholar CrossRef Search ADS PubMed  102 Bin Q, Hu X, Cao Y, et al.   The role of vitamin E (tocopherol) supplementation in the prevention of stroke: a meta-analysis of 13 randomised controlled trials. Thromb Haemost.  2011; 105: 579– 585. http://dx.doi.org/10.1160/TH10-11-0729 Google Scholar CrossRef Search ADS PubMed  103 Thomas SR, Leichtweis SB, Pettersson K, et al.   Dietary cosupplementation with vitamin E and coenzyme Q10 inhibits atherosclerosis in apolipoprotein E gene knockout mice. Arterioscler Thromb Vasc Biol.  2001; 21: 585– 593. http://dx.doi.org/10.1161/01.ATV.21.4.585 Google Scholar CrossRef Search ADS PubMed  104 Jandak J, Steiner M, Richardson PD. Alpha-tocopherol, an effective inhibitor of platelet adhesion. Blood . 1989; 73: 141– 149. Google Scholar PubMed  105 Steiner M, Glantz M, Lekos A. Vitamin E plus aspirin compared with aspirin alone in patients with transient ischemic attacks. Am J Clin Nutr.  1995; 62(6 suppl): 1381S– 1384S. Google Scholar CrossRef Search ADS   106 Stephens NG, Parsons A, Schofield PM, et al.   Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet.  1996; 347: 781– 786. http://dx.doi.org/10.1016/S0140-6736(96)90866-1 Google Scholar CrossRef Search ADS PubMed  107 Boaz M, Smetana S, Weinstein T, et al.   Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet.  2000; 356: 1213– 1218. http://dx.doi.org/10.1016/S0140-6736(00)02783-5 Google Scholar CrossRef Search ADS PubMed  108 Yusuf S, Dagenais G, Pogue J, et al.   Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med . 2000; 342: 154– 160. http://dx.doi.org/10.1056/NEJM200001203420302 Google Scholar CrossRef Search ADS PubMed  109 Chae CU, Albert CM, Moorthy MV, et al.   Vitamin E supplementation and the risk of heart failure in women. Circ Heart Fail.  2012; 5: 176– 182. http://dx.doi.org/10.1161/CIRCHEARTFAILURE.111.963793 Google Scholar CrossRef Search ADS PubMed  110 Lee IM, Cook NR, Gaziano JM, et al.   Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA . 2005; 294: 56– 65. http://dx.doi.org/10.1001/jama.294.1.56 Google Scholar CrossRef Search ADS PubMed  111 Meydani M, Kwan P, Band M, et al.   Long-term vitamin E supplementation reduces atherosclerosis and mortality in Ldlr−/− mice, but not when fed Western style diet. Atherosclerosis . 2014; 233: 196– 205. Google Scholar CrossRef Search ADS PubMed  112 Virtamo J, Rapola JM, Ripatti S, et al.   Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease. Arch Intern Med.  1998; 158: 668– 675. http://dx.doi.org/10.1001/archinte.158.6.668 Google Scholar CrossRef Search ADS PubMed  113 GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet . 1999; 354: 447– 455. http://dx.doi.org/10.1016/S0140-6736(99)07072-5 CrossRef Search ADS PubMed  114 Rapola JM, Virtamo J, Haukka JK, et al.   Effect of vitamin E and beta carotene on the incidence of angina pectoris. A randomized, double-blind, controlled trial. JAMA . 1996; 275: 693– 698. http://dx.doi.org/10.1001/jama.1996.03530330037026 Google Scholar CrossRef Search ADS PubMed  115 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet . 2002; 360: 23– 33. CrossRef Search ADS PubMed  116 Sesso HD, Buring JE, Christen WG, et al.   Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. JAMA . 2008; 300: 2123– 2133. http://dx.doi.org/10.1001/jama.2008.600 Google Scholar CrossRef Search ADS PubMed  117 Hodis HN, Mack WJ, LaBree L, et al.   Alpha-tocopherol supplementation in healthy individuals reduces low-density lipoprotein oxidation but not atherosclerosis: the Vitamin E Atherosclerosis Prevention Study (VEAPS). Circulation . 2002; 106: 1453– 1459. http://dx.doi.org/10.1161/01.CIR.0000029092.99946.08 Google Scholar CrossRef Search ADS PubMed  118 Suarna C, Wu BJ, Choy K, et al.   Protective effect of vitamin E supplements on experimental atherosclerosis is modest and depends on preexisting vitamin E deficiency. Free Radic Biol Med.  2006; 41: 722– 730. http://dx.doi.org/10.1016/j.freeradbiomed.2006.05.013 Google Scholar CrossRef Search ADS PubMed  119 Pratico D, Tangirala RK, Rader DJ, et al.   Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice. Nat Med.  1998; 4: 1189– 1192. http://dx.doi.org/10.1038/2685 Google Scholar CrossRef Search ADS PubMed  120 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell . 2011; 144: 646– 674. http://dx.doi.org/10.1016/j.cell.2011.02.013 Google Scholar CrossRef Search ADS PubMed  121 Klaunig JE, Kamendulis LM, Hocevar BA. Oxidative stress and oxidative damage in carcinogenesis. Toxicol Pathol.  2010; 38: 96– 109. http://dx.doi.org/10.1177/0192623309356453 Google Scholar CrossRef Search ADS PubMed  122 Prieme H, Loft S, Nyyssonen K, et al.   No effect of supplementation with vitamin E, ascorbic acid, or coenzyme Q10 on oxidative DNA damage estimated by 8-oxo-7,8-dihydro-2'-deoxyguanosine excretion in smokers. Am J Clin Nutr.  1997; 65: 503– 507. Google Scholar CrossRef Search ADS PubMed  123 Retana-Ugalde R, Casanueva E, Altamirano-Lozano M, et al.   High dosage of ascorbic acid and alpha-tocopherol is not useful for diminishing oxidative stress and DNA damage in healthy elderly adults. Ann Nutr Metab.  2008; 52: 167– 173. Google Scholar CrossRef Search ADS PubMed  124 Negis Y, Zingg JM, Libinaki R, et al.   Vitamin E and cancer. Nutr Cancer.  2009; 61: 875– 878. http://dx.doi.org/10.1080/01635580903285197 Google Scholar CrossRef Search ADS PubMed  125 Schindler R, Mentlein R. Flavonoids and vitamin E reduce the release of the angiogenic peptide vascular endothelial growth factor from human tumor cells. J Nutr . 2006; 136: 1477– 1482. Google Scholar CrossRef Search ADS PubMed  126 Ju J, Picinich SC, Yang Z, et al.   Cancer-preventive activities of tocopherols and tocotrienols. Carcinogenesis . 2010; 31: 533– 542. http://dx.doi.org/10.1093/carcin/bgp205 Google Scholar CrossRef Search ADS PubMed  127 Wright ME, Weinstein SJ, Lawson KA, et al.   Supplemental and dietary vitamin E intakes and risk of prostate cancer in a large prospective study. Cancer Epidemiol Biomarkers Prev . 2007; 16: 1128– 1135. http://dx.doi.org/10.1158/1055-9965.EPI-06-1071 Google Scholar CrossRef Search ADS PubMed  128 Rodriguez C, Jacobs EJ, Mondul AM, et al.   Vitamin E supplements and risk of prostate cancer in U.S. men. Cancer Epidemiol Biomarkers Prev . 2004; 13: 378– 382. Google Scholar PubMed  129 Kirsh VA, Hayes RB, Mayne ST, et al.   Supplemental and dietary vitamin E, β-carotene, and vitamin C intakes and prostate cancer risk. J Natl Cancer Inst.  2006; 98: 245– 254. Google Scholar CrossRef Search ADS PubMed  130 Bravi F, Polesel J, Bosetti C, et al.   Dietary intake of selected micronutrients and the risk of pancreatic cancer: an Italian case–control study. Ann Oncol.  2011; 22: 202– 206. http://dx.doi.org/10.1093/annonc/mdq302 Google Scholar CrossRef Search ADS PubMed  131 Bostick RM, Potter JD, Mckenzie DR, et al.   Reduced risk of colon cancer with high intake of vitamin E—the Iowa Women’s Health Study. Cancer Res.  1993; 53: 4230– 4237. Google Scholar PubMed  132 Jacobs EJ, Henion AK, Briggs PJ, et al.   Vitamin C and vitamin E supplement use and bladder cancer mortality in a large cohort of US men and women. Am J Epidemiol . 2002; 156: 1002– 1010. http://dx.doi.org/10.1093/aje/kwf147 Google Scholar CrossRef Search ADS PubMed  133 Key TJ, Appleby PN, Travis RC, et al.   Carotenoids, retinol, tocopherols, and prostate cancer risk: pooled analysis of 15 studies. Am J Clin Nutr.  2015; 102: 1142– 1157. http://dx.doi.org/10.3945/ajcn.115.114306 Google Scholar CrossRef Search ADS PubMed  134 Wu K, Willett WC, Chan JM, et al.   A prospective study on supplemental vitamin E intake and risk of colon cancer in women and men. Cancer Epidemiol Biomarkers Prev . 2002; 11: 1298– 1304. Google Scholar PubMed  135 Jacobs EJ, Connell CJ, Patel AV, et al.   Vitamin C and vitamin E supplement use and colorectal cancer mortality in a large American Cancer Society cohort. Cancer Epidemiol Biomarkers Prev . 2001; 10: 17– 23. Google Scholar PubMed  136 Jacobs EJ, Connell CJ, McCullough ML, et al.   Vitamin C, vitamin E, and multivitamin supplement use and stomach cancer mortality in the Cancer Prevention Study II cohort. Cancer Epidemiol Biomarkers Prev . 2002; 11: 35– 41. Google Scholar PubMed  137 Lonn E, Bosch J, Yusuf S, et al.   Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA . 2005; 293: 1338– 1347. http://dx.doi.org/10.1001/jama.293.11.1338 Google Scholar CrossRef Search ADS PubMed  138 Greenberg ER, Baron JA, Tosteson TD, et al.   A clinical trial of antioxidant vitamins to prevent colorectal adenoma. Polyp Prevention Study Group. N Engl J Med.  1994; 331: 141– 147. Google Scholar CrossRef Search ADS PubMed  139 Albanes D, Heinonen OP, Huttunen JK, et al.   Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. Am J Clin Nutr . 1995; 62(6 suppl): 1427S– 1430S. Google Scholar CrossRef Search ADS   140 Heinonen OP, Albanes D, Virtamo J, et al.   Prostate cancer and supplementation with α-tocopherol and β-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst.  1998; 90: 440– 446. Google Scholar CrossRef Search ADS PubMed  141 Lippman SM, Klein EA, Goodman PJ, et al.   Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). J Urol . 2009; 181: 1686– 1687. Google Scholar CrossRef Search ADS   142 Gaziano JM, Glynn RJ, Christen WG, et al.   Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians' Health Study II randomized controlled trial. JAMA . 2009; 301: 52– 62. http://dx.doi.org/10.1001/jama.2008.862 Google Scholar CrossRef Search ADS PubMed  143 Lavine JE, Schwimmer JB, Van Natta ML, et al.   Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA . 2011; 305: 1659– 1668. http://dx.doi.org/10.1001/jama.2011.520 Google Scholar CrossRef Search ADS PubMed  144 Traber MG, Mah E, Leonard SW, et al.   Metabolic syndrome increases dietary α-tocopherol requirements as assessed using urinary and plasma vitamin E catabolites: a double-blind, crossover clinical trial. Am J Clin Nutr.  2017; 105: 571– 579. Google Scholar CrossRef Search ADS PubMed  145 Christen WG, Glynn RJ, Chew EY, et al.   Vitamin E and age-related macular degeneration in a randomized trial of women. Ophthalmology . 2010; 117: 1163– 1168. http://dx.doi.org/10.1016/j.ophtha.2009.10.043 Google Scholar CrossRef Search ADS PubMed  146 Chong EW, Wong TY, Kreis AJ, et al.   Dietary antioxidants and primary prevention of age related macular degeneration: systematic review and meta-analysis. BMJ.  2007; 335: 755. doi: 10.1136/bmj.39350.500428.47 Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nutrition Reviews Oxford University Press

Effects of dietary RRR α-tocopherol vs all-racemic α-tocopherol on health outcomes

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Oxford University Press
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© The Author(s) 2017. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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0029-6643
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1753-4887
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10.1093/nutrit/nux067
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Abstract

Abstract Of the 8 vitamin E analogues, RRR α-tocopherol likely has the greatest effect on health outcomes. Two sources of α-tocopherol, naturally sourced RRR α-tocopherol and synthetic all-racemic α-tocopherol, are commonly consumed from foods and dietary supplements in the United States. A 2016 US Food and Drug Administration ruling substantially changed the RRR to all-racemic α-tocopherol ratio of biopotency from 1.36:1 to 2:1 for food-labeling purposes, but the correct ratio is still under debate in the literature. Few studies have directly compared the 2 α-tocopherol sources, and existing studies do not compare the efficacy of either source for preventing or treating disease in humans. To help close this gap, this review evaluates studies that investigated the effects of either RRR α-tocopherol or all-racemic α-tocopherol on health outcomes, and compares the overall findings. α-Tocopherol has been used to prevent and/or treat cancer and diseases of the central nervous system, the immune system, and the cardiovascular system, so these diseases are the focus of the review. No firm conclusions about the relative effects of the α-tocopherol sources on health outcomes can be made. Changes to α-tocopherol–relevant policies have proceeded without adequate scientific support. Additional research is needed to assemble the pieces of the α-tocopherol puzzle and to determine the RRR to all-racemic α-tocopherol ratio of biopotency for health outcomes. all-racemic α-tocopherol, health, RRR α-tocopherol, vitamin E INTRODUCTION Vitamin E, which was discovered by Katherine S. Bishop and Herbert M. Evans in the 1920s, is a lipid-soluble antioxidant that plays a crucial role in human and animal reproduction. Although the name “vitamin E” appears to refer to a single compound, there are actually 8 vitamin E analogues: 4 tocopherols (α, β, γ, and δ) and 4 tocotrienols (α, β, γ, and δ) (Figure 1). However, only α-tocopherol was used to set the recommended dietary allowance (RDA) of vitamin E for Americans.1 Humans consume 2 sources of α-tocopherol: naturally sourced α-tocopherol, which is commonly found in seed oils, and synthetic α-tocopherol, which is used to fortify food products such as ready-to-eat cereals. Figure 1 View largeDownload slide Forms of vitamin E. Abbreviation: RDA, recommended dietary allowance. Figure 1 View largeDownload slide Forms of vitamin E. Abbreviation: RDA, recommended dietary allowance. CHEMICAL STRUCTURE OF α-TOCOPHEROL Synthetic (all-racemic, or all-rac) α-tocopherol is an equimolar mix of its stereoisomers. The 3 chiral carbons of α-tocopherol (at positions 2, 4′, and 8′) can be in either an R or an S orientation, yielding 8 stereoisomers. One of the stereoisomers in all-rac α-tocopherol is 2R, 4′R, 8′R (or RRR), which is the sole stereoisomer found in nature. The other 7 stereoisomers consist of 3 2R stereoisomers (RSS, RSR, RRS) and 4 2S stereoisomers (SSS, SRR, SRS, SSR). The orientation (R or S) of the carbon at the 2-position is significant: the main α-tocopherol–binding protein in the liver, α-tocopherol transfer protein (α-TTP), has a higher affinity for RRR and the other 2R stereoisomers than for the 4 2S stereoisomers.2,3 This hepatic discrimination means that 2R stereoisomers will be preferentially packaged into very low-density lipoproteins for transport in the circulation and, consequently, will accumulate in peripheral tissues. INTAKE LEVELS OF α-TOCOPHEROL The RDA for adults is 15 mg of RRR α-tocopherol,1 but more than 88% of Americans do not meet this recommendation.4 To establish the RDA, erythrocyte hemolysis by hydrogen peroxide was used as a biomarker of vitamin E depletion and repletion.1 The use of this biomarker has been questioned,5 and there may be grounds for basing future recommendations for vitamin E intake on endpoints related to chronic disease instead.6 α-Tocopherol bioavailability is lower in cigarette smokers7,8 and individuals with metabolic syndrome,9 so certain populations may need more α-tocopherol than healthy individuals. Vitamin E deficiency is very rare, but vitamin E insufficiency may be common, given the dietary intakes reported for Americans.10 It is unknown whether marginal vitamin E deficiency leads to adverse health outcomes or to chronic disease.11 Some research suggests that the RDA is actually too high for healthy adults.12 BIOAVAILABILITY AND BIOPOTENCY OF α-TOCOPHEROL Determining the bioavailability and biopotency of synthetic and naturally sourced α-tocopherol is important for evaluating the roles of these vitamin E sources in health and disease. In the 1940s, experiments with rats showed that a dose of all-rac α-tocopheryl acetate 1.36 times the mass of a dose of naturally sourced α-tocopheryl acetate was required to prevent fetal resorption.13 Based on these studies, all-rac α-tocopheryl acetate was assigned a value of 1 IU/mg, and 1.36:1 became the accepted RRR to all-rac ratio of biopotency. International units have long been used to denote vitamin E content on food labels, but this will soon change. More recent research does not support the 1.36:1 ratio of biopotency in humans.5 Some animal and human bioavailability studies suggest a new ratio of RRR to all-rac biopotency of 2:1, as plasma and tissues accumulate about twice the amount of deuterated RRR α-tocopherol as all-rac α-tocopherol after simultaneous consumption.14–16 The preferential binding of hepatic α-TTP to the 4 2R stereoisomers over the 4 2S stereoisomers also supports the 2:1 ratio. Therefore, it has been assumed that, at doses of an equivalent mass, all-rac α-tocopherol has one-half the biopotency of RRR α-tocopherol. However, determining the RRR to all-rac α-tocopherol ratio of biopotency requires the measurement of a biological response, such as fetal resorption. The new 2:1 ratio relies solely on bioavailability data (α-tocopherol tissue concentrations) and does not reflect data on biopotency. Though there are only limited measurable clinical endpoints to study α-tocopherol biopotency,5,13 data from α-tocopherol–deficient animal models can provide insight. Future studies should explore the effects of different dose ratios of RRR to all-rac α-tocopherol on tissue accumulation and functional parameters. To eliminate competition between these 2 sources of vitamin E in the liver, a nonsimultaneous dosing regimen may be most appropriate. Still, some researchers hypothesize that there is no single ratio of biopotency for the 2 α-tocopherol sources. They assert that the bioavailability and biopotency of each source differs depending on the dosage, the type of tissue, and the duration of dosing.5,17,18 For example, RRR:SRR ratios in the brain consistently increased the longer rats were fed a diet containing mass-equivalent doses of deuterated RRR and SRR α-tocopherol (from a ratio of 1.5:1 after 4 days up to 5.3:1 after 154 days).18 The RRR:SRR ratios in other tissues changed much less than the ratios in the brain, but each tissue differed in its discrimination for RRR over time.18 These differences in availability across tissues and over time obfuscate efforts to determine the biopotency of individual α-tocopherol stereoisomers, since doing so would require the use of a precise dosing regimen and a specific tissue type. As already noted, the current unit of measurement of vitamin E on food labels (international units) will soon be replaced. Based on a May 2016 ruling, the US Food and Drug Administration (FDA) is modifying the labeling regulations for conventional foods and dietary supplements.19 Food manufacturers will be required to indicate vitamin E content in milligrams instead of international units. Furthermore, it will be assumed that 2 mg of all-rac α-tocopherol equals 1 mg of RRR α-tocopherol. This is a drastic change in the regulations, given the ongoing uncertainty over the ratio of biopotency. BIOLOGICAL BASIS FOR DIFFERENTIAL EFFECTS There is a solid biological basis for differential effects of RRR α-tocopherol and all-rac α-tocopherol on health outcomes. The body differentially distributes, metabolizes, and excretes α-tocopherol stereoisomers. As noted earlier, hepatic α-TTP has a clear preference for RRR α-tocopherol and the other 2R stereoisomers, and thus RRR α-tocopherol is preferentially taken up into tissues over SRR α-tocopherol.2,3,18,20,21 For example, the only study that quantified all 8 stereoisomers in rat brain tissue found that the 4 2R stereoisomers accumulated equally; this further demonstrates the importance of the 2-position chiral carbon for α-tocopherol availability in tissues.22 The preference of hepatic α-TTP for 2R stereoisomers suggests that 2R stereoisomers are able to perform their functions better than 2S stereoisomers. Interestingly, the 2S stereoisomers do accumulate to varying degrees in milk23 and other tissues such as the brain,18,21,22,24 presumably via chylomicron delivery. This raises 2 questions about the role of 2S stereoisomers once they reach extrahepatic tissues. First, is there competition between 2R and 2S stereoisomers within cells? And second, do 2R and 2S stereoisomers result in the same biological response? Evidence in humans, though very limited, shows preferential incorporation of RRR α-tocopherol (over all 7 other stereoisomers) into tissues of the human infant brain.24 The biological rationale for—and significance of—this is not clear, though discriminatory mechanisms in extrahepatic tissues have been proposed. For example, the blood–brain barrier may regulate the entry of α-tocopherol into the brain.18 Additionally, the α-tocopherol–binding protein α-TTP has been detected in the brains of humans25 and rats.26 Tocopherol-associated protein, which has the same lipid-binding motif as α-TTP, has also been suggested as a potential binding protein for α-tocopherol.27 Tocopherol-associated protein was detected in multiple human tissues (eg, brain, heart, lung)28 and may be a transcriptional activator.29 However, despite promising results with tocopherol-associated protein, the primary role of this protein (typically known as supernatant protein factor) is in cholesterol biosynthesis,30 which likely has little physiological relevance to α-tocopherol metabolism.31 As for excretion of vitamin E, simultaneous consumption of deuterium-labeled RRR α-tocopherol and all-rac α-tocopherol led to the preferential excretion of all-rac (as α-CEHC) over RRR in urine at a remarkably high ratio of approximately 3:1.32 This suggests that RRR is preserved over all-rac and provides evidence of the differential impact of the 2 sources of α-tocopherol. The scientific community’s understanding of vitamin E has evolved since its discovery nearly a century ago, but some aspects of vitamin E warrant further investigation. The existing research does not wholly support the FDA’s changes to the US food labeling regulations with regard to vitamin E. A change in the unit of measurement used on food labels (international units to milligrams) is appropriate, since the conversion factors for international units have not been confirmed. However, the assertion of a 2:1 ratio of biopotency between naturally sourced and synthetic α-tocopherol has not been confirmed, either. Because very few studies directly compare the effectiveness of different α-tocopherol sources for health outcomes, this review evaluates and compares studies that investigated one source or the other. It focuses on 4 areas of human health that are often associated with the effects of α-tocopherol: the central nervous system (CNS), the immune system, the cardiovascular system, and cancer. The potential mechanisms responsible for the benefits of α-tocopherol in these 4 areas are also explored briefly. Many of the reviewed studies did not use vitamin E-depleted animals—those that did are specifically noted. NEUROLOGICAL DISEASES Role of α-tocopherol in the CNS Animal studies show that α-tocopherol promotes brain health and reverses neurodegeneration by preventing oxidative stress to cell components (eg, lipids and mitochondria).33,34 Studies using the α-TTP gene knockout (Ttpa−/−) model have produced some of the most valuable findings. With age, these animals develop structural abnormalities in the cerebellum35 and spinal cord36 as well as behavioral deficits36 caused by severe α-tocopherol deficiency. The Ttpa−/− model is particularly useful because neurological tissues retain α-tocopherol, even during dietary restriction.36 This model is also relevant to humans who have ataxia with vitamin E deficiency. Individuals with this disorder have loss-of-function mutations in the α-TTP gene and experience severe neurological dysfunction.37 Management of ataxia with vitamin E deficiency includes lifelong supplemental doses of α-tocopherol, which helps normalize plasma α-tocopherol levels and may partially reverse neurological symptoms.38 Knowledge gained about the consequences of deficiency has led to increased understanding of the metabolic fate of α-tocopherol. There is conflicting evidence about the role of α-tocopherol in other neurological outcomes, such as Alzheimer’s disease (AD) and cognitive function in older adults. In epidemiological studies, high tocopherol intake is associated with decreased incidence of AD.39 Moreover, patients with AD tend to have low plasma α-tocopherol concentrations,40 and plasma α-tocopherol has been inversely associated with severity of dementia and positively associated with both abstract reasoning and retention in the Fuld Object-Memory Evaluation.41 In contrast, α-tocopherol brain concentrations were not associated with AD neuropathology in deceased humans.33 In other studies, there were no associations between plasma α-tocopherol and measures of cognitive function42 or risk of cognitive impairment43 in elderly participants. A 2017 Cochrane review concluded there is no evidence supporting the use of α-tocopherol for treatment of mild cognitive impairment, but the results of 1 trial indicate that α-tocopherol may slow the progression of AD.44 It is α-tocopherol’s antioxidant properties that are most commonly associated with neurological health and disease. Oxidative stress is a factor in many brain disorders, including AD, and thus α-tocopherol status could be a critical factor.45 Nonetheless, some research suggests that α-tocopherol has both antioxidant and nonantioxidant functions in the CNS.46 For example, α-tocopherol may regulate gene expression. Two studies showed substantial changes in the expression of genes related to myelination, synaptic function, and oxidative stress in the cortices of adult Ttpa−/− mice.47,48 Another study concluded that α-tocopherol regulates hippocampal genes involved in Parkinson disease and AD.49 Histological or behavioral indicators of neurodegeneration have not been observed in young Ttpa−/− rodents; histological markers were seen from 17 to 20 months of age,35,36 and behavioral markers were seen at 18 months of age.36 However, alterations in gene expression have been observed in younger mice. Molecular changes may therefore precede more advanced manifestations of neurodegeneration.48 Though only a handful of studies have compared the sources of α-tocopherol for their effects on neurological outcomes, work in equines has shown that RRR α-tocopherol more effectively increases serum and cerebrospinal fluid α-tocopherol concentrations than equivalent doses (international units) of all-rac α-tocopherol (Table 1).50–55 Table 1 Central nervous system, immune system, and cardiovascular health outcomes in studies that compared RRR and all-rac α-tocopherol treatments Reference  Body system  Study groupa  Treatment doses  Sample size (per group)  Dosing regimen  Dosing duration (days)  Outcomes  Overall effect of RRR vs all-rac  Pusterla et al. (2010)50  CNS  Horses  RRR α-toc: 10 000 IU (6711 mg)  4  Daily, mixed into 250 g of sweet feed  14  RRR α-toc: ↑ [α-toc]serum; 2.2- to 4.2-fold ↑ [α-toc]CSF by day 14  RRR α-toc, but not all-rac, increased serum and CSF α-toc levels  All-rac α-TA: 10 000 IU (10 000 mg)  5  All-rac α-TA: no differences in [α-toc]serum or [α-toc]CSF from day 0 to day 14  Han et al. (2010)51  Immune system  Mice  RRR α-TA: 30 mg/kg diet or 500 mg/kg diet  4  Ad libitum, added to diet  28  RRR α-TA: dose comparison—high: ↑ gene expression of signaling lymphocyte activation molecule, TNF, and others; low: ↑ gene expression of IL-3 and others. α-toc source comparison—RRR: ↑ gene expression of lymphocyte activation molecule, TNFSF9, and others  Differences in spleen T lymphocyte gene transcription between α-toc doses and α-toc sources following ex vivo stimulation  All-rac α-TA: 30 mg/kg diet or 500mg/kg diet  4  All-rac α-TA: dose comparison—high: ↑ gene expression of IL-2 and others; low: ↑ gene expression of IGF-1 and others  Horn et al. (2010)52  Immune system  Cattle  RRR α-TA: 1000 IU (735 mg)  50  Daily, corn-based supplement  –b  RRR α-TA: ↑ [α-toc]serum; no differences in calf [IgG]serum or leukocyte CD14 and CD18 protein expressions compared with control. Source comparison—no overall difference in response to OVA challenge  No differences in immune response in suckling calves between α-toc sources  All-rac α-TA: 1000 IU (1000 mg)  50  All-rac α-TA: ↑ [α-toc]serum; no differences in calf [IgG]serum or leukocyte CD14 and CD18 protein expressions compared with control  Amazan et al. (2014)53  Immune system  Pigs  RRR α-TA: 150 mg or 50 mg  12  Daily, in water  c  RRR α-TA: dose comparison—high: ↑ [α-toc]serum and ↑ [IgA]serum  Higher α-toc serum levels in piglets from sows fed RRR α-toc compared with piglets from sows fed all-rac α-toc; no differences in immunoglobulin levels  All-rac α-TA: 150 mg  12  Daily, in feed  Source comparison—RRR: ↑ [α-toc]serum; no differences in [IgA]serum, [IgG]serum, or [IgM]serum  Reaven & Witztum (1993)54  CV system  Humans  RRR α-TA: 800 mg  7  Twice daily, α-TA capsules  56  RRR α-TA: ↑ [α-toc]LDL; ≈ 30% ↑ lag time of LDL oxidation after 28 and 56 days of supplementation; ↓ TBARS; ↓ macrophage degradation of LDL  No differences in LDL α-toc levels, susceptibility to lipid peroxidation of LDL, or other outcomes between α-toc sources  All-rac α-TA: 800 mg  8  All-rac α-TA: ↑ [α-toc]LDL; ≈ 30% ↑ lag time of LDL oxidation after 28 and 56 days of supplementation; ↓ TBARS; ↓ macrophage degradation of LDL  Devaraj et al. (1997)55  CV system  Humans  RRR α-TA: 100 IU (73.5 mg); 200 IU (147 mg); 400 IU (294 mg); or 800 IU (588 mg)  9–10  Daily, α-TA or placebo (soybean oil) capsules  56  RRR α-TA: dose comparison—↑ [α-toc]plasma and ↑ [α-toc]LDL with increasing dose; no differences in plasma lipid, lipoprotein, or fatty acid levels across doses or over time; prolongation of lag phase of oxidation with doses ≥ 400 IU  No differences in oxidative susceptibility of LDL or plasma α-toc concentrations between α-toc sources at any dose        All-rac α-TA: 100 IU (100 mg); 200 IU (200 mg); 400 IU (400 mg); or 800 IU (800 mg)  9–10      All-rac α-TA: dose comparison—↑ [α-toc]plasma and ↑ [α-toc]LDL with increasing dose; no differences in plasma lipid, lipoprotein, or fatty acid levels across doses or over time; prolongation of lag phase of oxidation with doses ≥ 400 IU    Reference  Body system  Study groupa  Treatment doses  Sample size (per group)  Dosing regimen  Dosing duration (days)  Outcomes  Overall effect of RRR vs all-rac  Pusterla et al. (2010)50  CNS  Horses  RRR α-toc: 10 000 IU (6711 mg)  4  Daily, mixed into 250 g of sweet feed  14  RRR α-toc: ↑ [α-toc]serum; 2.2- to 4.2-fold ↑ [α-toc]CSF by day 14  RRR α-toc, but not all-rac, increased serum and CSF α-toc levels  All-rac α-TA: 10 000 IU (10 000 mg)  5  All-rac α-TA: no differences in [α-toc]serum or [α-toc]CSF from day 0 to day 14  Han et al. (2010)51  Immune system  Mice  RRR α-TA: 30 mg/kg diet or 500 mg/kg diet  4  Ad libitum, added to diet  28  RRR α-TA: dose comparison—high: ↑ gene expression of signaling lymphocyte activation molecule, TNF, and others; low: ↑ gene expression of IL-3 and others. α-toc source comparison—RRR: ↑ gene expression of lymphocyte activation molecule, TNFSF9, and others  Differences in spleen T lymphocyte gene transcription between α-toc doses and α-toc sources following ex vivo stimulation  All-rac α-TA: 30 mg/kg diet or 500mg/kg diet  4  All-rac α-TA: dose comparison—high: ↑ gene expression of IL-2 and others; low: ↑ gene expression of IGF-1 and others  Horn et al. (2010)52  Immune system  Cattle  RRR α-TA: 1000 IU (735 mg)  50  Daily, corn-based supplement  –b  RRR α-TA: ↑ [α-toc]serum; no differences in calf [IgG]serum or leukocyte CD14 and CD18 protein expressions compared with control. Source comparison—no overall difference in response to OVA challenge  No differences in immune response in suckling calves between α-toc sources  All-rac α-TA: 1000 IU (1000 mg)  50  All-rac α-TA: ↑ [α-toc]serum; no differences in calf [IgG]serum or leukocyte CD14 and CD18 protein expressions compared with control  Amazan et al. (2014)53  Immune system  Pigs  RRR α-TA: 150 mg or 50 mg  12  Daily, in water  c  RRR α-TA: dose comparison—high: ↑ [α-toc]serum and ↑ [IgA]serum  Higher α-toc serum levels in piglets from sows fed RRR α-toc compared with piglets from sows fed all-rac α-toc; no differences in immunoglobulin levels  All-rac α-TA: 150 mg  12  Daily, in feed  Source comparison—RRR: ↑ [α-toc]serum; no differences in [IgA]serum, [IgG]serum, or [IgM]serum  Reaven & Witztum (1993)54  CV system  Humans  RRR α-TA: 800 mg  7  Twice daily, α-TA capsules  56  RRR α-TA: ↑ [α-toc]LDL; ≈ 30% ↑ lag time of LDL oxidation after 28 and 56 days of supplementation; ↓ TBARS; ↓ macrophage degradation of LDL  No differences in LDL α-toc levels, susceptibility to lipid peroxidation of LDL, or other outcomes between α-toc sources  All-rac α-TA: 800 mg  8  All-rac α-TA: ↑ [α-toc]LDL; ≈ 30% ↑ lag time of LDL oxidation after 28 and 56 days of supplementation; ↓ TBARS; ↓ macrophage degradation of LDL  Devaraj et al. (1997)55  CV system  Humans  RRR α-TA: 100 IU (73.5 mg); 200 IU (147 mg); 400 IU (294 mg); or 800 IU (588 mg)  9–10  Daily, α-TA or placebo (soybean oil) capsules  56  RRR α-TA: dose comparison—↑ [α-toc]plasma and ↑ [α-toc]LDL with increasing dose; no differences in plasma lipid, lipoprotein, or fatty acid levels across doses or over time; prolongation of lag phase of oxidation with doses ≥ 400 IU  No differences in oxidative susceptibility of LDL or plasma α-toc concentrations between α-toc sources at any dose        All-rac α-TA: 100 IU (100 mg); 200 IU (200 mg); 400 IU (400 mg); or 800 IU (800 mg)  9–10      All-rac α-TA: dose comparison—↑ [α-toc]plasma and ↑ [α-toc]LDL with increasing dose; no differences in plasma lipid, lipoprotein, or fatty acid levels across doses or over time; prolongation of lag phase of oxidation with doses ≥ 400 IU    Abbreviations and symbols: α-TA, α-tocopheryl acetate; α-toc, α-tocopherol; CSF, cerebrospinal fluid; CV, cardiovascular; IgA, immunoglobulin A; IgG, immunoglobulin G; IGF-1, insulin-like growth factor 1; IgM, immunoglobulin M; IL-2, mouse interleukin 2; IL-3, mouse interleukin 3; LDL, low-density lipoprotein; OVA, ovalbumin; TBARS, thiobarbituric acid-reactive substances; TNF, mouse tumor necrosis factor; TNFSF9, mouse tumor necrosis factor (ligand) superfamily, member 9; ↑, increased; ↓, decreased. a Animal groups were not vitamin E depleted prior to the study. b Dams were supplemented at ≈ 6 weeks prepartum until the beginning of breeding season; outcomes were measured in their suckling calves. c Sows were fed either all-rac α-TA or one of two RRR α-TA doses beginning 84 days prepartum and through lactation; after weaning, piglets were fed 3.33 mg of all-rac α-TA per day until 42 days of age. Neurological studies investigating RRR α-tocopherol Most CNS-related studies with RRR α-tocopherol have used rodent models. For example, a daily dose of RRR α-tocopherol delayed the neurological symptoms of ataxia with vitamin E deficiency and decreased lipid peroxidation in Ttpa−/− mice.36 An RRR α-tocopherol–supplemented diet also attenuated development of the tau pathology (a key component of Parkinson disease) in a transgenic mouse model that overexpresses a human tau isoform.56 Studies have also used RRR α-tocopherol to treat induced seizures57 and permanent cerebral brain injuries58 in otherwise healthy, vitamin E–sufficient rats. In both cases, RRR α-tocopherol reduced unfavorable hippocampal microglia activation.57,58 Treatment also significantly decreased markers related to oxidative stress57 and prevented pyramidal cell death.58 Using a mouse model of AD and vitamin E deficiency (Ttpa−/− + APPsw), RRR α-tocopherol supplementation reduced plasma amyloid β levels59 and amyloid plaque areas in the cortex and hippocampus.60 Supplementation normalized performance in the Morris water maze but did not improve performance in other behavioral tasks, such as a contextual fear conditioning test.60 Some animal research does not support a benefit of RRR α-tocopherol for CNS function.61 Additionally, very few CNS-related trials in humans have studied the effect of RRR α-tocopherol. In a long-term trial of RRR α-tocopherol supplementation in healthy older women, no significant cognitive benefits after multiple assessments were observed.62 Neurological studies investigating all-rac α-tocopherol Rats fed an α-tocopherol–deficient diet for 38 weeks followed by an all-rac α-tocopherol repletion diet for 20 weeks had less functional neural deterioration than rats fed an α-tocopherol–deficient diet throughout the study.63 Their electrophysiological parameters were also more similar to those of controls.63 The diet of the control group contained low levels of RRR α-tocopherol, indicating that repletion with all-rac α-tocopherol may be sufficient to restore the normal neural function observed in animals fed RRR α-tocopherol. A second rodent study investigated long-term potentiation in the dentate gyrus (hippocampus) of aged and young rats fed a diet supplemented with all-rac α-tocopherol.64 Long-term potentiation is the long-lasting strengthening of synapses, and it is one cellular mechanism used to explain learning and memory.64 While aged control mice (consuming a diet containing standard α-tocopherol levels) exhibited reduced long-term potentiation and increased lipid peroxidation, aged rats fed all-rac α-tocopherol–supplemented diets showed sustained long-term potentiation and reduced lipid peroxidation, similar to findings in young rats.64 This suggests that all-rac α-tocopherol helped prevent age-related oxidative stress in the hippocampus. In a third animal study, transgenic mice were used to investigate apoE4, an apolipoprotein E isoform involved in CNS lipoprotein metabolism and implicated as an independent risk factor for AD. All-rac α-tocopherol supplementation did not affect most of the AD-related endpoints.65 In 2 randomized, placebo-controlled human trials, daily supplementation with high-doses synthetic α-tocopherol delayed AD progression in individuals with mild to moderately severe AD.66,67 RRR α-tocopherol vs all-rac α-tocopherol: conclusions for neurological outcomes Some studies (both animal and human) did not specify whether RRR or all-rac α-tocopherol was used, which severely limits the comparability of results across studies. Despite the known consequences of low α-tocopherol status, the relative effect of RRR vs all-rac α-tocopherol in CNS health is not clear; none of the CNS studies aimed to show the ratio of biopotency between the 2 sources. Most research in animals showed some benefits from both RRR and all-rac α-tocopherol for the doses used. In 2 studies conducted in AD patients, all-rac α-tocopherol supplementation resulted in positive outcomes. Several human trials have used poorly defined vitamin E supplements that contain multiple tocopherol analogues; these studies were not included in this review. IMMUNE RESPONSE Role of α-tocopherol in the immune system The role of α-tocopherol in the immune system has been studied through the lens of allergic airway disease and lung function. Following ovalbumin sensitization, Ttpa−/− mice displayed a reduced immune response in the lung, demonstrating a need for α-tocopherol.68 Furthermore, higher serum α-tocopherol is related to favorable spirometric markers in young adults,69 and α-tocopherol may improve or reverse the functional decline of T cells that occurs with aging.70 The best-known function of α-tocopherol (ie, antioxidant) may be linked to immune-related outcomes. Some studies suggest that antioxidant intake is inversely associated with asthma prevalence.71 A second relevant function of α-tocopherol in the immune system involves signal transduction pathways. In endothelial cells, α-tocopherol inhibits protein kinase C α, thereby inhibiting the recruitment of leukocytes72,73 and altering the inflammatory immune response. It may also regulate the expression of immune-related genes in the heart74 as well as a group of genes related to inflammation.75 A few immunological studies have explicitly compared all-rac α-tocopherol with RRR α-tocopherol (Table 1).51–53 One ex vivo study used T lymphocytes from spleens of aged adult wild-type mice. The animals were fed diets with high or low levels of either RRR or all-rac α-tocopherol. After 4 weeks of treatment, it was shown that both the dose and the source of α-tocopherol influenced gene transcription.51 Distinct gene expression profiles were observed, even when the high dose of all-rac α-tocopherol (500 mg per kilogram of diet) was compared with the low dose of RRR α-tocopherol (30 mg per kilogram of diet).51 This suggests that the 2 α-tocopherol sources interact differently with their cellular targets and are not equivalent, even when all-rac α-tocopherol doses are well above the hypothesized 2:1 ratio of biopotency. In another study, calves suckling cows whose diets were supplemented with either RRR α-tocopherol or all-rac α-tocopherol had higher serum α-tocopherol levels than controls, but there were no differences in immune function in calves after an ovalbumin challenge.52 A third study found that piglets of sows fed RRR α-tocopherol had higher serum α-tocopherol levels than piglets of sows fed all-rac α-tocopherol.53 However, serum immunoglobulin levels in the piglets did not differ between groups.53 Immune-response studies investigating RRR α-tocopherol Some studies have assessed the effect of RRR α-tocopherol and age on immune outcomes. Linker for Activation of T cells is necessary for T-cell activation, and changes in phosphorylation signifies an altered response.76 Phosphorylation of Linker for Activation of T cells was significantly reduced in spleen CD4+ T cells of aged control mice, but RRR α-tocopherol treatment normalized phosphorylation.76 RRR α-tocopherol may reduce allergic responses and lung inflammation. Rodent dams were fed an RRR α-tocopherol–supplemented diet, and then their pups were sensitized with ovalbumin to induce an immune response. The pups had significantly lower eosinophil recruitment and inflammation in their lung tissue compared with the pups of dams fed a standard diet.77 In the lungs of pups in the treatment group, there were also significant decreases in the expression of genes encoding allergen-induced proteins (eg, interleukin [IL]-4 and IL-33).77 In contrast, a different rodent study showed that short-term (10-day) pretreatment with RRR α-tocopherol was ineffective in preventing the effects of an antigen challenge.78 Only a few human studies have examined the effects of RRR α-tocopherol supplementation on immune system outcomes. Research in asthmatics has yielded conflicting results: Supplemental doses of RRR α-tocopherol significantly decreased airway oxidative stress in 1 study79 but had no measurable impact on asthma control in another.80 However, the former study was small and was not randomized or placebo controlled. Immune-response studies investigating all-rac α-tocopherol T-cell function becomes impaired with age, but this was partially remedied by α-tocopherol in rodent studies. Feeding aged mice a diet containing high-dose all-rac α-tocopherol triggered changes in the transcription of genes important for the immune response: α-tocopherol led to induced expression of IL-2 and repressed expression of IL-4 in the animals’ splenic T cells.81 In another study examining T-helper 1 cytokine production, old influenza-infected mice were fed a diet containing high-dose all-rac α-tocopherol.82 Splenocytes from these mice had higher production of some cytokines, eg, IL-2 and interferon-γ, but not of others, eg, IL-6 and IL-1β.82 Production of prostaglandin E2 (PGE2) was also significantly reduced in macrophages of these mice.82 Since PGE2 levels increase with age and may reduce the normal T-helper 1 response, α-tocopherol may enhance T-helper 1 cell function by decreasing PGE2.82 Numerous gene transcripts in lung tissue were either up- or downregulated in male and female mice fed diets supplemented with low-dose or high-dose all-rac α-tocopherol.83 Despite similar levels of α-tocopherol in lung between sexes fed the high all-rac diet, substantially more genes were affected by α-tocopherol treatment in females than in males (≈ 500 vs ≈ 80).83 Of particular interest was a cluster of 13 functionally related cytoskeleton genes that were all induced by an α-tocopherol–supplemented diet.83 Though these findings lack statistical power, this research provides a starting point for future studies assessing the impact of sex and α-tocopherol on gene expression in lung tissue. In a trial with healthy older adults, daily supplementation with all-rac α-tocopherol improved multiple measures; in particular, participants had significantly decreased plasma lipid peroxide concentrations and enhanced cell-mediated immunity.84 De la Fuente et al.,85 Meydani et al.,86 and Lee et al.87 also found that supplemental doses of all-rac α-tocopherol positively affected immune outcomes in older adults. Effects on airway disease have been studied as well. Participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study who received daily synthetic 2-ambo α-tocopherol (which is 50% RRR and 50% SRR) supplements showed no differences in the development of chronic obstructive pulmonary disease symptoms, such as chronic bronchitis and dyspnea.88 RRR α-tocopherol vs all-rac α-tocopherol: conclusions for immune response outcomes In human and animal studies, RRR α-tocopherol and all-rac α-tocopherol have resulted in both positive and null effects on immune-related outcomes. The human studies often provided very high daily doses of all-rac α-tocopherol, so it is possible that supplements provided sufficient amounts of RRR or other 2R stereoisomers to produce beneficial effects. Using biomarkers of immune function to establish recommendations for α-tocopherol intake could be a worthwhile approach. Older adults may benefit most from the effect of α-tocopherol on immune function and inflammation. CARDIOVASCULAR DISEASES Role of α-tocopherol in the cardiovascular system The development of cardiovascular diseases (CVDs), such as atherosclerosis, is intricately linked to the oxidation of low-density lipoprotein (LDL) particles and its consequences.89,90 Hence, vitamin E, which can inhibit this oxidation, has been used to prevent and treat negative CVD outcomes. Epidemiological studies have supported an inverse relationship between vitamin E intake and risk of coronary heart disease in both women91 and men.92 An inverse association between plasma α-tocopherol levels and mortality due to ischemic heart disease in men from 16 European study populations was also reported.93 In animal models, atherosclerosis-prone, vitamin E–deficient mice (Ttpa−/− Apoe−/−) had significantly larger aortic lesions (in the arch and thorax) than atherosclerosis-prone mice without a genetic predisposition for vitamin E deficiency (Ttpa+/+ Apoe−/−).94 The double knockout mice also showed increased lipid peroxidation in the proximal aorta.94 This compelling study showed that adequate vitamin E status may prevent oxidative damage and formation of atherosclerotic lesions. Gene regulation by α-tocopherol has been demonstrated in the heart, which could be an additional mechanism by which α-tocopherol prevents unfavorable cardiovascular outcomes. Genes related to proper immune response, lipid metabolism, and inflammation were dysregulated in hearts of Ttpa−/− mice.74 Other nonantioxidant roles are possible for α-tocopherol in the CV system, as α-tocopherol has been shown to inhibit vascular smooth muscle cell proliferation through a protein kinase C–dependent mechanism,95,96 to inhibit platelet aggregation,97–99 and to modulate the inflammatory response via changes in monocyte function.100 Results from human studies evaluating the effect of α-tocopherol on the cardiovascular system are inconsistent. One meta-analysis found that vitamin E supplementation positively affected flow-mediated vasodilation (which serves as a marker of endothelial function and CVD risk).101 In contrast, a separate meta-analysis concluded that α-tocopherol supplementation did not help prevent strokes.102 Both meta-analyses included studies that used RRR or all-rac α-tocopherol, and neither distinguished between the α-tocopherol sources in their analyses. This highlights the challenge of evaluating the health effects of individual sources of α-tocopherol. Very few studies have directly compared the effect of different α-tocopherol sources on cardiovascular health, and the 2 described below were conducted decades ago (Table 1).54,55 In 1, participants received very high daily doses (1600 mg/d) of either RRR α-tocopherol or all-rac α-tocopherol for 8 weeks; afterward, their lipid levels and the susceptibility of isolated lipoproteins to oxidation were measured.54 Although lag time for oxidation increased by approximately 30% in both treatment groups compared with controls, there were no differences between the 2 α-tocopherol sources for the outcomes measured.54 Devaraj et al.55 provided participants with 100 IU, 200 IU, 400 IU, or 800 IU of either RRR α-tocopherol or all-rac α-tocopherol for 8 weeks (8 treatment groups). As dose increased, total plasma α-tocopherol concentrations also increased (measured at week 8); this was true for both α-tocopherol sources.55 There were no significant differences in total plasma α-tocopherol levels between the RRR and all-rac α-tocopherol groups at any dose. This is not surprising, since even the lowest dose (100 IU) is high relative to the typical dietary intake. This study did not quantify individual α-tocopherol stereoisomers in the plasma, but future studies that compare RRR and all-rac α-tocopherol should consider doing so. Devaraj et al.55 also measured the susceptibility of isolated lipoproteins to oxidation. Only at doses ≥400 IU was there a prolonged lag phase of oxidation, and there were no differences between the 2 α-tocopherol sources.55 Lipoprotein oxidation may be a useful functional measurement, given its role in atherosclerosis. To investigate the ratio of biopotency of RRR to all-rac α-tocopherol, lower doses of α-tocopherol (closer to amounts normally consumed in the diet) are likely needed. Both studies included only healthy participants, so it is unclear whether similar results would be seen in populations with CVD. Cardiovascular studies investigating RRR α-tocopherol In adult Apoe−/− mice fed a high-fat diet, an RRR α-tocopherol intervention significantly decreased lesion size in the aortic root but did not affect a marker of oxidative stress or improve the resistance of plasma lipids to oxidation when exposed to peroxyl radicals.103 RRR α-tocopherol improved CVD-related endpoints in several human studies. In an ex vivo experiment, RRR α-tocopherol supplements drastically inhibited platelet adhesion in study participants,104 and researchers later showed that cosupplementation with RRR α-tocopherol and aspirin (a platelet antiaggregating agent) may help prevent ischemic events in patients with ischemic cerebrovascular disease.105,RRR α-tocopherol significantly reduced the risk of nonfatal myocardial infarction and cardiovascular events in patients with atherosclerosis106 and significantly reduced the risk of combined cardiovascular outcomes in hemodialysis patients.107 However, it had no effect on any cardiovascular outcomes measured in a high-risk population.108 In healthy women, RRR α-tocopherol significantly decreased cardiovascular-related deaths but did not reduce the risk of heart failure,109 myocardial infarction,110 or stroke.110 These trials indicate that α-tocopherol may be of benefit to only some populations. Cardiovascular studies investigating all-rac α-tocopherol In an atherosclerosis-prone murine model (LDL receptor–deficient mice, ie, Ldlr−/− ), mice fed a low-fat, low-cholesterol diet combined with long-term all-rac α-tocopherol supplementation initiated at an early age showed a significantly reduced area of lesion on the descending aorta and a higher survival rate when compared with mice not given all-rac α-tocopherol.111 Several studies have investigated synthetic α-tocopherol to treat or prevent cardiovascular disease in human populations with varying health statuses (eg, smokers, patients with CVD or diabetes, patients with a history of other conditions), but most have reported null results.112–116 In fact, α-tocopherol significantly increased the risk of hemorrhagic stroke in 1 study.116 Fewer studies have been conducted in healthy populations, but 1 study reported that all-rac α-tocopherol reduced LDL levels and lowered LDL susceptibility to oxidation.117 RRR α-tocopherol vs all-rac α-tocopherol: conclusions for cardiovascular outcomes Epidemiological studies have shown that the consumption of α-tocopherol from foods may provide some benefit to the cardiovascular system. The effectiveness of an α-tocopherol intervention may depend on the cardiovascular health status at the time the intervention is initiated. RRR α-tocopherol intake may improve cardiovascular outcomes in atherosclerosis-susceptible animal models and in humans with preexisting conditions, but not in healthy individuals or those at high risk for cardiovascular events. All-rac α-tocopherol has been beneficial in some animal studies, but most human research suggests no benefit to the cardiovascular system. Some potentially valuable research did not identify which α-tocopherol source was used. This was the case for 2 animal studies in which supplementary α-tocopherol reduced lesion areas in aortas of atherosclerosis-susceptible mice.118,119 The contradictory results reported in the literature for the 2 different α-tocopherol sources may stem from the wide-ranging dosing regimens used: every study used a different amount, frequency, and duration of dosing. CANCER Role of α-tocopherol in cancer To categorize the complex underpinnings of neoplastic diseases, Hanahan and Weinberg120 identified 8 hallmarks and 2 enabling characteristics of cancer. One enabling characteristic (genome instability and mutation) may be relevant to the functions of α-tocopherol. In other words, the ability of α-tocopherol to quench free radicals could prevent damage to DNA and reduce the risk of cancer development. Oxidative stress may indeed be linked to carcinogenesis, since it damages cell components.121 However, α-tocopherol has not been shown to prevent DNA damage via antioxidant action in humans, and it is unclear whether an antioxidant mechanism could result in clinically relevant health benefits.122–124 In vitro, α-tocopherol inhibits vascular endothelial growth factor released from human breast cancer cells,125 so α-tocopherol could theoretically influence another cancer hallmark, ie, angiogenesis.120 Nevertheless, the existing literature does not support this relationship. In preclinical studies, α-tocopherol and α-tocopherol derivatives have been ineffective in preventing tumor formation in the colon, and results have been inconsistent in lung, prostate, and mammary gland studies.126 Studies assessing α-tocopherol intake from food sources or supplements and cancer risk have not shown an unequivocal benefit from increased consumption, though there may be some benefit for particular types of cancer and specific patient populations.127–129 High vitamin E intake significantly decreased pancreatic cancer risk,130 colon cancer risk,131 and bladder cancer mortality.132 A significant inverse association between serum α-tocopherol and advanced and aggressive prostate cancer risk has also been reported.133 On the contrary, vitamin E supplementation was not associated with colorectal cancer risk,134 colon cancer mortality,135 or stomach cancer mortality.136 On the whole, the literature does not support a beneficial role for α-tocopherol in the treatment or prevention of cancer. Nevertheless, because of the proposed link between antioxidants and cancer, and because α-tocopherol has been administered in relevant human trials, the results of interventions with RRR α-tocopherol and all-rac α-tocopherol will be briefly summarized. Cancer studies investigating RRR α-tocopherol In a large, long-term trial, supplementation with RRR α-tocopherol had no significant effect on the incidence of total cancer, breast cancer, lung cancer, colon cancer, or cancer deaths,110 nor did it significantly reduce the incidence of total cancer, organ-specific cancer, or cancer deaths in a second trial with high-risk volunteers.137 Daily antioxidant supplements, which included RRR α-tocopherol, also did not reduce adenoma incidence in patients with previously removed adenomas.138 Cancer studies investigating all-rac α-tocopherol Debatably the most optimistic findings for cancer outcomes came from a trial in smokers, in which supplementation with synthetic α-tocopherol reduced colorectal cancer incidence,139 prostate cancer incidence,139 and prostate cancer mortality.140 Conversely, there was no effect of all-rac α-tocopherol on incidence of prostate cancer, total cancer, cancer at other sites or on cancer mortality in other randomized, placebo-controlled studies.141,142 In 1 of these studies, all-rac α-tocopherol supplementation actually nonsignificantly increased prostate cancer incidence.141 RRRα-tocopherol vs all-rac α-tocopherol: conclusions for cancer outcomes Cancer-related benefits from α-tocopherol consumption have been observed in some epidemiological studies, but the majority of clinical trials of α-tocopherol supplementation do not confirm these findings. It is conceivable that diets containing antioxidant-rich foods, eg, fruits and vegetables, could be beneficial but that supplements are not. Despite a plausible basis for cancer-related benefits, it seems that neither α-tocopherol source affects cancer outcomes. CONCLUSION The effects of α-tocopherol on nonalcoholic steatohepatitis,143,144 eye disorders,145,146 and other health conditions have been studied previously, but this review focused on 4 of the more well-known areas of disease associated with vitamin E. Comparing studies that investigated the sources of α-tocopherol revealed many limitations, such as differences in population characteristics (vitamin E status, sex, age, health status), dose and dosing frequency of α-tocopherol, study size and duration, and the wide array of different endpoints considered. There is stronger evidence for a beneficial role of α-tocopherol in some health outcomes (eg, neurological function) than in others (eg, cancer), but unfortunately, a number of studies neglected to disclose which α-tocopherol source was investigated. In 2000, Hoppe and Krennrich5 called on researchers to discover novel in vivo biomarkers for α-tocopherol status and new methods for assessing the ratio of RRR to all-rac biopotency.5 Almost 2 decades later, their optimistic call for action is still unrealized. Language used in the recent FDA ruling presumes a scientific consensus on the relative bioavailability and biopotency of the different α-tocopherol sources, and yet it is not possible to ascertain this essential information from the existing research. Studies have also failed to compare the effectiveness of RRR vs all-rac α-tocopherol for the selected health outcomes. In general, animal research has shown that both sources of α-tocopherol produce beneficial effects, while human trials have been less conclusive. Significant questions remain unanswered. These require more targeted research that directly compares relevant dose levels of RRR and all-rac α-tocopherol in relation to human diseases. Key questions include the following: (1) What factors beyond hepatic α-TTP determine the accumulation of particular stereoisomers in tissues, and how does the preferential accumulation of stereoisomers affect human health? (2) What is the appropriate RRR to all-rac ratio of biopotency? (3) What human-relevant biochemical markers could be established for measuring α-tocopherol sufficiency? (4) How do age and health status affect the metabolism of RRR and all-rac α-tocopherol? (5) What are the implications for the food and supplement industries? These questions and others must be addressed to develop optimal policies and set α-tocopherol intake recommendations. Acknowledgments Author contributions. K.M.Ranard wrote the first draft. Both K.M. Ranard and J.W. Erdman revised the manuscript and approved the final draft. Funding/support. This work was supported by a US Department of Agriculture (USDA) National Institute of Food and Agriculture (NIFA) Hatch grant (no. ILLU-698–915) and the Division of Nutritional Sciences Vision 20/20 Grant Program at the University of Illinois at Urbana-Champaign. Declaration of interest. The authors have no relevant interests to declare. References 1 Institute of Medicine, Food and Nutrition Board, Panel on Dietary Antioxidants and Related Compounds. Vitamin E. In: Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids . Washington, DC: National Academy Press; 2000: 186– 283. 2 Traber MG, Burton GW, Ingold KU, et al.   RRR- and SRR-α-tocopherols are secreted without discrimination in human chylomicrons, but RRR-α-tocopherol is preferentially secreted in very low density lipoproteins. J Lipid Res . 1990; 31: 675– 685. Google Scholar PubMed  3 Traber MG, Ramakrishnan R, Kayden HJ. Human plasma vitamin E kinetics demonstrate rapid recycling of plasma RRR-alpha-tocopherol. Proc Natl Acad Sci USA.  1994; 91: 10005– 10008. http://dx.doi.org/10.1073/pnas.91.21.10005 Google Scholar CrossRef Search ADS   4 2015 Dietary Guidelines Advisory Committee. Scientific Report of the 2015 Dietary Guidelines Advisory Committee. Washington, DC: US Dept of Agriculture, Dept of Health and Human Services. https://health.gov/dietaryguidelines/2015-scientific-report/PDFs/Scientific-Report-of-the-2015-Dietary-Guidelines-Advisory-Committee.pdf. Published Feburary 2015. Accessed August 8, 2017. 5 Hoppe PP, Krennrich G. Bioavailability and potency of natural-source and all-racemic alpha-tocopherol in the human: a dispute. Eur J Nutr.  2000; 39: 183– 193. http://dx.doi.org/10.1007/s003940070010 Google Scholar CrossRef Search ADS PubMed  6 Yetley EA, MacFarlane AJ, Greene-Finestone LS, et al.   Options for basing Dietary Reference Intakes (DRIs) on chronic disease endpoints: report from a joint US-/Canadian-sponsored working group. Am J Clin Nutr.  2017; 105: 249S– 285S. Google Scholar CrossRef Search ADS PubMed  7 Bruno RS, Traber MG. Cigarette smoke alters human vitamin E requirements. J Nutr.  2005; 135: 671– 674. Google Scholar CrossRef Search ADS PubMed  8 Bruno RS, Traber MG. Vitamin E biokinetics, oxidative stress and cigarette smoking. Pathophysiology.  2006; 13: 143– 149. http://dx.doi.org/10.1016/j.pathophys.2006.05.003 Google Scholar CrossRef Search ADS PubMed  9 Mah E, Sapper TN, Chitchumroonchokchai C, et al.   α-Tocopherol bioavailability is lower in adults with metabolic syndrome regardless of dairy fat co-ingestion: a randomized, double-blind, crossover trial. Am J Clin Nutr . 2015; 102: 1070– 1080. Google Scholar CrossRef Search ADS PubMed  10 Traber MG. Vitamin E inadequacy in humans: causes and consequences. Adv Nutr.  2014; 5: 503– 514. http://dx.doi.org/10.3945/an.114.006254 Google Scholar CrossRef Search ADS PubMed  11 Traber MG., Vitamin E. In: Erdman JW, Macdonald IA, Zeisel SH, eds. Present Knowledge in Nutrition. 10th ed . Oxford, UK: Wiley-Blackwell; 2012: 214– 229. Google Scholar CrossRef Search ADS   12 Novotny JA, Fadel JG, Holstege DM, et al.   This kinetic, bioavailability, and metabolism study of RRR-α-tocopherol in healthy adults suggests lower intake requirements than previous estimates. J Nutr.  2012; 142: 2105– 2111. Google Scholar CrossRef Search ADS PubMed  13 Jensen SK, Lauridsen C. α-Tocopherol stereoisomers. Vitam Horm.  2007; 76: 281– 308. Google Scholar CrossRef Search ADS PubMed  14 Leonard SW, Terasawa Y, Farese RVJr, et al.   Incorporation of deuterated RRR- or all-rac-α-tocopherol in plasma and tissues of α-tocopherol transfer protein–null mice. Am J Clin Nutr.  2002; 75: 555– 560. Google Scholar CrossRef Search ADS PubMed  15 Burton GW, Traber MG, Acuff RV, et al.   Human plasma and tissue alpha-tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E. Am J Clin Nutr.  1998; 67: 669– 684. Google Scholar CrossRef Search ADS PubMed  16 Acuff RV, Thedford SS, Hidiroglou NN, et al.   Relative bioavailability of RRR- and all-rac-alpha-tocopheryl acetate in humans: studies using deuterated compounds. Am J Clin Nutr . 1994; 60: 397– 402. Google Scholar CrossRef Search ADS PubMed  17 Blatt DH, Pryor WA, Mata JE, et al.   Re-evaluation of the relative potency of synthetic and natural α-tocopherol: experimental and clinical observations. J Nutr Biochem . 2004; 15: 380– 395. Google Scholar CrossRef Search ADS PubMed  18 Ingold KU, Burton GW, Foster DO, et al.   Biokinetics of and discrimination between dietary RRR- and SRR-alpha-tocopherols in the male rat. Lipids . 1987; 22: 163– 172. http://dx.doi.org/10.1007/BF02537297 Google Scholar CrossRef Search ADS PubMed  19 Food labeling: revision of the Nutrition and Supplement Facts labels. College Park, MD: US Food and Drug Administration. Fed Regist. 2016;81(103):33741–33999. 20 Kaneko K, Kiyose C, Ueda T, et al.   Studies of the metabolism of α-tocopherol stereoisomers in rats using [5-methyl-14C]SRR- and RRR-α-tocopherol. J Lipid Res . 2000; 41: 357– 367. Google Scholar PubMed  21 Kiyose C, Kaneko K, Muramatsu R, et al.   Simultaneous determination of RRR- and SRR-α-tocopherols and their quinones in rat plasma and tissues by using chiral high-performance liquid chromatography. Lipids . 1999; 34: 415– 422. Google Scholar CrossRef Search ADS PubMed  22 Weiser H, Riss G, Kormann AW. Biodiscrimination of the eight α-tocopherol stereoisomers results in preferential accumulation of the four 2R forms in tissues and plasma of rats. J Nutr.  1996; 126: 2539– 2549. Google Scholar PubMed  23 Gaur S, Kuchan MJ, Lai CS, et al.   Supplementation with RRR- or all-rac-α-tocopherol differentially affects the α-tocopherol stereoisomer profile in the milk and plasma of lactating women. J Nutr.  2017; 147: 1301– 1307. Google Scholar CrossRef Search ADS PubMed  24 Kuchan MJ, Jensen SK, Johnson EJ, et al.   The naturally occurring α-tocopherol stereoisomer RRR-α-tocopherol is predominant in the human infant brain. Br J Nutr.  2016; 116: 126– 131. Google Scholar CrossRef Search ADS PubMed  25 Copp RP, Wisniewski T, Hentati F, et al.   Localization of α-tocopherol transfer protein in the brains of patients with ataxia with vitamin E deficiency and other oxidative stress related neurodegenerative disorders. Brain Res . 1999; 822: 80– 87. Google Scholar CrossRef Search ADS PubMed  26 Hosomi A, Goto K, Kondo H, et al.   Localization of α-tocopherol transfer protein in rat brain. Neurosci Lett.  1998; 256: 159– 162. Google Scholar CrossRef Search ADS PubMed  27 Zimmer S, Stocker A, Sarbolouki MN, et al.   A novel human tocopherol-associated protein: cloning, in vitro expression, and characterization. J Biol Chem.  2000; 275: 25672– 25680. http://dx.doi.org/10.1074/jbc.M000851200 Google Scholar CrossRef Search ADS PubMed  28 Zingg JM, Kempna P, Paris M, et al.   Characterization of three human sec14p-like proteins: α-tocopherol transport activity and expression pattern in tissues. Biochimie . 2008; 90: 1703– 1715. Google Scholar CrossRef Search ADS PubMed  29 Yamauchi J, Iwamoto T, Kida S, et al.   Tocopherol-associated protein is a ligand-dependent transcriptional activator. Biochem Biophys Res Commun.  2001; 285: 295– 299. http://dx.doi.org/10.1006/bbrc.2001.5162 Google Scholar CrossRef Search ADS PubMed  30 Shibata N, Arita M, Misaki Y, et al.   Supernatant protein factor, which stimulates the conversion of squalene to lanosterol, is a cytosolic squalene transfer protein and enhances cholesterol biosynthesis. Proc Natl Acad Sci USA.  2001; 98: 2244– 2249. http://dx.doi.org/10.1073/pnas.041620398 Google Scholar CrossRef Search ADS   31 Panagabko C, Morley S, Hernandez M, et al.   Ligand specificity in the CRAL-TRIO protein family. Biochemistry . 2003; 42: 6467– 6474. http://dx.doi.org/10.1021/bi034086v Google Scholar CrossRef Search ADS PubMed  32 Traber MG, Elsner A, Brigelius-Flohé R. Synthetic as compared with natural vitamin E is preferentially excreted as α-CEHC in human urine: studies using deuterated α-tocopheryl acetates. FEBS Lett . 1998; 437: 145– 148. Google Scholar CrossRef Search ADS PubMed  33 Morris MC, Schneider JA, Li H, et al.   Brain tocopherols related to Alzheimer's disease neuropathology in humans. Alzheimers Dement . 2015; 11: 32– 39. http://dx.doi.org/10.1016/j.jalz.2013.12.015 Google Scholar CrossRef Search ADS PubMed  34 Ulatowski LM, Manor D. Vitamin E and neurodegeneration. Neurobiol Dis.  2015; 84: 78– 83. http://dx.doi.org/10.1016/j.nbd.2015.04.002 Google Scholar CrossRef Search ADS PubMed  35 Ulatowski L, Parker R, Warrier G, et al.   Vitamin E is essential for Purkinje neuron integrity. Neuroscience . 2014; 260: 120– 129. http://dx.doi.org/10.1016/j.neuroscience.2013.12.001 Google Scholar CrossRef Search ADS PubMed  36 Yokota T, Igarashi K, Uchihara T, et al.   Delayed-onset ataxia in mice lacking α-tocopherol transfer protein: model for neuronal degeneration caused by chronic oxidative stress. Proc Natl Acad Sci USA.  2001; 98: 15185– 15190. Google Scholar CrossRef Search ADS   37 Ouahchi K, Arita M, Kayden H, et al.   Ataxia with isolated vitamin E deficiency is caused by mutations in the α-tocopherol transfer protein. Nat Genet.  1995; 9: 141– 145. Google Scholar CrossRef Search ADS PubMed  38 Schuelke M, Mayatepek E, Inter M, et al.   Treatment of ataxia in isolated vitamin E deficiency caused by α-tocopherol transfer protein deficiency. J Pediatr.  1999; 134: 240– 244. Google Scholar CrossRef Search ADS PubMed  39 Morris MC, Evans DA, Bienias JL, et al.   Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA . 2002; 287: 3230– 3237. http://dx.doi.org/10.1001/jama.287.24.3230 Google Scholar CrossRef Search ADS PubMed  40 Lopes Da Silva S, Vellas B, Elemans S, et al.   Plasma nutrient status of patients with Alzheimer's disease: systematic review and meta-analysis. Alzheimers Dement . 2014; 10: 485– 502. http://dx.doi.org/10.1016/j.jalz.2013.05.1771 Google Scholar CrossRef Search ADS PubMed  41 Johnson EJ, Vishwanathan R, Johnson MA, et al.   Relationship between serum and brain carotenoids, α-tocopherol, and retinol concentrations and cognitive performance in the oldest old from the Georgia Centenarian Study. J Aging Res . 2013; 2013: 951786. doi:10.1155/2013/951786 Google Scholar CrossRef Search ADS PubMed  42 Ravaglia G, Forti P, Lucicesare A, et al.   Plasma tocopherols and risk of cognitive impairment in an elderly Italian cohort. Am J Clin Nutr.  2008; 87: 1306– 1313. Google Scholar PubMed  43 Mangialasche F, Solomon A, Kareholt I, et al.   Serum levels of vitamin E forms and risk of cognitive impairment in a Finnish cohort of older adults. Exp Gerontol . 2013; 48: 1428– 1435. http://dx.doi.org/10.1016/j.exger.2013.09.006 Google Scholar CrossRef Search ADS PubMed  44 Farina N, Llewellyn D, Isaac MGEKN, et al.   Vitamin E for Alzheimer's dementia and mild cognitive impairment. Cochrane Database Syst Rev . 2017; 4: CD002854. doi:10.1002/14651858.CD002854.pub5 Google Scholar PubMed  45 Zhao Y, Zhao B. Oxidative stress and the pathogenesis of Alzheimer's disease. Oxid Med Cell Longev.  2013; 2013: 316523. doi:10.1155/2013/316523 Google Scholar PubMed  46 Gohil K, Vasu VT, Cross CE. Dietary α-tocopherol and neuromuscular health: search for optimal dose and molecular mechanisms continues! Mol Nutr Food Res . 2010; 54: 693– 709. Google Scholar CrossRef Search ADS PubMed  47 Gohil K, Godzdanker R, O'Roark E, et al.   α-Tocopherol transfer protein deficiency in mice causes multi-organ deregulation of gene networks and behavioral deficits with age. Ann N Y Acad Sci.  2004; 1031: 109– 126. Google Scholar CrossRef Search ADS PubMed  48 Gohil K, Schock BC, Chakraborty AA, et al.   Gene expression profile of oxidant stress and neurodegeneration in transgenic mice deficient in alpha-tocopherol transfer protein. Free Radic Biol Med . 2003; 35: 1343– 1354. http://dx.doi.org/10.1016/S0891-5849(03)00509-4 Google Scholar CrossRef Search ADS PubMed  49 Rota C, Rimbach G, Minihane AM, et al.   Dietary vitamin E modulates differential gene expression in the rat hippocampus: potential implications for its neuroprotective properties. Nutr Neurosci . 2005; 8: 21– 29. http://dx.doi.org/10.1080/10284150400027123 Google Scholar CrossRef Search ADS PubMed  50 Pusterla N, Puschner B, Steidl S, et al.   α-Tocopherol concentrations in equine serum and cerebrospinal fluid after vitamin E supplementation. Vet Rec.  2010; 166: 366– 368. Google Scholar CrossRef Search ADS PubMed  51 Han SN, Pang E, Zingg JM, et al.   Differential effects of natural and synthetic vitamin E on gene transcription in murine T lymphocytes. Arch Biochem Biophys.  2010; 495: 49– 55. http://dx.doi.org/10.1016/j.abb.2009.12.015 Google Scholar CrossRef Search ADS PubMed  52 Horn MJ, Van Emon ML, Gunn PJ, et al.   Effects of maternal natural (RRR alpha-tocopherol acetate) or synthetic (all-rac alpha-tocopherol acetate) vitamin E supplementation on suckling calf performance, colostrum immunoglobulin G, and immune function. J Anim Sci.  2010; 88: 3128– 3135. http://dx.doi.org/10.2527/jas.2009-2035 Google Scholar CrossRef Search ADS PubMed  53 Amazan D, Cordero G, Lopez-Bote CJ, et al.   Effects of oral micellized natural vitamin E (D-α-tocopherol) v. synthetic vitamin E (DL-α-tocopherol) in feed on α-tocopherol levels, stereoisomer distribution, oxidative stress and the immune response in piglets. Animal.  2014; 8: 410– 419. Google Scholar CrossRef Search ADS PubMed  54 Reaven PD, Witztum JL. Comparison of supplementation of RRR-alpha-tocopherol and racemic alpha-tocopherol in humans. Effects on lipid levels and lipoprotein susceptibility to oxidation. Arterioscler Thromb Vasc Biol . 1993; 13: 601– 608. Google Scholar CrossRef Search ADS   55 Devaraj S, Adams-Huet B, Fuller CJ, et al.   Dose-response comparison of RRR-α-tocopherol and all-racemic α-tocopherol on LDL oxidation. Arterioscler Thromb Vasc Biol . 1997; 17: 2273– 2279. Google Scholar CrossRef Search ADS PubMed  56 Nakashima H, Ishihara T, Yokota O, et al.   Effects of alpha-tocopherol on an animal model of tauopathies. Free Radic Biol Med.  2004; 37: 176– 186. http://dx.doi.org/10.1016/j.freeradbiomed.2004.04.037 Google Scholar CrossRef Search ADS PubMed  57 Ambrogini P, Minelli A, Galati C, et al.   Post-seizure α-tocopherol treatment decreases neuroinflammation and neuronal degeneration induced by status epilepticus in rat hippocampus. Mol Neurobiol.  2014; 50: 246– 256. Google Scholar CrossRef Search ADS PubMed  58 Annahazi A, Mracsko E, Sule Z, et al.   Pre-treatment and post-treatment with alpha-tocopherol attenuates hippocampal neuronal damage in experimental cerebral hypoperfusion. Eur J Pharmacol . 2007; 571: 120– 128. http://dx.doi.org/10.1016/j.ejphar.2007.05.048 Google Scholar CrossRef Search ADS PubMed  59 Nishida Y, Ito S, Ohtsuki S, et al.   Depletion of vitamin E increases amyloid β accumulation by decreasing its clearances from brain and blood in a mouse model of Alzheimer disease. J Biol Chem.  2009; 284: 33400– 33408. Google Scholar CrossRef Search ADS PubMed  60 Nishida Y, Yokota T, Takahashi T, et al.   Deletion of vitamin E enhances phenotype of Alzheimer disease model mouse. Biochem Biophys Res Commun.  2006; 350: 530– 536. http://dx.doi.org/10.1016/j.bbrc.2006.09.083 Google Scholar CrossRef Search ADS PubMed  61 Gaedicke S, Zhang X, Huebbe P, et al.   Dietary vitamin E, brain redox status and expression of Alzheimer's disease–relevant genes in rats. Br J Nutr.  2009; 102: 398– 406. http://dx.doi.org/10.1017/S000711450819122X Google Scholar CrossRef Search ADS PubMed  62 Kang JH, Cook N, Manson J, et al.   A randomized trial of vitamin E supplementation and cognitive function in women. Arch Intern Med.  2006; 166: 2462– 2468. http://dx.doi.org/10.1001/archinte.166.22.2462 Google Scholar CrossRef Search ADS PubMed  63 Hayton SM, Kriss T, Wade A, et al.   Effects on neural function of repleting vitamin E–deficient rats with α-tocopherol. J Neurophysiol.  2006; 95: 2553– 2559. Google Scholar CrossRef Search ADS PubMed  64 Murray CA, Lynch MA. Dietary supplementation with vitamin E reverses the age-related deficit in long term potentiation in dentate gyrus. J Biol Chem.  1998; 273: 12161– 12168. http://dx.doi.org/10.1074/jbc.273.20.12161 Google Scholar CrossRef Search ADS PubMed  65 Huebbe P, Schaffer S, Jofre-Monseny L, et al.   Apolipoprotein E genotype and alpha-tocopherol modulate amyloid precursor protein metabolism and cell cycle regulation. Mol Nutr Food Res.  2007; 51: 1510– 1517. http://dx.doi.org/10.1002/mnfr.200700194 Google Scholar CrossRef Search ADS PubMed  66 Sano M, Ernesto C, Thomas RG, et al.   A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. N Engl J Med . 1997; 336: 1216– 1222. Google Scholar CrossRef Search ADS PubMed  67 Dysken MW, Sano M, Asthana S, et al.   Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA . 2014; 311: 33– 44. http://dx.doi.org/10.1001/jama.2013.282834 Google Scholar CrossRef Search ADS PubMed  68 Lim Y, Vasu V, Valacchi G, et al.   Severe vitamin E deficiency modulates airway allergic inflammatory responses in the murine asthma model. Free Radic Res.  2008; 42: 387– 396. http://dx.doi.org/10.1080/10715760801976600 Google Scholar CrossRef Search ADS PubMed  69 Marchese ME, Kumar R, Colangelo LA, et al.   The vitamin E isoforms α-tocopherol and γ-tocopherol have opposite associations with spirometric parameters: the CARDIA study. Respir Res.  2014; 15: 31. doi:10.1186/1465-9921-15-31 Google Scholar CrossRef Search ADS PubMed  70 Wu D, Meydani SN. Age-associated changes in immune and inflammatory responses: impact of vitamin E intervention. J Leukoc Biol.  2008; 84: 900– 914. http://dx.doi.org/10.1189/jlb.0108023 Google Scholar CrossRef Search ADS PubMed  71 Misso NL, Brooks-Wildhaber J, Ray S, et al.   Plasma concentrations of dietary and nondietary antioxidants are low in severe asthma. Eur Respir J . 2005; 26: 257– 264. http://dx.doi.org/10.1183/09031936.05.00006705 Google Scholar CrossRef Search ADS PubMed  72 Cook-Mills JM, Abdala-Valencia H, Hartert T. Two faces of vitamin E in the lung. Am J Respir Crit Care Med.  2013; 188: 279– 284. Google Scholar CrossRef Search ADS PubMed  73 Abdala-Valencia H, Berdnikovs S, Cook-Mills JM. Vitamin E isoforms differentially regulate intercellular adhesion molecule-1 activation of PKCα in human microvascular endothelial cells. PLoS One . 2012; 7:e41054. doi:10.1371/journal.pone.0041054 74 Vasu VT, Hobson B, Gohil K, et al.   Genome-wide screening of alpha-tocopherol sensitive genes in heart tissue from alpha-tocopherol transfer protein null mice (ATTP−/−). FEBS Lett.  2007; 581: 1572– 1578. Google Scholar CrossRef Search ADS PubMed  75 Azzi A, Gysin R, Kempna P, et al.   Regulation of gene expression by α-tocopherol. Biol Chem.  2004; 385: 585– 591. Google Scholar CrossRef Search ADS PubMed  76 Marko MG, Pang HJ, Ren Z, et al.   Vitamin E reverses impaired linker for activation of T cells activation in T cells from aged C57BL/6 mice. J Nutr.  2009; 139: 1192– 1197. http://dx.doi.org/10.3945/jn.108.103416 Google Scholar CrossRef Search ADS PubMed  77 Abdala-Valencia H, Berdnikovs S, Soveg FW, et al.   α-Tocopherol supplementation of allergic female mice inhibits development of CD11c+CD11b+ dendritic cells in utero and allergic inflammation in neonates. Am J Physiol Lung Cell Mol Physiol.  2014; 307: L482– L496. Google Scholar CrossRef Search ADS PubMed  78 Suchankova J, Voprsalova M, Kottova M, et al.   Effects of oral alpha-tocopherol on lung response in rat model of allergic asthma. Respirology.  2006; 11: 414– 421. http://dx.doi.org/10.1111/j.1440-1843.2006.00864.x Google Scholar CrossRef Search ADS PubMed  79 Hoskins A, Roberts JLII, Milne G, et al.   Natural source d-α-tocopheryl acetate inhibits oxidant stress and modulates atopic asthma in humans in vivo. Allergy . 2012; 67: 676– 682. Google Scholar CrossRef Search ADS PubMed  80 Pearson PJ, Lewis SA, Britton J, et al.   Vitamin E supplements in asthma: a parallel group randomised placebo controlled trial. Thorax . 2004; 59: 652– 656. http://dx.doi.org/10.1136/thx.2004.022616 Google Scholar CrossRef Search ADS PubMed  81 Han SN, Adolfsson O, Lee CK, et al.   Age and vitamin E-induced changes in gene expression profiles of T cells. J Immunol.  2006; 177: 6052– 6061. http://dx.doi.org/10.4049/jimmunol.177.9.6052 Google Scholar CrossRef Search ADS PubMed  82 Han SN, Wu D, Ha WK, et al.   Vitamin E supplementation increases T helper 1 cytokine production in old mice infected with influenza virus. Immunology . 2000; 100: 487– 493. http://dx.doi.org/10.1046/j.1365-2567.2000.00070.x Google Scholar CrossRef Search ADS PubMed  83 Oommen S, Vasu VT, Leonard SW, et al.   Genome wide responses of murine lungs to dietary α-tocopherol. Free Radic Res.  2007; 41: 98– 109. Google Scholar CrossRef Search ADS PubMed  84 Meydani SN, Barklund MP, Liu S, et al.   Vitamin E supplementation enhances cell-mediated immunity in healthy elderly subjects. Am J Clin Nutr.  1990; 52: 557– 563. Google Scholar CrossRef Search ADS PubMed  85 De la Fuente M, Hernanz A, Guayerbas N, et al.   Vitamin E ingestion improves several immune functions in elderly men and women. Free Radic Res.  2008; 42: 272– 280. http://dx.doi.org/10.1080/10715760801898838 Google Scholar CrossRef Search ADS PubMed  86 Meydani SN, Meydani M, Blumberg JB, et al.   Vitamin E supplementation and in vivo immune response in healthy elderly subjects. A randomized controlled trial. JAMA . 1997; 277: 1380– 1386. http://dx.doi.org/10.1001/jama.1997.03540410058031 Google Scholar CrossRef Search ADS PubMed  87 Lee CY, Man-Fan Wan J. Vitamin E supplementation improves cell-mediated immunity and oxidative stress of Asian men and women. J Nutr.  2000; 130: 2932– 2937. Google Scholar CrossRef Search ADS PubMed  88 Rautalahti M, Virtamo J, Haukka J, et al.   The effect of alpha-tocopherol and beta-carotene supplementation on COPD symptoms. Am J Respir Crit Care Med.  1997; 156: 1447– 1452. http://dx.doi.org/10.1164/ajrccm.156.5.96-11048 Google Scholar CrossRef Search ADS PubMed  89 Traber MG. Does vitamin E decrease heart attack risk? Summary and implications with respect to dietary recommendations. J Nutr.  2001; 131: 395S– 397S. Google Scholar CrossRef Search ADS PubMed  90 Steinberg D, Parthasarathy S, Carew TE, et al.   Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med.  1989; 320: 915– 924. Google Scholar CrossRef Search ADS PubMed  91 Stampfer MJ, Hennekens CH, Manson JE, et al.   Vitamin E consumption and the risk of coronary disease in women. N Engl J Med.  1993; 328: 1444– 1449. http://dx.doi.org/10.1056/NEJM199305203282003 Google Scholar CrossRef Search ADS PubMed  92 Rimm EB, Stampfer MJ, Ascherio A, et al.   Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med.  1993; 328: 1450– 1456. http://dx.doi.org/10.1056/NEJM199305203282004 Google Scholar CrossRef Search ADS PubMed  93 Gey KF, Puska P, Jordan P, et al.   Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Am J Clin Nutr . 1991; 53(1 suppl): 326S– 334S. Google Scholar CrossRef Search ADS   94 Terasawa Y, Ladha Z, Leonard SW, et al.   Increased atherosclerosis in hyperlipidemic mice deficient in α-tocopherol transfer protein and vitamin E. Proc Natl Acad Sci USA.  2000; 97: 13830– 13834. Google Scholar CrossRef Search ADS   95 Tasinato A, Boscoboinik D, Bartoli GM, et al.   D-α-tocopherol inhibition of vascular smooth muscle cell proliferation occurs at physiological concentrations, correlates with protein kinase C inhibition, and is independent of its antioxidant properties. Proc Natl Acad Sci USA.  1995; 92: 12190– 12194. Google Scholar CrossRef Search ADS   96 Boscoboinik D, Szewczyk A, Azzi A. α-Tocopherol (vitamin E) regulates vascular smooth muscle cell proliferation and protein kinase C activity. Arch Biochem Biophys.  1991; 286: 264– 269. Google Scholar CrossRef Search ADS PubMed  97 Freedman JE, Farhat JH, Loscalzo J, et al.   α-Tocopherol inhibits aggregation of human platelets by a protein kinase C–dependent mechanism. Circulation . 1996; 94: 2434– 2440. Google Scholar CrossRef Search ADS PubMed  98 Steiner M. Effect of alpha-tocopherol administration on platelet function in man. Thromb Haemost.  1983; 49: 73– 77. Google Scholar PubMed  99 Salonen JT, Salonen R, Seppanen K, et al.   Effects of antioxidant supplementation on platelet function: a randomized pair-matched, placebo-controlled, double-blind trial in men with low antioxidant status. Am J Clin Nutr.  1991; 53: 1222– 1229. Google Scholar CrossRef Search ADS PubMed  100 Devaraj S, Li D, Jialal I. The effects of alpha tocopherol supplementation on monocyte function. Decreased lipid oxidation, interleukin 1 beta secretion, and monocyte adhesion to endothelium. J Clin Invest.  1996; 98: 756– 763. Google Scholar CrossRef Search ADS PubMed  101 Joris PJ, Mensink RP. Effects of supplementation with the fat-soluble vitamins E and D on fasting flow-mediated vasodilation in adults: a meta-analysis of randomized controlled trials. Nutrients . 2015; 7: 1728– 1743. http://dx.doi.org/10.3390/nu7031728 Google Scholar CrossRef Search ADS PubMed  102 Bin Q, Hu X, Cao Y, et al.   The role of vitamin E (tocopherol) supplementation in the prevention of stroke: a meta-analysis of 13 randomised controlled trials. Thromb Haemost.  2011; 105: 579– 585. http://dx.doi.org/10.1160/TH10-11-0729 Google Scholar CrossRef Search ADS PubMed  103 Thomas SR, Leichtweis SB, Pettersson K, et al.   Dietary cosupplementation with vitamin E and coenzyme Q10 inhibits atherosclerosis in apolipoprotein E gene knockout mice. Arterioscler Thromb Vasc Biol.  2001; 21: 585– 593. http://dx.doi.org/10.1161/01.ATV.21.4.585 Google Scholar CrossRef Search ADS PubMed  104 Jandak J, Steiner M, Richardson PD. Alpha-tocopherol, an effective inhibitor of platelet adhesion. Blood . 1989; 73: 141– 149. Google Scholar PubMed  105 Steiner M, Glantz M, Lekos A. Vitamin E plus aspirin compared with aspirin alone in patients with transient ischemic attacks. Am J Clin Nutr.  1995; 62(6 suppl): 1381S– 1384S. Google Scholar CrossRef Search ADS   106 Stephens NG, Parsons A, Schofield PM, et al.   Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet.  1996; 347: 781– 786. http://dx.doi.org/10.1016/S0140-6736(96)90866-1 Google Scholar CrossRef Search ADS PubMed  107 Boaz M, Smetana S, Weinstein T, et al.   Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet.  2000; 356: 1213– 1218. http://dx.doi.org/10.1016/S0140-6736(00)02783-5 Google Scholar CrossRef Search ADS PubMed  108 Yusuf S, Dagenais G, Pogue J, et al.   Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med . 2000; 342: 154– 160. http://dx.doi.org/10.1056/NEJM200001203420302 Google Scholar CrossRef Search ADS PubMed  109 Chae CU, Albert CM, Moorthy MV, et al.   Vitamin E supplementation and the risk of heart failure in women. Circ Heart Fail.  2012; 5: 176– 182. http://dx.doi.org/10.1161/CIRCHEARTFAILURE.111.963793 Google Scholar CrossRef Search ADS PubMed  110 Lee IM, Cook NR, Gaziano JM, et al.   Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA . 2005; 294: 56– 65. http://dx.doi.org/10.1001/jama.294.1.56 Google Scholar CrossRef Search ADS PubMed  111 Meydani M, Kwan P, Band M, et al.   Long-term vitamin E supplementation reduces atherosclerosis and mortality in Ldlr−/− mice, but not when fed Western style diet. Atherosclerosis . 2014; 233: 196– 205. Google Scholar CrossRef Search ADS PubMed  112 Virtamo J, Rapola JM, Ripatti S, et al.   Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease. Arch Intern Med.  1998; 158: 668– 675. http://dx.doi.org/10.1001/archinte.158.6.668 Google Scholar CrossRef Search ADS PubMed  113 GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet . 1999; 354: 447– 455. http://dx.doi.org/10.1016/S0140-6736(99)07072-5 CrossRef Search ADS PubMed  114 Rapola JM, Virtamo J, Haukka JK, et al.   Effect of vitamin E and beta carotene on the incidence of angina pectoris. A randomized, double-blind, controlled trial. JAMA . 1996; 275: 693– 698. http://dx.doi.org/10.1001/jama.1996.03530330037026 Google Scholar CrossRef Search ADS PubMed  115 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet . 2002; 360: 23– 33. CrossRef Search ADS PubMed  116 Sesso HD, Buring JE, Christen WG, et al.   Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. JAMA . 2008; 300: 2123– 2133. http://dx.doi.org/10.1001/jama.2008.600 Google Scholar CrossRef Search ADS PubMed  117 Hodis HN, Mack WJ, LaBree L, et al.   Alpha-tocopherol supplementation in healthy individuals reduces low-density lipoprotein oxidation but not atherosclerosis: the Vitamin E Atherosclerosis Prevention Study (VEAPS). Circulation . 2002; 106: 1453– 1459. http://dx.doi.org/10.1161/01.CIR.0000029092.99946.08 Google Scholar CrossRef Search ADS PubMed  118 Suarna C, Wu BJ, Choy K, et al.   Protective effect of vitamin E supplements on experimental atherosclerosis is modest and depends on preexisting vitamin E deficiency. Free Radic Biol Med.  2006; 41: 722– 730. http://dx.doi.org/10.1016/j.freeradbiomed.2006.05.013 Google Scholar CrossRef Search ADS PubMed  119 Pratico D, Tangirala RK, Rader DJ, et al.   Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice. Nat Med.  1998; 4: 1189– 1192. http://dx.doi.org/10.1038/2685 Google Scholar CrossRef Search ADS PubMed  120 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell . 2011; 144: 646– 674. http://dx.doi.org/10.1016/j.cell.2011.02.013 Google Scholar CrossRef Search ADS PubMed  121 Klaunig JE, Kamendulis LM, Hocevar BA. Oxidative stress and oxidative damage in carcinogenesis. Toxicol Pathol.  2010; 38: 96– 109. http://dx.doi.org/10.1177/0192623309356453 Google Scholar CrossRef Search ADS PubMed  122 Prieme H, Loft S, Nyyssonen K, et al.   No effect of supplementation with vitamin E, ascorbic acid, or coenzyme Q10 on oxidative DNA damage estimated by 8-oxo-7,8-dihydro-2'-deoxyguanosine excretion in smokers. Am J Clin Nutr.  1997; 65: 503– 507. Google Scholar CrossRef Search ADS PubMed  123 Retana-Ugalde R, Casanueva E, Altamirano-Lozano M, et al.   High dosage of ascorbic acid and alpha-tocopherol is not useful for diminishing oxidative stress and DNA damage in healthy elderly adults. Ann Nutr Metab.  2008; 52: 167– 173. Google Scholar CrossRef Search ADS PubMed  124 Negis Y, Zingg JM, Libinaki R, et al.   Vitamin E and cancer. Nutr Cancer.  2009; 61: 875– 878. http://dx.doi.org/10.1080/01635580903285197 Google Scholar CrossRef Search ADS PubMed  125 Schindler R, Mentlein R. Flavonoids and vitamin E reduce the release of the angiogenic peptide vascular endothelial growth factor from human tumor cells. J Nutr . 2006; 136: 1477– 1482. Google Scholar CrossRef Search ADS PubMed  126 Ju J, Picinich SC, Yang Z, et al.   Cancer-preventive activities of tocopherols and tocotrienols. Carcinogenesis . 2010; 31: 533– 542. http://dx.doi.org/10.1093/carcin/bgp205 Google Scholar CrossRef Search ADS PubMed  127 Wright ME, Weinstein SJ, Lawson KA, et al.   Supplemental and dietary vitamin E intakes and risk of prostate cancer in a large prospective study. Cancer Epidemiol Biomarkers Prev . 2007; 16: 1128– 1135. http://dx.doi.org/10.1158/1055-9965.EPI-06-1071 Google Scholar CrossRef Search ADS PubMed  128 Rodriguez C, Jacobs EJ, Mondul AM, et al.   Vitamin E supplements and risk of prostate cancer in U.S. men. Cancer Epidemiol Biomarkers Prev . 2004; 13: 378– 382. Google Scholar PubMed  129 Kirsh VA, Hayes RB, Mayne ST, et al.   Supplemental and dietary vitamin E, β-carotene, and vitamin C intakes and prostate cancer risk. J Natl Cancer Inst.  2006; 98: 245– 254. Google Scholar CrossRef Search ADS PubMed  130 Bravi F, Polesel J, Bosetti C, et al.   Dietary intake of selected micronutrients and the risk of pancreatic cancer: an Italian case–control study. Ann Oncol.  2011; 22: 202– 206. http://dx.doi.org/10.1093/annonc/mdq302 Google Scholar CrossRef Search ADS PubMed  131 Bostick RM, Potter JD, Mckenzie DR, et al.   Reduced risk of colon cancer with high intake of vitamin E—the Iowa Women’s Health Study. Cancer Res.  1993; 53: 4230– 4237. Google Scholar PubMed  132 Jacobs EJ, Henion AK, Briggs PJ, et al.   Vitamin C and vitamin E supplement use and bladder cancer mortality in a large cohort of US men and women. Am J Epidemiol . 2002; 156: 1002– 1010. http://dx.doi.org/10.1093/aje/kwf147 Google Scholar CrossRef Search ADS PubMed  133 Key TJ, Appleby PN, Travis RC, et al.   Carotenoids, retinol, tocopherols, and prostate cancer risk: pooled analysis of 15 studies. Am J Clin Nutr.  2015; 102: 1142– 1157. http://dx.doi.org/10.3945/ajcn.115.114306 Google Scholar CrossRef Search ADS PubMed  134 Wu K, Willett WC, Chan JM, et al.   A prospective study on supplemental vitamin E intake and risk of colon cancer in women and men. Cancer Epidemiol Biomarkers Prev . 2002; 11: 1298– 1304. Google Scholar PubMed  135 Jacobs EJ, Connell CJ, Patel AV, et al.   Vitamin C and vitamin E supplement use and colorectal cancer mortality in a large American Cancer Society cohort. Cancer Epidemiol Biomarkers Prev . 2001; 10: 17– 23. Google Scholar PubMed  136 Jacobs EJ, Connell CJ, McCullough ML, et al.   Vitamin C, vitamin E, and multivitamin supplement use and stomach cancer mortality in the Cancer Prevention Study II cohort. Cancer Epidemiol Biomarkers Prev . 2002; 11: 35– 41. Google Scholar PubMed  137 Lonn E, Bosch J, Yusuf S, et al.   Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA . 2005; 293: 1338– 1347. http://dx.doi.org/10.1001/jama.293.11.1338 Google Scholar CrossRef Search ADS PubMed  138 Greenberg ER, Baron JA, Tosteson TD, et al.   A clinical trial of antioxidant vitamins to prevent colorectal adenoma. Polyp Prevention Study Group. N Engl J Med.  1994; 331: 141– 147. Google Scholar CrossRef Search ADS PubMed  139 Albanes D, Heinonen OP, Huttunen JK, et al.   Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. Am J Clin Nutr . 1995; 62(6 suppl): 1427S– 1430S. Google Scholar CrossRef Search ADS   140 Heinonen OP, Albanes D, Virtamo J, et al.   Prostate cancer and supplementation with α-tocopherol and β-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst.  1998; 90: 440– 446. Google Scholar CrossRef Search ADS PubMed  141 Lippman SM, Klein EA, Goodman PJ, et al.   Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). J Urol . 2009; 181: 1686– 1687. Google Scholar CrossRef Search ADS   142 Gaziano JM, Glynn RJ, Christen WG, et al.   Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians' Health Study II randomized controlled trial. JAMA . 2009; 301: 52– 62. http://dx.doi.org/10.1001/jama.2008.862 Google Scholar CrossRef Search ADS PubMed  143 Lavine JE, Schwimmer JB, Van Natta ML, et al.   Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA . 2011; 305: 1659– 1668. http://dx.doi.org/10.1001/jama.2011.520 Google Scholar CrossRef Search ADS PubMed  144 Traber MG, Mah E, Leonard SW, et al.   Metabolic syndrome increases dietary α-tocopherol requirements as assessed using urinary and plasma vitamin E catabolites: a double-blind, crossover clinical trial. Am J Clin Nutr.  2017; 105: 571– 579. Google Scholar CrossRef Search ADS PubMed  145 Christen WG, Glynn RJ, Chew EY, et al.   Vitamin E and age-related macular degeneration in a randomized trial of women. Ophthalmology . 2010; 117: 1163– 1168. http://dx.doi.org/10.1016/j.ophtha.2009.10.043 Google Scholar CrossRef Search ADS PubMed  146 Chong EW, Wong TY, Kreis AJ, et al.   Dietary antioxidants and primary prevention of age related macular degeneration: systematic review and meta-analysis. BMJ.  2007; 335: 755. doi: 10.1136/bmj.39350.500428.47 Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

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Nutrition ReviewsOxford University Press

Published: Mar 1, 2018

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