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Olive-oil Phenolics and Health: Potential Biological Properties

Olive-oil Phenolics and Health: Potential Biological Properties NPC Natural Product Communications Vol. 3 No. 12 2085 - 2088 a* b b b Francesco Visioli , Francesca Ieri , Nadia Mulinacci , Franco F. Vincieri and Annalisa Romani Laboratory of “Micronutrients and Cardiovascular Disease”, UMR7079, UPMC University of Paris 06, Paris, France Department of Pharmaceutical Science, University of Florence, 50019 Sesto F.no, Florence, Italy [email protected] th th Received: September 15 , 2008; Accepted: October 29 , 2008 Extra virgin olive oil, the primary source of oil in the Mediterranean diet, differs significantly in composition from dietary lipids that are consumed by other populations. The several minor constituents of virgin olive oil include vitamins such as alpha- and gamma-tocopherols (around 200 ppm) and beta-carotene, phytosterols, pigments, terpenic acids, flavonoids, squalene, and a number of phenolic compounds, such as hydroxytyrosol, usually grouped under the rubric “polyphenols”. The antioxidant and enzyme-modulating activities of extra virgin olive oil phenolics, such as their ability to inhibit NF-kB activation in human monocyte/macrophages has been demonstrated in vitro. There is also solid evidence that extra virgin olive oil phenolic compounds are absorbed and their human metabolism has been elucidated. Several activities that might be associated with cardiovascular protection, such as inhibition of platelet aggregation and reduction of plasma rHcy have been demonstrated in vivo. The biologically relevant properties of olive phenolics are described, although further investigations in controlled clinical trials are needed to support the hypothesis that virgin olive oil consumption may contribute to lower cardiovascular mortality. Keywords: extravirgin olive oil, phenolic compounds, Mediterranean diet, hydroxytyrosol. Numerous epidemiological studies have shown that Epidemiological studies: From a nutritional point of the incidence of coronary heart disease (CHD) and view, the choice of a phenol-rich olive oil contributes certain cancers, for example breast and colon cancers, to the dietary intake of biologically-active is lowest in the Mediterranean basin [1]. It has been compounds in quantities that have been correlated suggested that this is largely due to the protective with a reduced risk of developing CHD [4]. Indeed, dietary habits of this area [1,2]. The traditional the use of extra-virgin olive oil as the principle Mediterranean diet, rich in fruit, vegetables, fish, source of dietary oil instead of animal fat, in addition and whole grain, is thought to promote good to providing a considerable amount of oleic acid, health and longevity. Olive oil, the primary oil provides an intake of bioactive compounds with source of this diet, differs significantly in potential healthful effects, as described above. It also composition from dietary lipids that are consumed by appears that the intake and interaction of several other populations. The formulation of an "micronutrients" provided by a healthy diet, such as antioxidant/atherosclerosis hypothesis stimulated that in use in the Mediterranean area during the mid- experimental and epidemiological studies on the 1940s, is likely to be the link that affords protection possible role of antioxidants, including olive oil from such pathologies [5]. In turn, the answer to the phenolics, in the protection from CHD observed in current debate on the efficacy of antioxidant the Mediterranean area. Included among the minor supplements is likely to be found in the adoption of a constituents of virgin olive oil are vitamins such as α- Mediterranean-style diet, in which the abundance of and γ-tocopherols (around 200 ppm) and β-carotene, bioactive, functional compounds provided by fruits, phytosterols, pigments, terpenic acids, flavonoids, vegetables, wine, and olive oil grants a higher squalene, and a number of phenolic compounds, protection toward reactive oxygen species (ROS)- usually grouped under the rubric “polyphenols” [3]. induced diseases. 2086 Natural Product Communications Vol. 3 (12) 2008 Visioli et al. In vitro studies: The lower incidence of CHD μM) and are 40-fold weaker than those of the widely- observed in the Mediterranean area [1] lead to the employed reducing agent ascorbate [13]. hypothesis that olive oil phenolics exert a protective Interestingly, two human intervention studies [14,15] effect with respect to chemically-induced oxidation confirmed these data in vivo, indicating that extra of human LDL, which is one of the initial steps in the virgin olive oil might decrease DNA damage, hence onset of atherosclerosis [6]. lessening cancer risk. Results obtained on human LDL demonstrate that Oleuropein increases the functional activity of catechol-like compounds present in virgin olive oil immune-competent cells (macrophages), as inhibit the formation of lipid oxidation products in a demonstrated by a significant increase (58.7 ± 4.6%) dose dependent manner and are effective at a in the lipopolysaccharide (LPS)-induced production concentration lower than that of pure tyrosol, a of nitric oxide, a bactericidal and cytostatic agent phenolic component of the oil, and of probucol, used [10a]. This increase is consequent to a direct tonic as reference compounds. This effect is probably due effect of oleuropein on the inducible form of the to the synergistic action of hydroxytyrosol, enzyme nitric oxide synthase (iNOS), as oleuropein aglycones, and some flavonoids, such as demonstrated by Western blot analysis of cell quercetin, luteolin, and apigenin present in the virgin homogenates and by coincubation of LPS-challenged olive oil extract in minute amounts. In addition, cells with the iNOS inhibitor L-nitromethylarginine changes in electrophoretic mobility of apo B are also methylester [10b]. prevented by the phenols. A correlation between inflammation and Pure hydroxytyrosol (HT) and oleuropein (OE) both cardiovascular diseases has long been established; potently and dose-dependently inhibit copper sulfate- monocyte/macrophages and NF-κB play a pivotal -6 induced oxidation of LDL at concentrations of 10 to role. The effects of an extra-virgin olive oil extract, -4 10 M [7,8]. The free radical scavenging activities of particularly rich in phenolic compounds, were hydroxytyrosol and oleuropein have been further investigated on NF-κB translocation in monocytes confirmed [8,9] by the use of metal-independent and monocyte-derived macrophages (MDM) isolated oxidative systems and stable free radicals, such as from healthy volunteers. In a concentration- DPPH [10a], in a series of experiments that dependent manner, the extra-virgin olive oil extract demonstrated both a strong metal-chelation and a inhibited p50 and p65 NF-kB translocation in both free-radical scavenging action. As far as the unstimulated and phorbol-myristate acetate (PMA)- mechanism of action of olive oil phenolics is challenged cells, being particularly effective on the concerned, it is well-known that the antioxidant p50 subunit. Interestingly, this effect occurred at properties of o-diphenols are related to hydrogen- concentrations found in human plasma after donation, which is their ability to improve radical nutritional ingestion of virgin olive oil and was stability by forming an intramolecular hydrogen bond quantitatively similar to that exerted by ciglitazone, a between the free hydrogens of their hydroxyl group PPAR-γ ligand. However, the extra-virgin olive oil and their phenoxyl radicals [10b]. Although specific extract did not affect PPAR-γ expression in investigations of olive oil phenols are yet to be monocytes and MDM. These data provide further carried out, studies performed on the structure- evidence of the beneficial effects of extra-virgin olive activity relationship of flavonoids indicated that the oil by indicating its ability to inhibit NF-κB degree of antioxidant activity is strictly related to the activation in human monocyte/macrophages [16]. number of hydroxyl substitutions [11]. In vivo studies: Experimental evidence that The mutagenic properties of oxidatively-damaged phenolic compounds of different origin are absorbed DNA suggest that antioxidants might have protective from the diet is accumulating. Animal studies in rats activity toward tumor formation. Low concentrations and rabbits demonstrated that LDL isolated from of hydroxytyrosol (50 μM) are able to scavenge animals fed virgin olive oil exhibit a higher resistance peroxynitrite and therefore prevent ONOO - to oxidation when compared with animals given a dependent DNA damage and tyrosine nitration triglyceride preparation with an equivalent amount of [12,13]; also, in a model of copper-induced DNA oleic acid, i.e. triolein [17], or «plain» olive oil [18]. damage, the prooxidant activities of hydroxytyrosol We demonstrated that olive oil phenolics are dose- (due to its copper-reducing properties) become dependently absorbed in humans and that they are evident at non-physiological concentrations (>500 excreted in the urine, mainly as glucuronide Biological significance of virgin olive oil Natural Product Communications Vol. 3 (12) 2008 2087 conjugates; it is noteworthy that increasing amounts The effect of EVOO on platelet aggregation and of phenolics administered with olive oil stimulated plasma concentrations of homocysteine (Hcy) redox the rate of conjugation with glucuronide [18]. These forms, in relation to the phenolic compounds’ data add to the growing experimental evidence that concentration, was also investigated in rats. Three indicates absorption and urinary disposition of olive oil samples with similar fatty acid, but different flavonoids in humans [19]. phenolic compound concentrations were used: refined olive oil (RF) with traces of phenolic It is noteworthy that HT exists in the brain as an compounds (control oil), native extra virgin olive oil endogenous catabolite of catecholic neurotrans- with low phenolic compounds concentration (LC), mitters, such as dopamine and norepinephrine [20], and extra virgin olive oil with high phenolic but its presence in urine has never, until recently, compounds concentration (HC) enriching LC with its been described. On the other hand, the formation of own phenolic compounds. Oil samples were homovanillic alcohol (HVAlc), the O-methylated administered to rats by gavage (1.25 mL/kg body derivative of HT, was reported by Manna et al [21] in weight) using two experimental designs: acute (24 h human Caco-2 cell incubated with HT. We also food deprivation and killed 1 h after oil reported the urinary excretion of HVAlc, in large administration) and subacute (12 d treatment, a daily excess over its basal excretion (57 ± 3 µg excreted in dose of oil for 12 d, and killed after 24 h of food 24 hours, means ± SD, n= 6). We also described the deprivation). substrate-induced enhancement of HVA formation, also a product of catecholamines metabolism, in Platelet aggregation was induced by ADP (ex vivo addition to its basal urinary excretion (1660 ± 350 µg tests) and a reduction in platelet reactivity occurred in excreted in 24 hours, means ± SD, n= 6). Indeed, the cells from rats given LC in the subacute study and in results reported suggest that HT increases the basal cells from rats administered HC in both studies, as excretion of HVA, even at the low doses of phenols indicated by an increase in the agonist half maximal administered. Future investigations will adopt effective concentration. HC inhibited platelet commercially available virgin olive oils, thus aggregation induced by low ADP doses (reversible allowing the further elucidation of the in vivo kinetics aggregation) in cells of rats in both the acute and of olive oil phenolics in habitual consumption subacute studies, whereas LC had this effect only in quantities. the subacute experiment. Moreover, in rats administered HC in both experiments, the plasma In terms of biological activities, Covas et al. recently concentration of free reduced Hcy (rHcy) was lower reviewed approximately 15 human intervention and Hcy bound to protein by disulfide bonds (bHcy) studies, the vast majority of which indicate that extra was greater than in RF-treated rats. bHcy was also virgin olive oil (rich in phenols) is superior to seed greater in rats given LC than in RF-treated rats in the oils and olive oil devoid of phenols in modulating subacute experiment. Plasma free-oxidized Hcy was selected surrogate markers of cardiovascular disease greater in rats given LC and HC than in those [22]. One example is an investigation of the effects of administered RF only in the subacute experiment. olive oil phenols on post prandial events. Bogani et These results show that phenolic compounds in al. evaluated the effects of moderate, real life doses EVOO inhibit platelet aggregation and reduce the of two olive oils, differing only in their phenolic plasma rHcy concentration, effects that may be content, on some in vivo indexes of oxidative stress associated with cardiovascular protection [24]. (plasma antioxidant capacity and urinary hydrogen peroxide levels) in a post prandial setting. Moreover, In conclusion, the biologically relevant properties of the authors assessed whether phenolic compounds olive phenolics described in this article, although still influence a few arachidonic acid metabolites to be further investigated in other controlled clinical involved in the atherosclerotic processes, such as trials, provide evidence to support the hypothesis that leukotriene B (LTB ) and thromboxane B (TXB ). virgin olive oil consumption may contribute to lower 4 4 2 2 Six subjects in each group received the three oils [30 CHD mortality. mL/day of olive oil (OO), corn oil (CO), or extra Acknowledgement – This paper celebrates Professor virgin olive oil (EVOO), distributed among meals] in Vincieri’s birthday. We wish to acknowledge his a Latin square design. The results demonstrate that important contributions to the field. EVOO is capable of reducing the post prandial events that associate with inflammation and oxidative stress [23]. 2088 Natural Product Communications Vol. 3 (12) 2008 Visioli et al. References [1] Keys A. (1995) Mediterranean diet and public health: personal reflections. American Journal of Clinical Nutrition, 61, 1321S-1323S. [2] Hertog MG, Kromhout D, Aravanis C, Blackburn H, Buzina F, Fidanza F, Giampaoli S, Jansen A, Menotti A, Nedeljkovic S, Pekkarinen M, Simic BS, Toshima H, Feskens EJM, Hollman PCH, Katan MB. (1995) Flavonoid intake and long-term risk of coronary heart disease and cancer in the Seven Countries Study [published erratum appears in Archives of Internal Medicine, 155, 1184]. Archives of Internal Medicine, 155, 381-386. nd [3] Boskou D. (2006) Olive oil: Chemistry and Technology. 2 Edition. AOCS Press, Urbana, IL, USA. [4] Hertog MLG, Feskens EJM, Katan MB, Kromhout D. (1993) Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet, 342, 1007-1011. [5] Visioli F, Hagen TM. (2007) Nutritional strategies for healthy cardiovascular aging: focus on micronutrients. Pharmacological Research 55, 199-206. [6] Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witzum JL. (1989) Beyond cholesterol. Modifications of low-density lipoprotein that increases its atherogenicity. New England Journal of Medicine, 320, 915-924. [7] Visioli F, Bellomo G, Montedoro G, Galli C. (1995) Low density lipoprotein oxidation is inhibited in vitro by olive oil constituents. Atherosclerosis, 117, 25-32. [8] Visioli F, Vincieri FF, Galli C. (1995) 'Waste waters' from olive oil production are rich in natural antioxidants. Experientia, 51, 32-34 [9] Aruoma OI, Deiana M, Jenner A, Halliwell B, Harparkash K, Banni S, Corongiu F, Dessi MA, Aeschbach R. (1998) Effect of hydroxytyrosol found in extra virgin olive oil on oxidative DNA damage and on low-density lipoprotein oxidation. Journal of Agricultural and Food Chemistry, 46, 5181-5187. [10] (a) Visioli F, Galli C. (1998) Olive oil polyphenols and their potential effects on human health. Journal of Agricultural and Food Chemistry, 46, 4292-4296; (b) Visioli F, Galli C. (1998) The effect of minor constituents of olive oil on cardiovascular disease: new findings. Nutrition Reviews, 56, 142-147. [11] Rice-Evans CA, Miller NJ, Paganga G. (1996) Structure-antioxidant activity relationship of flavonoids and phenolic acids. Free Radical Biology and Medicine, 20, 933-956. [12] Aruoma OI, Halliwell B. (1987) Action of hypochlorous acid on the antioxidant protective enzymes superoxide dismutase, catalase and glutathione peroxidase. Biochemical Journal, 248, 973-976. [13] Deiana M, Aruoma OI, Bianchi MLP, Spencer JPE, Kaur H, Halliwell B, Aeschbach R, Banni S, Dessi MA, Corongiu F. (1999) Inhibition of peroxynitrite dependent DNA base modification and tyrosine nitration by the extra virgin olive oil-derived antioxidant hydroxytyrosol. Free Radical Biology and Medicine, 26, 762-769. [14] Weinbrenner T, Fitó M, de la Torre R, Saez GT, Rijken P, Tormos C, Coolen S, Albaladejo MF, Abanades S, Schroder H, Marrugat J, Covas MI. (2004) Olive oils high in phenolic compounds modulate oxidative/antioxidative status in men. Journal of Nutrition, 134, 2314-2321. [15] Salvini S, Sera F, Caruso D, Giovannelli L, Visioli F, Saieva C, Masala G, Ceroti M, Giovacchini V, Pitozzi V, Galli C, Romani A, Mulinacci N, Bortolomeazzi R, Dolara P, Palli D. (2006) Daily consumption of a high-phenol extra-virgin olive oil reduces oxidative DNA damage in postmenopausal women. British Journal of Nutrition, 95, 742-751. [16] Brunelleschi S, Bardelli C, Amoruso A, Gunella G, Ieri F, Romani A, Malorni W, Franconi F. (2007) Minor polar compounds extra-virgin olive oil extract (MPC-OOE) inhibits NF-kappaB translocation in human monocyte/macrophages. Pharmacological Research, 56, 542-549. [17] Scaccini C, Nardini M, D'Aquino M, Gentili V, Di Felice M, Tomassi G. (1992) Effect of dietary oils on lipid peroxidation and on antioxidant parameters of rat plasma and lipoprotein fractions. Journal of Lipid Research, 33, 627-633. [18] Visioli F, Galli C, Bornet F, Mattei A, Galli G, Caruso D. (2000) Olive oil phenols are dose-dependently absorbed in humans. FEBS Letters, 468, 159-160. [19] Wiseman SA, Mathot JN, de Fouw NJ, Tijburg LB. (1996) Dietary non-tocopherol antioxidants present in extra virgin olive oil increase the resistance of low density lipoproteins to oxidation in rabbits. Atherosclerosis, 120, 15-23. [20] Lamensdorf I, Eisenhofer G, White HJ, Hayakawa Y, Kirk K, Kopin IY. (2000) Metabolic stress in PC12 cells induces the formation of the endogenous dopaminergic neurotoxin, 3,4-dihydroxyphenylacetaldehyde. Journal of Neuroscience Research, 60, 552-556. [21] Manna C, Galletti C, Maisto G, Cucciolla V, D’Angelo S, Zappia V. (2000) Transport mechanism and metabolism of olive oil 3,4- dihydroxyphenylethanol in CACO-2 cells. FEBS Letters, 470, 341-344. [22] Covas MI. (2007) Olive oil and the cardiovascular system. Pharmacological Research, 55, 175-186. [23] Bogani P, Galli C, Villa M, Visioli F. (2007) Postprandial anti-inflammatory and antioxidant effects of extra virgin olive oil. Atherosclerosis, 190, 181-186. [24] Priora R, Summa D, Frosali S, Margaritis A, Di Giuseppe D, Lapucci C, Ieri F, Pulcinelli FM, Romani A, Franconi F, Di Simplicio P. (2008) Administration of minor polar compound-enriched extra virgin olive oil decreases platelet aggregation and the plasma concentration of reduced homocysteine in rats. Journal of Nutrition, 138, 36-41. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Natural Product Communications SAGE

Olive-oil Phenolics and Health: Potential Biological Properties

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Abstract

NPC Natural Product Communications Vol. 3 No. 12 2085 - 2088 a* b b b Francesco Visioli , Francesca Ieri , Nadia Mulinacci , Franco F. Vincieri and Annalisa Romani Laboratory of “Micronutrients and Cardiovascular Disease”, UMR7079, UPMC University of Paris 06, Paris, France Department of Pharmaceutical Science, University of Florence, 50019 Sesto F.no, Florence, Italy [email protected] th th Received: September 15 , 2008; Accepted: October 29 , 2008 Extra virgin olive oil, the primary source of oil in the Mediterranean diet, differs significantly in composition from dietary lipids that are consumed by other populations. The several minor constituents of virgin olive oil include vitamins such as alpha- and gamma-tocopherols (around 200 ppm) and beta-carotene, phytosterols, pigments, terpenic acids, flavonoids, squalene, and a number of phenolic compounds, such as hydroxytyrosol, usually grouped under the rubric “polyphenols”. The antioxidant and enzyme-modulating activities of extra virgin olive oil phenolics, such as their ability to inhibit NF-kB activation in human monocyte/macrophages has been demonstrated in vitro. There is also solid evidence that extra virgin olive oil phenolic compounds are absorbed and their human metabolism has been elucidated. Several activities that might be associated with cardiovascular protection, such as inhibition of platelet aggregation and reduction of plasma rHcy have been demonstrated in vivo. The biologically relevant properties of olive phenolics are described, although further investigations in controlled clinical trials are needed to support the hypothesis that virgin olive oil consumption may contribute to lower cardiovascular mortality. Keywords: extravirgin olive oil, phenolic compounds, Mediterranean diet, hydroxytyrosol. Numerous epidemiological studies have shown that Epidemiological studies: From a nutritional point of the incidence of coronary heart disease (CHD) and view, the choice of a phenol-rich olive oil contributes certain cancers, for example breast and colon cancers, to the dietary intake of biologically-active is lowest in the Mediterranean basin [1]. It has been compounds in quantities that have been correlated suggested that this is largely due to the protective with a reduced risk of developing CHD [4]. Indeed, dietary habits of this area [1,2]. The traditional the use of extra-virgin olive oil as the principle Mediterranean diet, rich in fruit, vegetables, fish, source of dietary oil instead of animal fat, in addition and whole grain, is thought to promote good to providing a considerable amount of oleic acid, health and longevity. Olive oil, the primary oil provides an intake of bioactive compounds with source of this diet, differs significantly in potential healthful effects, as described above. It also composition from dietary lipids that are consumed by appears that the intake and interaction of several other populations. The formulation of an "micronutrients" provided by a healthy diet, such as antioxidant/atherosclerosis hypothesis stimulated that in use in the Mediterranean area during the mid- experimental and epidemiological studies on the 1940s, is likely to be the link that affords protection possible role of antioxidants, including olive oil from such pathologies [5]. In turn, the answer to the phenolics, in the protection from CHD observed in current debate on the efficacy of antioxidant the Mediterranean area. Included among the minor supplements is likely to be found in the adoption of a constituents of virgin olive oil are vitamins such as α- Mediterranean-style diet, in which the abundance of and γ-tocopherols (around 200 ppm) and β-carotene, bioactive, functional compounds provided by fruits, phytosterols, pigments, terpenic acids, flavonoids, vegetables, wine, and olive oil grants a higher squalene, and a number of phenolic compounds, protection toward reactive oxygen species (ROS)- usually grouped under the rubric “polyphenols” [3]. induced diseases. 2086 Natural Product Communications Vol. 3 (12) 2008 Visioli et al. In vitro studies: The lower incidence of CHD μM) and are 40-fold weaker than those of the widely- observed in the Mediterranean area [1] lead to the employed reducing agent ascorbate [13]. hypothesis that olive oil phenolics exert a protective Interestingly, two human intervention studies [14,15] effect with respect to chemically-induced oxidation confirmed these data in vivo, indicating that extra of human LDL, which is one of the initial steps in the virgin olive oil might decrease DNA damage, hence onset of atherosclerosis [6]. lessening cancer risk. Results obtained on human LDL demonstrate that Oleuropein increases the functional activity of catechol-like compounds present in virgin olive oil immune-competent cells (macrophages), as inhibit the formation of lipid oxidation products in a demonstrated by a significant increase (58.7 ± 4.6%) dose dependent manner and are effective at a in the lipopolysaccharide (LPS)-induced production concentration lower than that of pure tyrosol, a of nitric oxide, a bactericidal and cytostatic agent phenolic component of the oil, and of probucol, used [10a]. This increase is consequent to a direct tonic as reference compounds. This effect is probably due effect of oleuropein on the inducible form of the to the synergistic action of hydroxytyrosol, enzyme nitric oxide synthase (iNOS), as oleuropein aglycones, and some flavonoids, such as demonstrated by Western blot analysis of cell quercetin, luteolin, and apigenin present in the virgin homogenates and by coincubation of LPS-challenged olive oil extract in minute amounts. In addition, cells with the iNOS inhibitor L-nitromethylarginine changes in electrophoretic mobility of apo B are also methylester [10b]. prevented by the phenols. A correlation between inflammation and Pure hydroxytyrosol (HT) and oleuropein (OE) both cardiovascular diseases has long been established; potently and dose-dependently inhibit copper sulfate- monocyte/macrophages and NF-κB play a pivotal -6 induced oxidation of LDL at concentrations of 10 to role. The effects of an extra-virgin olive oil extract, -4 10 M [7,8]. The free radical scavenging activities of particularly rich in phenolic compounds, were hydroxytyrosol and oleuropein have been further investigated on NF-κB translocation in monocytes confirmed [8,9] by the use of metal-independent and monocyte-derived macrophages (MDM) isolated oxidative systems and stable free radicals, such as from healthy volunteers. In a concentration- DPPH [10a], in a series of experiments that dependent manner, the extra-virgin olive oil extract demonstrated both a strong metal-chelation and a inhibited p50 and p65 NF-kB translocation in both free-radical scavenging action. As far as the unstimulated and phorbol-myristate acetate (PMA)- mechanism of action of olive oil phenolics is challenged cells, being particularly effective on the concerned, it is well-known that the antioxidant p50 subunit. Interestingly, this effect occurred at properties of o-diphenols are related to hydrogen- concentrations found in human plasma after donation, which is their ability to improve radical nutritional ingestion of virgin olive oil and was stability by forming an intramolecular hydrogen bond quantitatively similar to that exerted by ciglitazone, a between the free hydrogens of their hydroxyl group PPAR-γ ligand. However, the extra-virgin olive oil and their phenoxyl radicals [10b]. Although specific extract did not affect PPAR-γ expression in investigations of olive oil phenols are yet to be monocytes and MDM. These data provide further carried out, studies performed on the structure- evidence of the beneficial effects of extra-virgin olive activity relationship of flavonoids indicated that the oil by indicating its ability to inhibit NF-κB degree of antioxidant activity is strictly related to the activation in human monocyte/macrophages [16]. number of hydroxyl substitutions [11]. In vivo studies: Experimental evidence that The mutagenic properties of oxidatively-damaged phenolic compounds of different origin are absorbed DNA suggest that antioxidants might have protective from the diet is accumulating. Animal studies in rats activity toward tumor formation. Low concentrations and rabbits demonstrated that LDL isolated from of hydroxytyrosol (50 μM) are able to scavenge animals fed virgin olive oil exhibit a higher resistance peroxynitrite and therefore prevent ONOO - to oxidation when compared with animals given a dependent DNA damage and tyrosine nitration triglyceride preparation with an equivalent amount of [12,13]; also, in a model of copper-induced DNA oleic acid, i.e. triolein [17], or «plain» olive oil [18]. damage, the prooxidant activities of hydroxytyrosol We demonstrated that olive oil phenolics are dose- (due to its copper-reducing properties) become dependently absorbed in humans and that they are evident at non-physiological concentrations (>500 excreted in the urine, mainly as glucuronide Biological significance of virgin olive oil Natural Product Communications Vol. 3 (12) 2008 2087 conjugates; it is noteworthy that increasing amounts The effect of EVOO on platelet aggregation and of phenolics administered with olive oil stimulated plasma concentrations of homocysteine (Hcy) redox the rate of conjugation with glucuronide [18]. These forms, in relation to the phenolic compounds’ data add to the growing experimental evidence that concentration, was also investigated in rats. Three indicates absorption and urinary disposition of olive oil samples with similar fatty acid, but different flavonoids in humans [19]. phenolic compound concentrations were used: refined olive oil (RF) with traces of phenolic It is noteworthy that HT exists in the brain as an compounds (control oil), native extra virgin olive oil endogenous catabolite of catecholic neurotrans- with low phenolic compounds concentration (LC), mitters, such as dopamine and norepinephrine [20], and extra virgin olive oil with high phenolic but its presence in urine has never, until recently, compounds concentration (HC) enriching LC with its been described. On the other hand, the formation of own phenolic compounds. Oil samples were homovanillic alcohol (HVAlc), the O-methylated administered to rats by gavage (1.25 mL/kg body derivative of HT, was reported by Manna et al [21] in weight) using two experimental designs: acute (24 h human Caco-2 cell incubated with HT. We also food deprivation and killed 1 h after oil reported the urinary excretion of HVAlc, in large administration) and subacute (12 d treatment, a daily excess over its basal excretion (57 ± 3 µg excreted in dose of oil for 12 d, and killed after 24 h of food 24 hours, means ± SD, n= 6). We also described the deprivation). substrate-induced enhancement of HVA formation, also a product of catecholamines metabolism, in Platelet aggregation was induced by ADP (ex vivo addition to its basal urinary excretion (1660 ± 350 µg tests) and a reduction in platelet reactivity occurred in excreted in 24 hours, means ± SD, n= 6). Indeed, the cells from rats given LC in the subacute study and in results reported suggest that HT increases the basal cells from rats administered HC in both studies, as excretion of HVA, even at the low doses of phenols indicated by an increase in the agonist half maximal administered. Future investigations will adopt effective concentration. HC inhibited platelet commercially available virgin olive oils, thus aggregation induced by low ADP doses (reversible allowing the further elucidation of the in vivo kinetics aggregation) in cells of rats in both the acute and of olive oil phenolics in habitual consumption subacute studies, whereas LC had this effect only in quantities. the subacute experiment. Moreover, in rats administered HC in both experiments, the plasma In terms of biological activities, Covas et al. recently concentration of free reduced Hcy (rHcy) was lower reviewed approximately 15 human intervention and Hcy bound to protein by disulfide bonds (bHcy) studies, the vast majority of which indicate that extra was greater than in RF-treated rats. bHcy was also virgin olive oil (rich in phenols) is superior to seed greater in rats given LC than in RF-treated rats in the oils and olive oil devoid of phenols in modulating subacute experiment. Plasma free-oxidized Hcy was selected surrogate markers of cardiovascular disease greater in rats given LC and HC than in those [22]. One example is an investigation of the effects of administered RF only in the subacute experiment. olive oil phenols on post prandial events. Bogani et These results show that phenolic compounds in al. evaluated the effects of moderate, real life doses EVOO inhibit platelet aggregation and reduce the of two olive oils, differing only in their phenolic plasma rHcy concentration, effects that may be content, on some in vivo indexes of oxidative stress associated with cardiovascular protection [24]. (plasma antioxidant capacity and urinary hydrogen peroxide levels) in a post prandial setting. Moreover, In conclusion, the biologically relevant properties of the authors assessed whether phenolic compounds olive phenolics described in this article, although still influence a few arachidonic acid metabolites to be further investigated in other controlled clinical involved in the atherosclerotic processes, such as trials, provide evidence to support the hypothesis that leukotriene B (LTB ) and thromboxane B (TXB ). virgin olive oil consumption may contribute to lower 4 4 2 2 Six subjects in each group received the three oils [30 CHD mortality. mL/day of olive oil (OO), corn oil (CO), or extra Acknowledgement – This paper celebrates Professor virgin olive oil (EVOO), distributed among meals] in Vincieri’s birthday. We wish to acknowledge his a Latin square design. The results demonstrate that important contributions to the field. EVOO is capable of reducing the post prandial events that associate with inflammation and oxidative stress [23]. 2088 Natural Product Communications Vol. 3 (12) 2008 Visioli et al. References [1] Keys A. (1995) Mediterranean diet and public health: personal reflections. American Journal of Clinical Nutrition, 61, 1321S-1323S. [2] Hertog MG, Kromhout D, Aravanis C, Blackburn H, Buzina F, Fidanza F, Giampaoli S, Jansen A, Menotti A, Nedeljkovic S, Pekkarinen M, Simic BS, Toshima H, Feskens EJM, Hollman PCH, Katan MB. (1995) Flavonoid intake and long-term risk of coronary heart disease and cancer in the Seven Countries Study [published erratum appears in Archives of Internal Medicine, 155, 1184]. Archives of Internal Medicine, 155, 381-386. nd [3] Boskou D. (2006) Olive oil: Chemistry and Technology. 2 Edition. AOCS Press, Urbana, IL, USA. [4] Hertog MLG, Feskens EJM, Katan MB, Kromhout D. 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Natural Product Communications – SAGE

Published: Dec 1, 2008

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