Human and Experimental Toxicology

Oberbaum, M ;Samuels, N ;Ben-Arye, E ;Amitai, Y ;Singer, SR

doi: 10.1177/0960327111417270pmid: 21803779

Background: A recent report showed increased frequency of apparent life-threatening events (ALTEs) in infants treated with the homeopathic medication GaliCol-Baby (GCB). The premise was that the ALTEs resulted from toxic effects of the drug’s components. We examine an alternative explanation. Method: The toxicological literature was searched for known reactions to the various GCB components, noting doses and reported symptoms. Dosage quantities and severity of reaction to the GCB were ranked independently by two groups of physicians, and a dose–response curve was generated. Reported toxic doses and symptoms were compared with those of the GCB series. The homeopathic literature was searched as well to determine the propensity of the GCB components to cause ALTE symptoms, when given in homeopathic doses to healthy volunteers (proving). Results: Doses ingested in the GCB series were 10–13 orders of magnitude smaller than those reported to cause toxic reactions in humans. There was poor correlation between symptoms with GCB and toxic profiles of the components. A nonsignificant, inverse relationship between dose and severity of reaction was observed. Conversely, four GCB components (in homeopathic doses) had a high propensity to produce at least one of five symptoms which define ALTE, two of which had intermediate to high propensity to produce three symptoms. Conclusions: It is unlikely that the ALTE following ingestion of GCB was a toxic reaction to any of the drug’s component. Homeopathic theory may explain this linkage, though further research is needed to understand the pathogenic effects of highly diluted homeopathic compounds.

Geier, DA ;Carmody, T ;Kern, JK ;King, PG ;Geier, MR

doi: 10.1177/0960327111417264pmid: 21803780

Dental amalgams are a commonly used dental restorative material, and amalgams are about 50% mercury (Hg). In our study, urinary Hg levels was examined in children of age 8–18 years, with and without dental amalgam fillings, from a completed clinical trial (parent study) that was designed to evaluate the potential health consequences of prolonged exposure to Hg from dental amalgam fillings. Our study was designed to determine whether there was a significant dose-dependent correlation between increasing Hg exposure from dental amalgams and urinary Hg levels. Hg exposure depends on the size and number of teeth with dental amalgams. Overall, consistent with the results observed in the parent study, there was a statistically significant dose-dependent correlation between cumulative exposure to Hg from dental amalgams and urinary Hg levels, after covariate adjustment. Further, it was observed that urinary Hg levels increased by 18% to 52% among 8 to 18 year old individuals, respectively, with an average exposure to amalgams, in comparison to study subjects with no exposure to amalgams. The results of our study suggest that dental amalgams contribute to ongoing Hg exposure in a dose-dependent fashion.

Moon, JM ;Chun, BJ

doi: 10.1177/0960327111412090pmid: 21653625

The adjuvant for Gramoxone INTEON is composed of 20% methanol, 20% sodium lingo sulphonate, 10% alkylaryl polyoxyethylene ether, and 50% water. Although the adjuvant is a potential source of intoxication due to the widespread use of Gramoxone INTEON, there has been no prior report characterizing the acute toxicity of this adjuvant. This study evaluated the acute toxicity of adjuvant ingestion. Seven patients presenting with acute adjuvant intoxication at Chonnam National University Hospital were enrolled in this retrospective study. The patients had intentionally or accidentally ingested 20–150 mL of adjuvant. Gastrointestinal symptoms such as nausea and vomiting were most common, and no ocular symptoms were reported. Cardiovascular symptoms were limited to electrocardiogram changes such as corrected QT interval (QTc) prolongation (71.4%) and sinus tachycardia (28.6%). All patients had an elevated serum osmolar gap and lactate levels. One patient had metabolic acidosis with a high anion gap that required administration of sodium bicarbonate. These clinical symptoms were resolved within 3 days with supportive treatment without any sequelae. There were no life-threatening symptoms and no deaths. However, the physician should keep in mind the possibility of methanol intoxication in patients poisoned with this adjuvant.

Erdem, O ;Eken, A ;Akay, C ;Arsova-Sarafinovska, Z ;Matevska, N ;Suturkova, L ;Erten, K ;Özgök, Y ;Dimovski, A ;Sayal, A ;Aydın, A

doi: 10.1177/0960327111411499pmid: 21636625

Prostate cancer is the second most common cancer in men worldwide. Although the aetiology of this disease remains largely unclear, several lines of evidence suggest that oxidative stress plays a role in prostate carcinogenesis. The antioxidant enzyme glutathione peroxidase 1 (GPX1) is part of the enzymatic antioxidant defence, preventing oxidative damage to DNA, proteins and lipids by detoxifying hydrogen and lipid peroxides that may contribute to prostate cancer development. Some studies indicate an association between GPX1 Pro198Leu polymorphism and an increased risk of cancer. The purpose of the present study was to determine the possible association of GPX1 Pro198Leu polymorphism and erythrocyte GPX activity with the risk of developing prostate cancer and to clarify whether erythrocyte GPX activity levels were correlated with the GPX1 Pro198Leu genotype in the Turkish population. The GPX1 Pro198Leu genotype was determined in 33 prostate cancer patients and 91 control individuals. As evident from our results, there was no difference between genotype and/or allele frequencies in prostate cancer patients and controls. No significant difference was found in GPX1 genotype or allele frequency between aggressive and non-aggressive prostate cancer patients. It can be suggested with these findings that individual susceptibility of prostate cancer may be modulated by GPX1 polymorphism, but it needs further studies.

Liu, Mei ;Yang, Xiao ;Fan, Jinjin ;Zhang, Rui ;Wu, Jun ;Zeng, Youjia ;Nie, Jing ;Yu, Xueqing

doi: 10.1177/0960327111407645pmid: 21558304

Aristolochic acid (AA) can accumulate in the tubulointerstitium and cause kidney-specific injuries. However, the mechanism by which AA induces nephropathy remains largely unknown. This study explored the effect of AA-I on tight junctions (TJs), and the fence function in a renal epithelial cell (REC). NRK-52E cells were exposed to different concentrations of AA-I for 4 h or 25 μM AA-I for different time. Cell viability was detected by MTT, cell apoptosis by flow cytometric analysis, the expression of zonula occludens-1 (ZO-1), E-cadherin and polarity scaffold (Par3) by western blot and immunofluorescence, cell membrane permeability by transepithelial electrical resistance (TEER). It was found that AA-I reduced the expression of ZO-1, E-cadherin, and Par3 in a concentration- and time-dependent fashion, and altered the distribution of ZO-1 and Par3 from cell membrane to cell plasma. In parallel to the reduced expression of TJ proteins, TEER exhibited a significant reduction in response to AA-I treatment in a time- and concentration-dependent manner. Meanwhile, α-SMA expression in cells was increased following AA-I treatment. In contrast, cell viability and apoptosis were unaltered with the doses of AA-I tested. Our findings show for the first time that AA-I treatment in cultured RECs induced a rapid disruption of TJ and the fence function preceding apoptosis, which indicated that aberrant expression of TJ proteins within RECs may be involved in initiating the renal tubulointerstitial disorders.

Karagiannis, Tom C ;Li, Xuelei ;Tang, Michelle M ;Orlowski, Christian ;El-Osta, Assam ;Tang, Mimi LK ;Royce, Simon G

doi: 10.1177/0960327111407228pmid: 21508073

Airway epithelial damage and repair represents a novel therapeutic target in asthma and chronic obstructive pulmonary disease. An established mouse model of airway epithelial damage involves the Clara cell cytotoxicity of parenterally administered naphthalene, an important environmental toxicant with genotoxic and carcinogenic potential. The objective of the current study was to investigate naphthalene-induced toxicity and to identify and quantify DNA double-strand breaks in a murine naphthalene model of airway epithelial damage. Male C57/BL6 mice were injected with 200 mg/kg naphthalene and culled at 12-, 24-, 48- and 72-h time points. Lung function and bronchoalveolar lavage was performed and the lungs were dissected for histological analysis and for quantitation of DNA double-strand breaks using γH2AX as a molecular marker. Mice injected with naphthalene had increased epithelial denudation, bronchoalveolar lavage fluid cellularity and reactivity to nebulized methacholine chloride as compared to corn oil vehicle controls. Histological changes were most pronounced at the 12- and 24-h time points. DNA double-strand breaks, quantitated as the number of γH2AX foci per cell, were highest at the 24- and 48-h time points. All parameters had decreased at the 72-h time point, consistent with airway re-epithelization and cellular repair. Our findings indicate a time-dependent accumulation of γH2AX foci in mouse airway epithelial cells following administration of naphthalene. Naphthalene airway epithelial injury constitutes a model of DNA double-strand breaks in mice, which can be adapted as a suitable model for further investigation of genotoxic damage for evaluating the efficacy of potential therapeutics.

Mehta, AK ;Halder, S ;Khanna, N ;Tandon, OP ;Sharma, KK

doi: 10.1177/0960327111417908pmid: 21803783

The present study aims to investigate the influence of electrical stimulation of periaqueductal gray (PAG) following peripheral nerve injury and its modulation by naloxone and N-methyl-D-aspartate (NMDA). Chronic neuropathic pain was induced by chronic constriction injury of the sciatic nerve, and subsequently a cannula was implanted in the PAG area for the purpose of electrical stimulation and intra-PAG drug administration. Intra-PAG administration of morphine, ketamine, and their combination were found to elicit antinociceptive response on hot-plate test. Electrical stimulation of PAG was also observed to demonstrate decreased pain response on hot-plate test, and this effect was reversed by the administration of naloxone, NMDA, and their combination, when injected into the PAG area. These findings suggest that apart from the opioid receptors, probably NMDA receptors also have a role to play in stimulation-produced analgesia.

Singh, AB ;Khaliq, T ;Chaturvedi, JP ;Narender, T ;Srivastava, AK

doi: 10.1177/0960327111407227pmid: 21653626

Hypoglycemic effect of ethanol extracts of Peganum harmala (commonly known as ‘Harmal’) seeds has been reported on normal and streptozotocin-induced diabetic rats. In the present study, the authors determine anti-diabetic and anti-oxidative properties of 4-hydroxypipecolic acid (4-HPA) isolated from seeds of P. harmala in C57BL/KsJ-db/db mice. Twelve week old male mice were administered 50 mg/kg body weight (4-HPA suspension were made in 1% gum acacia) for the period of 10 days, and a significant reduction in the fasting blood glucose, plasma triglycerides (TG), cholesterol, free fatty acid, low-density lipoprotein-cholesterol and a significant increase in high-density lipoprotein-cholesterol level was observed with respect to vehicle-treated db/db mice. The anti-oxidant activity of 4-hydroxypipecolic acid was studied in liver and kidney tissues by assessing malondialdehyde levels for lipid peroxidation and enzyme activity of catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD). Treatment of 4-HPA significantly lowered the lipid peroxidation in hepatic and renal tissue and increased the activity of CAT, GSH-Px and SOD in treated mice.

Pratheeshkumar, P ;Kuttan, G

doi: 10.1177/0960327111414279pmid: 21708884

The inhibitory effect of vernolide-A (C21H28O7) on lung metastasis induced by B16F-10 melanoma cells was studied using C57BL/6 mice. Vernolide-A was administered in three different modalities such as simultaneously with tumor, prophylactic to tumor and after tumor development. Maximum inhibition in the metastasis was observed when vernolide-A was administered simultaneously with tumor. There was 89.39% inhibition of lung tumor nodule formation and 88.51% increase in the life span of metastatic tumor-bearing animals. Highly elevated levels of lung hydroxyproline, lung uronic acid, lung hexosamine, serum sialic acid, serum γ-glutamyl transpeptidase (GGT) and serum vascular endothelial growth factor (VEGF) in the metastatic control animals were found to be significantly lowered in the vernolide-A-treated animals. Histopathological analysis of lung tissues also correlated with these results. Vernolide-A administration downregulated the expression of matrix metalloproteinase-2 (MMP-2), MMP-9, extracellular-signal-regulated kinase-1 (ERK-1), ERK-2 and VEGF in the lung tissue of B16F-10 melanoma challenged animals. In the in vitro system, vernolide-A showed a significant inhibition of invasion of B16F-10 melanoma cells across the collagen matrix. Vernolide-A treatment also inhibited the migration of B16F-10 melanoma cells across a polycarbonate filter in vitro. Vernolide-A could inhibit MMP-2 and MMP-9 protein expression in gelatin zymographic analysis of B16F-10 cells. 3H-thymidine proliferation assay showed that vernolide-A could inhibit the proliferation of B16F-10 melanoma cells in vitro. These results indicate that vernolide-A could inhibit the metastatic progression of B16F-10 melanoma cells in mice.

Koh, Pei Hoon ;Mokhtar, Ruzaidi Azli Mohd. ;Iqbal, Mohammad

doi: 10.1177/0960327111407226pmid: 21508074

This study was aimed to evaluate the effect of Cymbopogon citratus against carbon tetrachloride (CCl4)-mediated hepatic oxidative damage in rats. Rats were administrated with C. citratus extract (100, 200 and 300 mg/kg b.w.) for 14 days before the challenge of CCl4 (1.2 ml/kg b.w. p.o) on 13th and 14th days. Hepatic damage was evaluated by employing serum biochemical parameters (alanine aminotransferase-ALT, aspartate aminotransferase-AST and lactate dehydrogenase-LDH), malondialdehye (MDA) level, reduced GSH and antioxidant enzymes (catalase: CAT, glutathione peroxidase: GPX, quinone reductase: QR, glutathione S-transferase: GST, glutathione reductase: GR, glucose-6-phosphate dehyrogenase: G6PD). In addition, CCl4-mediated hepatic damage was further evaluated by histopathological examination. However, most of these changes were alleviated by prophylactic treatment of animals with C. citratus dose dependently (p < 0.05). The protection was further evident through decreased histopathological alterations in liver. The results of the present study indicated that the hepatoprotective effect of C. citratus might be ascribable to its antioxidant and free radical scavenging property.