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Role of Genetic Polymorphism of Glutathione-S-Transferase T1 and Microsomal Epoxide Hydrolase in Aflatoxin-associated Hepatocellular Carcinoma¹

Division of Human Nutrition and Epidemiology, Wageningen University, 6700 EV Wageningen, the Netherlands [E. W. T., R. E. O., J. E. B., P. v. V., F. J. K., E. K.]; Department of Crop Protection, Faculty of Agriculture [R. E. O., M. O. I.] and Department of Medicine, Faculty of Medicine [A. M. Y. K.], University of Khartoum, Khartoum, 11123 Sudan; and National Center for Gastrointestinal and Liver Diseases, Khartoum, Sudan [S. S. F.]

Exposure to aflatoxins is a risk factor for hepatocellular carcinoma (HCC). Aflatoxins occur in peanut butter and are metabolized by genetically polymorphic enzymes such as glutathione-S-transferases encoded by glutathione-S-transferase µ 1 gene (GSTM1) and glutathione-S-transferase 1 gene (GSTT1) and microsomal epoxide hydrolase encoded by epoxide hydrolase gene (EPHX). The rate at which aflatoxins become activated or detoxified may depend on polymorphisms in the encoding genes. GSTM1 homozygous deletion was indeed found to modify the association between peanut butter consumption and HCC. In this study, we investigate possible roles of GSTT1 and EPHX polymorphisms in this relationship. From a Sudanese case-control study on HCC, we analyzed data of 112 incident cases and 194 controls. All participants were interviewed using a standardized questionnaire inquiring about social and demographic factors, peanut butter consumption, and other known HCC risk factors. Univariate analysis showed that GSTT1 polymorphism was not associated with HCC, whereas EPHX 113HH and 139HH genotypes increased the risk of HCC (Odds ratio, 3.10; 95% Confidence interval, 1.18–8.12). Adjustment for age and region of origin slightly attenuated this association (Odds ratio, 2.56; 95% Confidence interval, 0.83–7.95). Interestingly, unlike GSTM1, both GSTT1 and EPHX polymorphism did not modify the association between peanut butter consumption and HCC. In conclusion, these epidemiological findings do not suggest significant roles of GSTT1 and EPHX in aflatoxin metabolism, although EPHX polymorphism is possibly related to the increased risk of HCC. Further studies are needed to investigate mechanisms by which the EPHX polymorphism potentially modifies cancer risk.

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