Role of CYP2E1 and NQO1 polymorphisms in oxidative stress derived cancer in Thais with and without dyslipidemia

Abstract

Background: Hyperlipidemia can induce the endogenous production of reactive oxygen species (ROS), which may cause carcinogenesis. Cytochrome P450 (CYP)2E1 activity, induced by various factors including polyunsaturated fatty acids, effects the incidence of cancers, whereas NQO1, a flavoprotein, may protect against ROS. Objectives: To investigate the effect of CYP2E1 and NQO1 polymorphism on oxidative stress status in Thais with and without dyslipidemia. Methods: We included 1380 apparently healthy employees of the Electricity Generating Authority of Thailand in this study. We determined their CYP2E1 and NQO1 genotypes and related these to blood lipid profiles, and circulating levels of antioxidant enzymes, malondialdehyde (MDA), and reduced glutathione (GSH). Lifestylerelated factors were determined from questionnaires. Results: All tested genotype frequencies were in Hardy-Weinberg equilibrium. The heterozygous and variant genotype distribution and allele frequency of CYP2E1*5B were less common than CYP2E1*6. Heterozygous NQO1 was the most prevalent form. The frequency of the mutated allele CYP2E1*5B was 0.16, CYP2E1*6 was 0.22, and NQO1*2 was 0.43. Significant differences were observed for blood cholesterol, triglyceride, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol between normolipidemic participants, and those with hypercholesterolemia, hypertriglyceridemia, and combined hyperlipidemia. Participants in the hyperlipidemic subgroup who bore any variant alleles of genes had higher plasma MDA and GSH levels, and superoxide dismutase and glutathione peroxidase activity, but lower catalase activity when compared with normolipidemic participants bearing wild-type alleles. Conclusions: Variations in genetic disposition and dyslipidemia can modify oxidative stress status. Relatively more free radicals may be generated in individuals in subgroups with hyperlipidemia bearing any variant alleles.

Oxidative Stress and Disease

“…Another mechanism of CYP2E1 activation is the reduction of glutathione levels, upon acetaminophen administration, for example. Besides, this drug increases lipid peroxidation and protein carbonylation, enhancing the ROS production due to higher activity of CYP2E1 and being associated to hepatotoxicity mediated by MAP-kinase pathway [16,19].…”