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Ethanol‐induced cytochrome P4502E1 causes carcinogenic etheno‐DNA lesions in alcoholic liver disease

Oxidative stress is thought to play a major role in the pathogenesis of hepatocellular cancer (HCC), a frequent complication of alcoholic liver disease (ALD). However, the underlying mechanisms are poorly understood. In hepatocytes of ALD patients, we recently detected by immunohistochemistry significantly increased levels of carcinogenic etheno‐DNA adducts that are formed by the reaction of the major lipid peroxidation product, 4‐hydroxynonenal (4‐HNE) with nucleobases. In the current study, we show that protein‐bound 4‐HNE and etheno‐DNA adducts both strongly correlate with cytochrome P450 2E1 (CYP2E1) expression in patients with ALD (r = 0.9, P < 0.01). Increased levels of etheno‐DNA adducts were also detected in the liver of alcohol‐fed lean (Fa/?) and obese (fa/fa) Zucker rats. The number of nuclei in hepatocytes stained positively for etheno‐DNA adducts correlated significantly with CYP2E1 expression (r = 0.6, P = 0.03). To further assess the role of CYP2E1 in the formation of etheno‐DNA adducts, HepG2 cells stably transfected with human CYP2E1 were exposed to ethanol with or without chlormethiazole (CMZ), a specific CYP2E1 inhibitor. Ethanol increased etheno‐DNA adducts in the nuclei of CYP2E1‐transfected HepG2 cells in a concentration‐dependent and time‐dependent manner, but not in vector mock‐transfected control cells. CMZ blocked the generation of etheno‐DNA adducts by 70%‐90% (P < 0.01). Conclusion: Our data support the assumption that ethanol‐mediated induction of hepatic CYP2E1 leading inter alia to highly miscoding lipid peroxidation–derived DNA lesions may play a central role in hepatocarcinogenesis in patients with ALD. (HEPATOLOGY 2009.)