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Background. Alcohol is a carcinogen for the liver. Chronic alcohol consumption increases Cytochrome P450 2E1 (CYP2E1) in liver which is associated with a generation of highly carcinogenic DNA lesions. The purpose of the present study was to investigate whether the CYP2E1 inhibitor chlormethiazole (CMZ) has an effect on hepatic carcinogenesis induced by diethylnitrosamine (DEN).Methods. Rats received Lieber–DeCarli ethanol containing control diets with and without CMZ and a single intraperitoneal injection of a low dose of DEN (20 mg per kg body weight). The formation of hepatic preneoplastic foci was assessed by immunostaining of placental glutathione-S-transferase (p-GST). In addition, hepatic proliferation was assessed by immunohistochemistry for proliferating cellular nuclear antigen, Ki-67 and cyclin D1. In addition, hepatic expression of TNF-α and activation of NF-κB and CYP2E1 were assessed by either real-time PCR or western blotting analysis.Results. Ethanol feeding resulted in a significant induction of hepatic CYP2E1 increased nuclear accumulation of NF-κB protein and TNF-α expression which was associated with increased hepatocyte proliferation markers and cyclin D1 protein expression as well as increased p-GST-positive altered hepatic foci in rat liver tissues. Chlormethiazole treatment significantly inhibited ethanol-induced CYP2E1 expression, TNF-α mRNA expression, NF-κB activation, hepatocyte proliferation and altered hepatic foci formation after a 1-month period.Conclusion. These data indicate that the inhibition of ethanol-induced CYP2e1 can block hepatic preneoplastic lesion by decreasing TNF-α expression and NF-κB activation in DEN-treated rats. [ABSTRACT FROM AUTHOR]