Cytochrome P450 2E1 inhibition prevents hepatic carcinogenesis induced by diethylnitrosamine in alcohol-fed rats

Chronic alcohol ingestion increases hepatic cytochrome P450 2E1 (CYP2E1), which isassociated with hepatocarcinogenesis. We investigated whether treatment with chlormethiazole (CMZ), aCYP2E1 inhibitor, protects against alcohol-associated hepatic carcinogenesis in rats. Rats were fed eitheran ethanol liquid diet or a non-ethanol liquid diet, with or without CMZ for one and ten months. A singleintraperitoneal injection of diethylnitrosamine (DEN, 20 mg/kg) was given to initiate hepatic carcinogenesis.CYP2E1 expression, inflammatory proteins, cell proliferation, protein-bound 4-HNE, etheno-DNAadducts, 8-hydroxy-2 -deoxyguanosine (8-OHdG), retinoid concentrations, and hepatic carcinogenesis wereexamined. Ethanol feeding for 1 month with DEN resulted in significantly increased hepatic CYP2E1 levelsand increased nuclear accumulation of NF-κB protein and TNF-α expression, which were associated withincreased cyclin D1 expression and p-GST positive altered hepatic foci. All of these changes induced byethanol feeding were significantly inhibited by the one month CMZ treatment. At 10-months of treatment,hepatocellular adenomas were detected in ethanol-fed rats only, but neither in control rats nor in animalsreceiving ethanol and CMZ. The 8-OHdG formation was found to be significantly increased in ethanolfed animals and normalized with CMZ treatment. In addition, alcohol-reduced hepatic retinol and retinoicacid concentrations were restored by CMZ treatment to normal levels in the rats at 10 months of treatment.These data demonstrate that the inhibition of ethanol-induced CYP2E1 as a key pathogenic factor can counteract the tumor-promoting action of ethanol by decreasing TNF-α expression, NF-κB activation, andoxidative DNA damage as well as restoring normal hepatic levels of retinoic acid in DEN-treated rats.