Submitted to: Hepatobiliary Surgery and Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/30/2012
Publication Date: 12/1/2012
Citation: Ye, Q., Lian, F., Chavez, P.R., Chung, J., Qin, H., Sitz, H.K., Wang, X. 2012. Cytochrome P450 2E1 inhibition prevents hepatic carcinogenesis induced by diethylnitrosamine in alcohol-fed rats. Hepatobiliary Surgery and Nutrition. 1(1):5-18. Interpretive Summary: Chronic alcohol intake increases the risk of several cancers including cancer of the liver. In this study we investigated whether or not treatments with an enzyme inhibitor (chlormethiazole) protects against alcohol-associated liver cancer in rats. The resulting data demonstrated that the inhibition of alcohol induced enzyme is a key factor that can counteract tumor development in the presence of chronic alcohol intake. This study provided useful information for the treatment of alcoholics with a high risk of liver cancer development.
Technical Abstract: Chronic alcohol ingestion increases hepatic cytochrome P450 2E1 (CYP2E1), which is associated with hepatocarcinogenesis. We investigated whether treatment with chlormethiazole (CMZ), a CYP2E1 inhibitor, protects against alcohol-associated hepatic carcinogenesis in rats. Rats were fed either an ethanol liquid diet or a non-ethanol liquid diet, with or without CMZ for one and ten months. A single intraperitoneal injection of diethylnitrosamine (DEN, 20 mg/kg) was given to initiate hepatic carcinogenesis. CYP2E1 expression, inflammatory proteins, cell proliferation, protein-bound 4-HNE, etheno-DNA adducts, 8-hydroxy-2’-deoxyguanosine (8-OHdG), retinoid concentrations, and hepatic carcinogenesis were examined. Ethanol feeding for 1 month with DEN resulted in significantly increased hepatic CYP2E1 levels and increased nuclear accumulation of NF-KB protein and TNF-alpha expression, which were associated with increased cyclin D1 expression and p-GST positive altered hepatic foci. All of these changes induced by ethanol 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 animals receiving ethanol and CMZ. The 8-OHdG formation was found to be significantly increased in ethanol fed animals and normalized with CMZ treatment. In addition, alcohol-reduced hepatic retinol and retinoic acid 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-alpha expression, NF-KB activation, and oxidative DNA damage as well as restoring normal hepatic levels of retinoic acid in DEN-treated rats.