Abstract 964: Chlormethiazole, an inhibitor of CYP2E1, prevented chemical carcinogen-initiated and alcohol-promoted hepatic carcinongenesis in rats.

Abstract

Abstract Chronic and excessive alcohol ingestion, a known risk factor of liver cancer, has been shown to upregulate hepatic cytochrome P450 2E1 (CYP2E1), which is associated with the production of reactive oxygen species and carcinogenic acetaldehyde, the activation of procarcinogens as well as the enhanced catabolism of retinoid. Further, treatment with the CYP2E1 inhibitors, including chlormethiazole (CMZ), have been shown to protect against alcohol-induced liver injury. In order to determine whether treatment with CYP2E1 inhibitor protects against diethylnitrosamine (DEN)-initiated, alcohol-promoted carcinogenesis in the liver, we fed rats (n=6) with either an ethanol liquid diet (Lieber-DeCarli diet) or a non-ethanol liquid diet with isocaloric maltodextrin, with or without CMZ (100 mg/kg BW), for a short-term (1 month) and a long-term (10 months). DEN was given as an initiator for hepatic carcinogenesis by i.p. injection of 20 mg DEN/kg BW. Hepatocarcinogenesis was assessed by examining the placental glutathione-s-transferase (p-GST) immunostaining of altered hepatic foci (AHF) and hepatic tumors lesions. Hepatocyte proliferation was assessed by immunohistochemistry for proliferating cellular nuclear antigen and Ki67, as well as cyclin D1. Hepatic expression of TNF-α and activation of NF-κB and CYP2E1 were assessed by either RT-PCR or Western blotting analysis. Hepatic retinol and retinoic acid were analyzed by reverse-phase HPLC. Results showed that CMZ treatment significantly inhibited ethanol-induced AHF formation, CYP2E1 expression and activity, TNF-α mRNA expression, NF-κB activation and hepatocyte proliferation after a 1-month period. After 10-months of treatment, hepatic nodular regenerative hyperplasia, and hepatocellular adenoma and carcinoma were detected in the ethanol-fed rats, but not in the rest of rat groups with the same dose of DEN treatment, including non-ethanol fed rats and ethanol-fed rats with CMZ treatment. In addition, the CMZ treatment prevented alcohol-reduced retinol and retinoic acid in the livers of rats after 1- and 10-months of treatment. These data demonstrate that CYP2E1 inhibitor can counter the tumor-promoting action of ethanol by restoring normal hepatic levels of retinoic acid. In considering the efficacy and complex biological functions of retinoids in human cancer prevention, intervention using CYP2E1 inhibitors that target alcohol-induced CYP2E1, could provide complementary or synergistic protective effects against alcohol-related cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 964.