Role of ethanol-inducible cytochrome p-450 2E1 in the development of hepatocellular carcinoma by the chemical carcinogen, N-nitrosodimethylamine

Authors

  • Mikihiro Tsutsumi,

    1. Division of Gastroenterology, Department of Internal Medicine, Kanazawa Medical University, Ishikawa 920–02, Japan
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  • Yoshiro Matsuda,

    1. Division of Gastroenterology, Department of Internal Medicine, Kanazawa Medical University, Ishikawa 920–02, Japan
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  • Akira Takada M. D.

    Corresponding author
    1. Division of Gastroenterology, Department of Internal Medicine, Kanazawa Medical University, Ishikawa 920–02, Japan
    • Division of Gastroenterology, Department of Internal Medicine, Kanazawa Medical University, Uchinada, Ishikawa 920–02, Japan
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Abstract

Cytochrome P-450 2E1 is a specific isozyme of cytochrome P-450 induced by ethanol. P-450 2E1 may also be the only enzyme that metabolizes N-nitrosodimethylamine at a very low concentration. Because N-nitrosodimethylamine is a procarcinogen, the possibility that induction of P-450 2E1 by alcohol abuse may accelerate the carcinogenic action of a very small dose of N-nitrosodimethylamine should be considered. To investigate this possibility, effects of ethanol on the hepatic carcinogenic action of a very small dose of N-nitrosodimethylamine were analyzed in rats. Sixty Wistar male rats were divided into two groups (ethanol and control) according to the liquid diets they were fed. After preliminary feeding, N-nitrosodimethylamine in two concentrations (1.5 ng/ml and 3.0 μg/ml) in drinking water was given with the diets for 40 or 60 wk. To avoid metabolic competition between ethanol and n-nitrosodimethylamine, we gave N-nitrosodimethylamine and the diets alternately. The average amount of N-nitrosodimethylamine consumed per day was 11 to 37 ng/kg body weight in the 1.5-ng group and was 27 to 37 μg/kg body weight in the 3.0-μg group. Hepatic P-450 2E1 content was six times higher in the ethanol-treated groups than in the control groups throughout the experiment. Visible nodules and enzyme-altered foci were not found in rats in any group at the end of the fortieth week. These preneoplastic changes were found at the end of the sixtieth week only in rats in the groups treated with both ethanol and N-nitrosodimethylamine. However, these changes were not found in rats treated with N-nitrosodimethylamine or ethanol alone for the same period. These results suggest that long-term administration of ethanol may accelerate the development of liver cancer induced by N-nitrosodimethylamine, and this enhancing effect may be related to the induction of P-450 2E1 by ethanol. Enhancement was observed in rats given a small dose of N-nitrosodimethylamine, suggesting that in alcoholic individuals cancer may develop from exposure to small doses of carcinogen in normal life. (HEPATOLOGY 1993;18:1483–1489.)

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