Role of ethanol-inducible cytochrome P-450 2E1 in the development of hepatocellular carcinoma by the chemical carcinogen, N-nitrosodimethylamine.
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 micrograms/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 micrograms/kg body weight in the 3.0-microgram 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Tsutsumi
M
M
Department of Internal Medicine, Kanazawa Medical University, Ishikawa, Japan.
Matsuda
Y
Y
Takada
A
A
D000818:Animals; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000502:physiology*; D004790:Enzyme Induction; D000431:Ethanol / Q000009:adverse effects*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology*; D008297:Male; D009603:Nitroso Compounds / Q000008:administration & dosage / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis / Q000502:physiology*; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar
D009603:Nitroso Compounds; C008651:4-nitrosodimethylaniline; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating