Differential effect of chronic ethanol consumption by the rat on microsomal oxidation of hepatocarcinogens and their activation to mutagens.
The effect of chronic ethanol consumption by rats on hepatic microsomal activation of the hepatocarcinogens dimethylnitrosamine (DMN) and 2-acetylaminofluorene (2-AAF) was investigated. There was a marked increase in the rate of the oxidative demethylation of DMN and its activation to a mutagen by microsomes following ethanol intake. N- and C-hydroxylation of 2-AAF were measured at substrate concentrations ranging from 2 to 70 microM. The ratio of formation of N-hydroxy-2-acetylaminofluorene to C-hydroxy-2-acetylaminofluorenes increased with decreasing substrate concentration, suggesting enhanced carcinogenic potential of 2-AAF with diminishing levels of carcinogen. Kinetic analysis indicated that N-hydroxylation as well as 7-, 5- and 3-hydroxylation of 2-AAF do not follow Michaelis-Menten kinetics. In contrast to the marked inductive effect of ethanol consumption on the metabolic activation of DMN, only a minimal random effect on the N-hydroxylation of 2-AAF was demonstrable in two separate experiments. Furthermore, N-hydroxylation of 2-AAF by microsomes from control and ethanol-treated rats followed similar kinetics. While ethanol consumption enhanced the mutagenic activation of DMN by hepatic microsomes, no such effect of ethanol consumption on the conversion of 2-AAF to a mutagen was observed. The data indicate that chronic ethanol consumption does not have a general inductive effect on the microsomal activation of hepatocarcinogens.
D015073:2-Acetylaminofluorene / Q000378:metabolism*; D000437:Alcoholism / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D004128:Dimethylnitrosamine / Q000378:metabolism*; D004435:Eating; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009153:Mutagens / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
D009153:Mutagens; D015073:2-Acetylaminofluorene; D004128:Dimethylnitrosamine