title: Differential effect of chronic ethanol consumption by the rat on microsomal oxidation of hepatocarcinogens and their activation to mutagens.
abstract: 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.
mesh_terms: 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
chemical_list: D009153:Mutagens; D015073:2-Acetylaminofluorene; D004128:Dimethylnitrosamine