Participation of phenobarbital-inducible cytochrome P450 in the mutagenic activation of N-nitrosopropylamines by liver and lung 9000 g fractions from five animal species and man.
The mutagenicity of nine carcinogenic N-nitrosopropylamines was studied by the Ames preincubation assay using 9000 g supernatant (S9) fractions or alcohol dehydrogenase. Treatment of animals with polychlorinated biphenyls or phenobarbital resulted in a marked increase in the ability of liver S9 to activate N-nitrosobis(2-hydroxypropyl)amine, N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine, N-nitrosobis(2-oxopropyl)amine, N-nitrosobis(2-acetoxypropyl)amine, N-nitroso-2,6-dimethylmorpholine, N-nitroso(2-hydroxypropyl)methylamine, N-nitroso(2-oxopropyl)methylamine, N-nitroso(2,3-dihydroxypropyl)methylamine and N-nitroso(2,3-dihydroxypropyl)(2-hydroxypropyl)amine to mutagens, whereas 3-methylcholanthrene induction was not effective. All reactions required NADP as a cofactor for mutagenic activation, and nitrogen, carbon monoxide, cytochrome c and metyrapone considerably inhibited their mutagenic activities, whereas 7,8-benzoflavone did not. Five propanol derivatives were not mutagenic in the presence of NAD and alcohol dehydrogenase. We conclude that the phenobarbital-inducible major cytochrome P450 in liver S9 from five animal species tested was selectively involved in mutagenic activation. The same cytochrome in human liver S9 and in lung S9 from three rodent species also activated the mutagenicity of N-nitroso(2-hydroxypropyl)methylamine.
Mori
Y
Y
Laboratory of Radiochemistry, Gifu Pharmaceutical University, Japan.
Konishi
Y
Y
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D051379:Mice; D009153:Mutagens / Q000378:metabolism*; D009249:NADP / Q000494:pharmacology; D009602:Nitrosamines / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats
D002273:Carcinogens; D009153:Mutagens; D009602:Nitrosamines; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital