A comparative study of the mutagenic activation of N-nitrosopropylamines by various animal species and man: evidence for a cytochrome P-450 dependent reaction.

The mutagenic potential of seven carcinogenic N-nitrosopropylamines was examined by means of Ames' preincubation assay using liver 9000 g superanatant (S9) fractions from rats, hamsters, mice, rabbits, monkeys and humans for metabolic activation. N-Nitroso(2-hydroxypropyl) (2-oxopropyl)amine (HPOP), N-nitrosobis(2-oxopropyl)amine (BOP), N-nitrosobis(2-acetoxypropyl)amine (BAP), N-nitroso-2,6-dimethylmorpholine, N-nitrosomethyl(2-hydroxypropyl)amine (MHP) and N-nitrosomethyl(2-oxopropyl)amine all showed positive mutagenicity in strain TA100 in the presence of liver S9 from each of the uninduced animals, but N-nitrosobis(2-hydroxypropyl)amine was negative. The mutagenic activity of MHP was highest with liver S9 from the hamster, but that of BAP was lowest with hamster liver S9. With regard to the activities of the other N-nitrosopropylamines, there were no significant differences among five animal species. In the presence of liver S9 from humans, HPOP, BOP and MHP showed positive mutagenicity. With the exception of HPOP and BOP, the animal or human liver S9-mediated mutagenicity of these N-nitrosopropylamines was almost completely lost upon removal of NADP+ from the assay system, preincubation in an atmosphere of carbon monoxide, or addition of cytochrome c to the S9 mixture. metyrapone decreased the activities of five compounds (except for BOP) by between 29 and 71%, whereas 7,8-benzoflavone was totally lacking in this effect. These results demonstrated that the phenobarbital-inducible major cytochrome P-450 in animal and human livers is involved in the mutagenic activation of the N-nitrosopropylamines.