Mutagenic activation of carcinogenic N-nitrosopropylamines by liver S9 fractions from mice, rats and hamsters: evidence for a cytochrome P-450-dependent reaction

Abstract

The mutagenic potential of nine carcinogenic N-nitrosopropylamines was examined by Ames preincubation assay using liver 9000 g supernatant (S9) fractions from female rats and male hamsters and mice for metabolic activation. 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-nitrosomethyl(2-hydroxypropyl)amine, N-nitrosomethyl(2-oxopropyl)amine, N-nitroso(2,3-dihydroxypropyl)(2-hydroxypropyl)amine and N-nitrosomethyl(2,3-dihydroxypropyl)amine all showed positive mutagenicity in strain TA100 in the presence of liver S9 from three animal species pretreated with polychlorinated biphenyls or phenobarbital (PB). The S9-mediated mutagenicity of these N-nitrosamines was almost completely diminished by the removal of NADP⁺ from the assay system. All the activities were considerably decreased by preincubation in an atmosphere of carbon monoxide or adding cytochrome c to the S9 mixture. Metyrapone considerably inhibited mutagenicity, whereas 7,8-benzoflavone was totally lacking this effect. These results demonstrate a correlation between the mutagenicity of nine N-nitrosopropylamines mediated by liver S9 from three animal species and their known carcinogenicity in rodent in vivo experiments, and that the PB-inducible major cytochrome P-450 is selectively involved in the mutagenic activation. A relationship between mutagenic potencies of the N-nitrosamines and their known carcinogenic potencies in rats and hamsters is discussed