Mutagenicity of N-nitrosopyrrolidine derivatives in salmonella (Ames) and Escherichia coli K-12 (343/113) assays

Abstract

The mutagenicity of nitrosopyrrolidine (NPYR) and its derivatives was determined by use of the Ames Salmonella assay. A clear specificity to revert the missense strain TA1535 and a requirement for the phenobarbital-induced rat-liver ctivation system (S9 mix) were noted. 3,4-Dichloronitrosopyrrolidine was more mutagenic than NPYR, whereas 3-hydroxynitrosopyrrolidine was weakly mutagenic. The carcinogenic nitroso-3-pyrrolidine was not mutagenic under the test conditions. The noncarcinogenic derivatives (2,5-dimethylnitrosopyrrolidine, nitrosoproline and 4-hydroxynitrosoproline) were not mutagenic. Liquid preincubation assays were not any more effective than the pour-plate assays. Selected derivatives of NPYR were tested in the Escherichia coli K-12 (343/113) assay. A specificity to revert the missense mutation at the arg locus and a dependence on phenobarbital-induced rat-liver S9 mix were noted with NPYR and its derivatives. 3,4-Dibromonitrosopyrrolidine, which was not mutagenic in Salmonella, was effective in E. coli and the weakly carcinogenic NPRL was a weak mutagen resulting in a 2-fold enhancement in the E. coli arginine reversion assay. These results suggest that NPYR and its mutagenic derivatives are indirect mutagens acting by the mechanism of base-pair substitution. Metabolic activation of these derivatives probably involves the carbon atoms alpha to the N-nitroso group, since a block in that position with methyl groups eliminates the biological activity. The two bacterial mutagenesis assays complement each other and provide a better means of identifying mutagenic compounds.