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Contribution of DNA methylation and benzylation to N-nitroso-N-benzyl-methylamine-induced mutagenesis in bacteria: effects of rat liver cytochrome P450 isozymes and glutathione transferases.

The mutagenicity of N-nitroso-N-benzyl-methylamine (NBzMA), N-benzyl-N-nitrosourea (BzNU) and N-methyl-N-nitrosourea (MNU) in Salmonella typhimurium strains was investigated. BzNU selectively mutated TA100 strain as compared to TA1535, whereas MNU showed an inverse strain response, an effect probably related to the fact that benzylation of DNA is a stronger inducer of SOS DNA repair than methylation, as indicated by the higher activity of BzNU in the SOS chromotest. Benzylation of bacterial DNA by NBzMA, as deduced from the differential strain responsiveness, contributed predominantly to its mutagenicity in the presence of liver preparation from untreated, Aroclor- or ethanol-treated rats. Since benzyl alcohol, a metabolite of NBzMA, was not mutagenic in S. typhimurium, it appears that benzyl carbonium cations responsible for the mutagenicity of NBzMA in TA100 are formed via cytochrome P450-mediated hydroxylation of the methyl group. Neither ferric-EDTA nor desferrioxamine altered the mutagenicity of NBzMA, suggesting that activation occurs mainly within the catalytic site of P450. Experiments with isozyme-specific monoclonal antibodies showed that P450IIE1 did not contribute to N-demethylation of NBzMA at either low or high substrate concentrations and that P450IA contributed only weakly. Debenzylation was catalysed predominantly by P450IA at high NBzMA concentration. Antibodies against rat liver P450IIB enhanced NBzMA mutagenicity in S. typhimurium TA1535 strain up to 17-fold at low substrate concentration, but were without effect at high concentration. In liquid incubation assays, a 100% GSH-dependent reduction of NBzMA mutagenicity was found with liver S9 from untreated Wistar rats. The reducing effect of GSH was less pronounced in the presence of liver S9 from BDVI or Fischer 344 rats.