Examination of α-carbonyl derivatives of nitrosodimethylamine and ethylnitrosomethylamine as putative proximate carcinogens
Abstract
Abstract Metabolites produced by enzymic oxidation are believed to be responsible for the mutagenicity and carcinogenkity of N -nitrosamines. Although α-hydroxy compounds are often considered, a related and more stable oxidation product, the α-carbonyl compound, was studied here. The α-carbonyl derivatives of nitrosodimethylamine (NDMA) and ethylnitrosomethylamine (oxidized at either the methyl or the ethyl group) were synthesized. The derivatives were methylnitrosoformamide (MNFA), ethylnitrosoformamide (ENFA) and methylnitsosoacetamide (MNAA). These compounds were then studied as potential toxic, mutagenic and carcinogenic intermediates. All three compounds were very potent directly acting mutagens to Salmonella typhimurium TA1535. Mutational Fingerprints in Escherichia coli of MNFA and ENFA (but not MNAA) matched those produced by S N l-type methylating and ethylating compounds respectively. The latter results indicate that the two alkylnitrosoformamides could be intermediates in the mutagenicity of the parent nitrosamines. In animal studies the putative metabolite MNFA was more acutely toxic than NDMA in F344 rats. In chronic experiments with MNFA in F344 rats and Syrian golden hamsters, tumors of the forestomach were induced by oral administration in most animals (except female hamsters) within 8 months. The properties of these oxidized derivatives of N -nitrosamines are consistent with expectations for proximate carcinogenic intermediates. © Oxford University Press