EXAMINATION OF ALPHA-CARBONYL DERIVATIVES OF NITROSODIMETHYLAMINE ANDETHYLNITROSOMETHYLAMINE AS PUTATIVE PROXIMATE CARCINOGENS

Metabolites produced by enzymic oxidation are believed to be responsib le for the mutagenicity and carcinogenicity of N-nitrosamines. Althoug h alpha-hydroxy compounds are often considered, a related and more sta ble oxidation product, the alpha-carbonyl compound, was studied here. The alpha-carbonyl derivatives of nitrosodimethylamine (NDMA) and ethy lnitrosomethylamine (oxidized at either the methyl or the ethyl group) were synthesized. The derivatives were methylnitrosoformamide (MNFA), ethylnitrosoformamide (ENFA) and methylnitrosoacetamide (MNAA). These compounds were then studied as potential toxic, mutagenic and carcino genic intermediates. All three compounds were very potent directly act ing mutagens to Salmonella typhimurium TA1535. Mutational Fingerprints in Escherichia coli of MNFA and ENFA (but not MNAA) matched those pro duced by S(N)1-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 a nimal 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 mont hs. The properties of these oxidized derivatives of N-nitrosamines are consistent with expectations for proximate carcinogenic intermediates .