Primary attention has been given to the biological chemistry of the carcinogenic nitrosamines. Evidence has been found that the mechanism by which methylamine arises metabolically from N-nitrosodimethylamine (NDMA) is identical to that of the """"""""denitrosation"""""""" pathway being studied in vitro. Pharmacokinetic data indicating that deuteration of the substrate may cause metabolic switching to this potentially detoxifying pathway have been obtained; if a similar means of shifting the metabolism of undeuterated NDMA away from the activating alpha-hydroxylation/methylation pathway can be found, protection of individuals from the effects of exposure to the carcinogen might be realized. Beta-hydroxylation of N- nitrosomethylethylamine (NMEA) has been shown to be a major metabolic pathway for this carcinogen, as predicted from published deuterium isotope effect studies; this process may play a key role in determining the species selectivity and organotropic effects of NMEA. Both conformers of the methanediazotate ion have been prepared as the thallium(I) derivatives, providing a new look at the chemistry of the diazohydroxides/primary nitrosamines thought to be the ultimate alkylating intermediates in carcinogenesis by a variety of compounds containing nitrogen-nitrogen bonds. Several barbiturates, hydantoins, and acylureas have been synthesized in kilogram quantities for structure-activity investigations in tumor promotion being performed in collaboration with other LCC scientists.
