The possibility that the recently discovered and multifaceted bioregulatory agent, nitric oxide (NO), may serve as an endogenous mutagen with the potential to induce cancer in people is under vigorous scrutiny. The mutagenicity of nitroglycerin in Salmonella typhimurium strain TA1535 has been confirmed, and the point mutations it induced, like those of other NO-releasing drugs we have studied, were identified as G:C to A:T transitions; nitroglycerin proved to be negative in the other six Salmonella strains we tested, however. In contrast to the Salmonella results, the point mutations seen when the supF gene in a plasmid shuttle vector was exposed to NO in neutral aqueous solution, then replicated in human Ad293 cells, were primarily A:T to G:C transitions. None of the NO- releasing compounds displayed tumor initiating activity on application to mouse skin, but the isopropylamine-NO complex dose-responsively increased lung adenoma incidence in Strain A mice. The results are consistent with a mutational mechanism initiated by deamination of DNA bases. Additional compounds containing the NO-releasing [N(O)NO]- group have been synthesized. Novel analogues of the above-mentioned isopropylamine-NO complex having half-lives ranging from 1 min to 1 day in physiological buffer are now available. The NO-releasing [N(O)NO]- group has also been incorporated into polymers, alkylated to form potential prodrugs, and coordinated to metal centers as possible approaches to targeting nitric oxide to selected tissues. Oxidation and nitrosation by reactive intermediates formed in NO/O2 mixtures were shown to have the same rate equation, and inhibition (both reversible and irreversible) of cytochromes P450 by NO has been characterized.
