INHIBITION OF MUTAGENICITY OF N-NITROSAMINES BY TOBACCO-SMOKE AND ITSCONSTITUENTS

Tobacco smoke is a complex chemical mixture including pyridine alkaloi ds and N-nitrosamines, with the concentration of the former several or ders of magnitude higher than that of the N-nitrosamines. The major bi ologically important N-nitrosamines present in tobacco smoke are N-nit rosodimethylamine (NDMA), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butano ne (NNK), and N'-nitrosonornicotine (NNN). These nitrosamines require metabolic activation by cytochrome P-450s for the expression of mutage nicity. Although nicotine, the major pyridine alkaloid in tobacco, has been shown to inhibit the metabolic activation of NNK, its effect on the mutagenicity of NNK and other N-nitrosamines has not been reported . In the present study, the ability of three pyridine alkaloids (nicot ine, cotinine, nornicotine) and aqueous cigarette smoke condensate ext ract (ACE) to inhibit the mutagenicity of tobacco-related N-nitrosamin es was tested on Salmonella typhimurium strain TA1535 in the presence of a metabolic activation system (S9). All three of the pyridine alkal oids tested, as well as ACE, inhibited the mutagenicity of NDMA and NN K, but not NNN, in a concentration-dependent manner. The induction of SCEs in mammalian cells (CHO) by NNK in the presence of metabolic acti vation was also significantly reduced by nicotine and cotinine. None o f the observed reductions in mutagenicity could be explained by cytoto xicity. These results demonstrate that tobacco smoke contains chemical s, pyridine alkaloids and other unidentified constituent(s), which inh ibit the mutagenicity of N-nitrosamines.