Synthesis of Tobacco-Specific N-Nitrosamines and Their Metabolites and Results of Related Bioassays
Tobacco-specific N-nitrosamines (TSNA) are the most abundant, strong carcinogens in tobacco smoke. N'-Nitrosonornicotine (NNN) was the first N-nitrosamine derived from the Nicotiana alkaloids to be identified in tobacco products. Because 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its metabolic reduction product 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol are present in tobacco products and were needed for bioassays, authors synthesized both compounds in gram amounts and for biochemical studies also in C-labeled and H-labeled form. In the comparative bioassay in A/J mice there were no toxic effects, as indicated by the average weights of the animals throughout the bioassay, except for the positive control mice treated with N-nitrosodimethylamine at a total dose of 20 µmol. The metabolic pathways of NNK and NNN, the two most carcinogenic TSNA, have been studied in some detail by authors group. All metabolites have been characterized by their spectral properties or by comparison to synthetic standards.