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. Seven TSNA have been identified in tobacco products: N'-nitrosonornicotine (NNN), N'-nitrosoanabasine (NAB), N'-nitrosoanatabine (NAT), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanol (iso-NNAL), and 4-(methylnitrosamino)-4-3-pyridyl)butyric acid (iso-NNAC). The syntheses of these compounds are reviewed. The syntheses of 14C- and 3H-labeled NNK as well as metabolites of NNK and NNN are also discussed. Comparative assays for lung tumorigenesis in female A/J mice were carried out for six of the TSNA and for two related compounds, N-nitrosodimethylamine (NDMA) and N-nitrosopyrrolidine (NPYR). They yielded the following ranking of potency: NDMA > NNK > NNAL > NPYR > NNN > NAB. Iso-NNAL and iso-NNAC were inactive. These results are also compared with previous assays of TSNA carcinogenicity in rats and hamsters.
Amin
S
S
American Health Foundation, Valhalla, NY 10595, USA.
Desai
D
D
Hecht
S S
SS
Hoffmann
D
D
D000236:Adenoma / Q000139:chemically induced*; D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D005260:Female; D008175:Lung Neoplasms / Q000139:chemically induced*; D051379:Mice; D009602:Nitrosamines / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D010947:Plants, Toxic; D051381:Rats; D014026:Nicotiana / Q000737:chemistry*
D002273:Carcinogens; D009602:Nitrosamines