The in vivo tissue disposition and in vitro target-tissue metabolism of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in Syrian golden hamsters.
The tobacco-specific N-nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), labeled with 14C in the carbonyl group, was given i.v. or s.c. to Syrian golden hamsters. Whole-body autoradiography indicated that NNK is distributed evenly in the intra- and extracellular tissue water and reaches all tissues. An accumulation of radioactivity was observed in the stomach contents, probably due to the basicity of NNK and its metabolites, which are trapped in the acid gastric juice. The basicity of these compounds is also responsible for their binding to the eye melanin. A high level of tissue-bound metabolites occurred in the mucosa of the ethmoturbinates, in the lungs and in the trachea, which are the targets for the carcinogenicity of NNK in the hamster. In the lungs and the trachea, the radioactivity was confined to the epithelium of the air-conducting ways (the bronchial, bronchiolar and tracheal epithelium). Microautoradiography of the nasal olfactory mucosa showed the highest labeling over Bowman's glands in the lamina propria mucosae. The liver was the only non-target tissue which retained detectable tissue-bound metabolites in vivo. Levels of in vitro degradation of NNK to tissue bound and unbound metabolites were the highest in the nasal mucosa. This tissue as well as the other target tissues - the lung and the trachea - produced considerable amounts of metabolites which are probably derived from alpha-carbon hydroxylations of NNK. In the liver, on the other hand, the main metabolite was a reduction product of NNK. Our results demonstrate that tumorigenesis is correlated with NNK metabolism and binding in the target tissues and support the hypothesis that alpha-carbon hydroxylation is the mechanism of activation of NNK.
D000818:Animals; D002273:Carcinogens / Q000378:metabolism; D006224:Cricetinae; D005260:Female; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008647:Mesocricetus; D009297:Nasal Mucosa / Q000378:metabolism; D009602:Nitrosamines / Q000097:blood / Q000378:metabolism*; D014018:Tissue Distribution; D014132:Trachea / Q000378:metabolism
D002273:Carcinogens; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone