Metabolism of tobacco-specific nitrosamines by cultured rat nasal mucosa

The metabolism of two nasal carcinogens, N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), was investigated using cultured nasal septa of F344 rats. The explants were cultured with 14C-labeled N-nitrosamines, and unbound metabolites present in the medium were quantitated by high-performance liquid chromatography. The results indicated that the mucosa of the nasal septum had a marked capacity to metabolize NNN and NNK to hydroxylated products which were released into the culture media. Extensive activation by alpha-carbon hydroxylation of NNN (preferentially 2'-carbon hydroxylation) and NNK was observed, whereas no deactivation by pyridine N-oxidation could be detected. Microautoradiographic studies of explants showed that binding of radioactivity occurred preferentially in the respiratory and olfactory epithelia and in the subepithelial glands of the nasal mucosa. The results suggest that reactive metabolites of NNN and NNK are formed within the target tissue rather than being transported from the liver to the nasal mucosa. The results also show that the culture of nasal septa can be used to ascertain the role of the nasal mucosa in the activation of nasal-specific carcinogens