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Metabolism of Tobacco-specific Nitrosamines by Cultured Rat Nasal Mucosa¹

Department of Pharmacology, Faculty of Veterinary Medicine, Uppsala Biomedical Centre, Box 573, S-75123, Uppsala, Sweden [E. B. B.], and Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York 10595 [A. C., K. F., S. S. H]

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 -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.

¹ This study was supported by National Cancer Institute Grant CA 21393 and by the Swedish Academy of Pharmaceutical Sciences. This is Paper 50 in the series, "A Study of Chemical Carcinogenesis.".

This study is dedicated to the founder of the American Health Foundation, Dr Ernst L. Wynder, on the occasion of the 10th anniversary of the Naylor Dana Institute for Disease Prevention.

² To whom requests for reprints should be addressed.

Received 12/ 1/82. Accepted 6/ 6/83.

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