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A Relevant Dose of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Is Extensively Metabolized and Rapidly Absorbed in the Canine Tracheal Mucosa¹

Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87185 [P. G., B. A. M., T. S., J. L. L., K. H. P., A. R. D.], and Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden, in cooperation with the Swedish National Institute for Working Life [P. G.]

Lung cancer is largely a site-of-entry disease caused by inhaled carcinogenic agents, especially tobacco smoke. Two major groups of procarcinogens, tobacco-specific nitrosamines and polycyclic aromatic hydrocarbons, are putative agents, but their relative contributions are disputed. An important indicator of relative potency for these compounds is the dose to the target epithelial cells. Although we have reported the dose of polycyclic aromatic hydrocarbons to the canine tracheal epithelium [Gerde et al., Carcinogenesis (Lond.), 18: 1825–1832, 1997; Gerde et al., Carcinogenesis (Lond.), in press, 1998], the purpose of the current study was to characterize the absorption and metabolism of low levels of one tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in the canine trachea. One hundred ng of tritiated NNK were instilled in the distal trachea of the dog. Blood was repeatedly sampled from the azygous vein and both sides of the systemic circulation from 15 s to 30 min after instillation. Tissues were then removed and analyzed for the tritiated NNK and its metabolites. Autoradiography was used to determine the depth distribution of tritium in the tracheal mucosa. Most NNK appeared rapidly in the blood draining the airway mucosa, but there was also a slow clearance phase. During absorption, NNK was distributed within the entire depth of the mucosa to the tracheal cartilage; however, a portion was conspicuously bound to the mucin component of the mucous lining layer. Reversible binding to mucin may be largely responsible for the slow clearance phase. Despite the rapid absorption of most of the tritium, NNK was nonetheless extensively metabolized in the tracheal mucosa. Systemic metabolism was also rapid: within 18 min of instillation, the NNK parent compound had disappeared from the systemic circulation, and 45 min after instillation, no NNK was found in the trachea or any distal tissue. Although the rapid absorption and distribution of NNK and its metabolites ensured widespread and extensive distal binding in all tissues, first-pass metabolism and activation of NNK in the airway mucosa were sufficiently rapid to cause levels of binding at the site of absorption to be 20-fold those of distal tissues. NNK may thus act as a site-of-entry carcinogen. This observation may be important in estimating the contribution of NNK to lung cancer relative to other carcinogens and for explaining increased incidences of oral cancers in users of snuff and chewing tobacco in which NNK is present in high concentrations.

¹ This research was sponsored by NIH Grant RO1-5910 from the National Institute of Environmental Health Sciences in facilities belonging to the United States Department of Energy, Office of Health and Environmental Research under Contract DE-AC04-76EV01013 and Cooperative Agreement DE-FC04-96AL76406, with contributing funding from the Swedish Council for Working Life Research (Grant 91-0359).

² To whom requests for reprints should be addressed, at Lovelace Respiratory Research Institute, P. O. Box 5890, Albuquerque, NM 87185.

³ Present address: Center for Population Health, Dept. of Internal Medicine, University of New Mexico, 2400 Tucker NE, Albuquerque, NM 87131-5267.

⁴ Present address: Robert Wood Johnson Medical School, Education and Research Building, 401 Haddon Ave., Camden, NJ 08103.

Received 9/ 9/97. Accepted 1/27/98.

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