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Modulation of the Uptake and Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone by Nicotine in Hamster Lung¹

Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37901-1071 [H. M. S., M. O.], and Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Quebec, Canada G1K 7P4 [A. C., G. R.]

The tobacco-specific carcinogenic nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is formed during the curing and processing of tobacco by nitrosation of nicotine. Nicotine and NNK have structural similarities, and they are both metabolized extensively by lung tissue via several steps known to require oxidative enzyme systems, such as cytochrome P450. On the other hand, nicotine exerts many biological effects similar to those caused by the physiological neurotransmitter acetylcholine, a phenomenon mediated through selective uptake mechanisms via nicotinic cholinergic cell membrane receptors. The aim of this study was to determine if nicotine modulates NNK metabolism in hamster lung explants and if NNK competes with nicotine for binding sites on nicotinic cholinergic receptors in the hamster lung in vivo. Our data show a concentration-dependent inhibition of NNK metabolism in vitro by -carbon hydroxylation and pyridine N-oxidation, whereas the carbonyl reduction of NNK remained unchanged. Radioreceptor assays with membrane receptor fractions of hamster lung after exposure to radiolabeled (S)-(-)-nicotine revealed significant numbers of nicotinic binding sites only in the lungs of hamsters with hyperplasia of pulmonary neuroendocrine cells caused by 4-wk preexposure to hyperoxia. In such animals, radiolabeled nicotine was displaced from the receptor binding sites by NNK. Our data suggest that nicotine can potentially interfere with the carcinogenicity of NNK by competition for enzyme systems essential for the metabolic activation of the nitrosamine and by competition as ligand for nicotinic cholinergic receptors.

¹ This study was supported by the University of Tennessee Center of Excellence Program and Grant MA-9959 from the Medical Research Council (Canada). Hamsters were treated in accordance with the USPHS policy on human care and use of laboratory animals and the guidelines adopted by the Canadian Council on Animal Care.

² To whom requests for reprints should be addressed.

Received 11/ 2/90. Accepted 2/ 1/91.

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