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Carcinogenesis |
University of Minnesota Cancer Center [S. S. H., S. G. C., M. Y., K. L.], College of Pharmacy [C. L. Z.], and Transdisciplinary Tobacco Use Research Center [S. S. H., S. G. C., J. A. J., D. K. H.], Minneapolis, Minnesota 55455
Two major metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were previously shown to be highly persistent in human urine after cessation of cigarette smoking. We hypothesized that NNK or its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), was sequestered in the lung. In this study, we further evaluated this hypothesis by quantifying the NNK metabolites, NNAL and its glucuronides (NNAL-Gluc), in urine and plasma after cessation of smokeless tobacco use, in which NNK is administered p.o. rather than by inhalation. Thirteen male nonsmokers, 11 snuff dippers and 2 tobacco chewers, participated in the study. Urine and plasma were obtained at baseline and at intervals 2–126 days after cessation of smokeless tobacco use. The distribution half-lives t1/2
(days) of NNAL (1.32 ± 0.85 versus 3.35 ± 1.86) and NNAL-Gluc (1.53 ± 1.22 versus 3.89 ± 2.43) were significantly shorter in smokeless tobacco users than in smokers. There were no significant differences in the terminal half-lives t1/2ß (days) of NNAL (26.3 ± 16.7 versus 45.2 ± 26.9) and NNAL-Gluc (26.1 ± 15.1 versus 39.6 ± 26.0) in smokeless tobacco users and smokers. Baseline levels as well as renal clearance of the NNK metabolites correlated with number of tins or pouches of smokeless tobacco consumed. Ratios of (S)-NNAL:(R)-NNAL and (S)-NNAL-Gluc:(R)-NNAL-Gluc in urine were significantly (3.1–5.7 times) higher 7 days after cessation than at baseline in both smokeless tobacco users and smokers, indicating stereoselective retention of (S)-NNAL. Collectively, the results of this study suggest that there is a receptor in the human body, possibly in the lung, for (S)-NNAL, the more carcinogenic NNAL enantiomer. These data may have considerable implications for understanding mechanisms of tumor induction by NNK.
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