title: Quantitation of metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone after cessation of smokeless tobacco use.
abstract: 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 t(1/2alpha) (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 t(1/2beta) (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.
authors.affiliation: University of Minnesota Cancer Center, Minneapolis, Minnesota 55455, USA. hecht002@umn.edu
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Hecht
authors.forename: Steven G
authors.initials: SG
authors.lastname: Carmella
authors.forename: Ming
authors.initials: M
authors.lastname: Ye
authors.forename: Ky-anh
authors.initials: KA
authors.lastname: Le
authors.forename: Joni A
authors.initials: JA
authors.lastname: Jensen
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Zimmerman
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Hatsukami
mesh_terms: D000284:Administration, Oral; D000328:Adult; D005965:Glucuronates / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009602:Nitrosamines / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine*; D020340:Tobacco Use Cessation; D014030:Tobacco, Smokeless / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: C099564:4-((methylnitrosoamino)-1-(3-pyridyl)but-1-yl)beta-omega-glucosiduronic acid; D005965:Glucuronates; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C099565:4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol