title: Stereochemistry of metabolites of a tobacco-specific lung carcinogen in smokers' urine.
abstract: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific lung carcinogen, is believed to be important as a causative agent for lung cancer in smokers. NNK is extensively metabolized to its carbonyl reduction product 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which, in turn, can be glucuronidated, producing [4-methylnitrosamino)-1-(3-pyridyl)but-1-yl]-beta-O-D-glucosiduronic+ ++ acid (NNAL-Gluc). Metabolism of NNK to NNAL produces a chiral center. A recent study demonstrated that (R)-NNAL is more tumorigenic in mice than (S)-NNAL and that these enantiomers have substantially different metabolic pathways. Therefore, it is important to determine the stereochemistry of NNAL and NNAL-Gluc in smokers. In this study, we used chiral stationary phase-gas chromatography-nitrosamine-selective detection with confirmation by liquid chromatography-tandem mass spectrometry to determine the stereochemistry of NNAL and NNAL-Gluc in smokers' urine. The two methods agreed well. The results of analyses of urine samples from 30 smokers demonstrated that the enantiomeric distribution of NNAL in urine was 54% (R) and 46% (S) +/- 7.0 (SD), whereas the diastereomeric distribution of NNAL-Gluc was 68% (R) and 32% (S) +/- 8.1. These results conclusively demonstrate that both (R)- and (S)-NNAL are formed metabolically from NNK in smokers. These data are essential for furthering our understanding of the role of NNK as a cause of lung cancer in smokers.
authors.affiliation: University of Minnesota Cancer Center, Minneapolis 55455, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Carmella
authors.forename: M
authors.initials: M
authors.lastname: Ye
authors.forename: P
authors.initials: P
authors.lastname: Upadhyaya
authors.forename: S S
authors.initials: SS
authors.lastname: Hecht
mesh_terms: D002273:Carcinogens / Q000737:chemistry* / Q000493:pharmacokinetics; D002849:Chromatography, Gas; D002853:Chromatography, Liquid; D005965:Glucuronates / Q000737:chemistry* / Q000652:urine; D006801:Humans; D013058:Mass Spectrometry; D009602:Nitrosamines / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000652:urine; D010947:Plants, Toxic; D012906:Smoke; D012907:Smoking / Q000652:urine*; D013237:Stereoisomerism; D014026:Nicotiana
chemical_list: C099564:4-((methylnitrosoamino)-1-(3-pyridyl)but-1-yl)beta-omega-glucosiduronic acid; D002273:Carcinogens; D005965:Glucuronates; D009602:Nitrosamines; D012906:Smoke; C051577:4-(methylnitrosoamino)-4-(3-pyridyl)-1-butanol; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone