title: Analysis of N- and O-glucuronides of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in human urine.
abstract: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a tobacco-specific lung carcinogen which may play an important role as a cause of lung cancer in smokers. NNK is extensively metabolized to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which like NNK is a potent pulmonary carcinogen. NNAL in turn is glucuronidated, and both NNAL and its glucuronides are excreted in human urine. Previous studies have clearly demonstrated the presence in human urine of 4-(methylnitrosamino)-1-(3-pyridyl)-1-(O-beta-D-glucopyranuronosyl)butane (NNAL-O-Gluc), but did not exclude the presence of 4-(methylnitrosamino)-1-(3-pyridyl-N-beta-D-glucopyranuronosyl)-1-butanolonium inner salt (NNAL-N-Gluc). In this study, we quantified NNAL, NNAL-N-Gluc, and NNAL-O-Gluc in the urine of smokers, snuff-dippers, and people who used the oral tobacco product "toombak". The presence of NNAL-N-Gluc in the urine of toombak users was confirmed by LC-ESI-MS/MS. In smokers' urine, NNAL-N-Gluc, NNAL-O-Gluc, and NNAL comprised (mean +/- SD) 26.5 +/- 6.2, 32.1 +/- 17.6, and 41.4 +/- 16.6%, respectively, of total NNAL. In snuff-dippers' urine, the corresponding figures were 13.6 +/- 5.1, 46.6 +/- 11.7, and 36.6 +/- 9.3%. NNAL-N-Gluc comprised 50 +/- 25% of total glucuronidated NNAL in smokers and 24 +/- 12% in snuff-dippers. This difference was significant (P = 0.01), suggesting that smoking induces glucuronidation of NNAL. The results of this study demonstrate that NNAL-N-Gluc contributes substantially to NNAL-glucuronides in human urine. These results are important for a clearer understanding of mechanisms of detoxification of NNK in humans.
authors.affiliation: University of Minnesota Cancer Center, Minneapolis, Minnesota 55455, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Carmella
authors.forename: Ky-anh
authors.initials: KA
authors.lastname: Le Ka
authors.forename: Pramod
authors.initials: P
authors.lastname: Upadhyaya
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Hecht
mesh_terms: D002273:Carcinogens / Q000032:analysis* / Q000145:classification; D005965:Glucuronates / Q000145:classification / Q000652:urine*; D006801:Humans; D009602:Nitrosamines / Q000145:classification / Q000652:urine*; D010947:Plants, Toxic; D012907:Smoking / Q000652:urine; D014030:Tobacco, Smokeless / Q000378:metabolism
chemical_list: C099564:4-((methylnitrosoamino)-1-(3-pyridyl)but-1-yl)beta-omega-glucosiduronic acid; D002273:Carcinogens; D005965:Glucuronates; D009602:Nitrosamines; C099565:4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol