title: Correlation between the urine profile of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolites and N7-methylguanine in urothelial carcinoma patients.
abstract: A major carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is present in cigarette smoke and its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), is used as an exposure biomarker for environmental tobacco smoke (ETS). This metabolite (NNAL) can be either detoxified into glucuronidated NNAL (NNAL-Gluc) or activated into an unstable reactive metabolite that methylates DNA along with formation of 4-hydroxy-4-(3-pyridyl)-butyric acid [hydroxy acid (HA)]. Therefore, the carcinogenic risk associated with ETS exposure is greatly modulated by individual variations in metabolic activation and detoxification capabilities. In this study, we defined the urinary HA/total NNAL [HA/total NNAL] ratio as the activation index and NNAL-Gluc/free NNAL [(total NNAL-free NNAL)/free NNAL] ratio as the detoxification index of NNK. The major methylated DNA adduct N(7)-methylguanine (N(7)-MeG), considered as the carcinogenic biomarker for cigarette smoking, was excreted in urine. The objective of this study was to investigate the effects of these metabolic indexes of NNK on N(7)-MeG urinary excretion in a population of urothelial carcinoma patients. Urinary levels of total NNAL (free NNAL plus NNAL-Gluc), free NNAL, HA, and N(7)-MeG were positively correlated with smoking. Furthermore, activation index and detoxification index correlated positively and negatively with N(7)-MeG levels, respectively. Our results suggest that these metabolic indices may represent the phenotype of individual metabolism capability and modulate the carcinogenic risk of ETS exposure.
authors.affiliation: Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County, Taiwan 350.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Lee
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Hsueh
authors.forename: Chi-Jung
authors.initials: CJ
authors.lastname: Chung
authors.forename: Yeong-Shiau
authors.initials: YS
authors.lastname: Pu
authors.forename: Louis W
authors.initials: LW
authors.lastname: Chang
authors.forename: Dennis Paul Hsientang
authors.initials: DP
authors.lastname: Hsieh
authors.forename: Saou-Hsing
authors.initials: SH
authors.lastname: Liou
authors.forename: Pinpin
authors.initials: P
authors.lastname: Lin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000652:urine; D002273:Carcinogens / Q000378:metabolism*; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000652:urine; D006801:Humans; D008297:Male; D008875:Middle Aged; D009602:Nitrosamines / Q000652:urine*; D011725:Pyridines / Q000652:urine*; D012907:Smoking / Q000009:adverse effects*; D011795:Surveys and Questionnaires; D001749:Urinary Bladder Neoplasms / Q000652:urine*
chemical_list: D015415:Biomarkers; D002273:Carcinogens; D009602:Nitrosamines; D011725:Pyridines; D006147:Guanine; C008450:7-methylguanine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C099565:4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol