title: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism-related enzymes gene polymorphisms, NNK metabolites levels and urothelial carcinoma.
abstract: Gene polymorphisms of the 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism-related enzymes-cytochrome P450 (CYP) monooxygenase 2A13 (CYP2A13) and UDP-glucuronosyltransferases (UGT)-2B7 could contribute to the levels of NNK-related metabolites in urine, thereby increasing the susceptibility to urothelial carcinoma (UC). Therefore, our study aimed to evaluate the roles of two gene polymorphisms (CYP2A13 and UGT2B7) of NNK metabolism-related enzymes in the carcinogenesis of UC in Taiwan. A hospital-based pilot case-control study was conducted. There were 121 UC cases and 121 age- and sex-matched healthy participants recruited from March 2007 to April 2009. Urine samples were analyzed for NNK-related metabolites using the liquid chromatography-tandem mass spectrometry method. Genotyping was conducted using a polymerase chain reaction-restriction fragment length polymorphism technique. ANCOVA and multivariate logistic regression were applied for data analyses. In healthy controls, former smokers had significantly higher total NNAL and higher NNAL-Gluc than never smokers or current smokers. Subjects carrying the UGT2B7 268 His/Tyr or Tyr/Tyr genotype had significantly lower total NNAL than those carrying His/His genotype. However, no association was seen between gene polymorphisms of CYP2A13 and UGT2B7 and UC risk after adjustment for age and sex. Significant dose -response associations between total NNAL, free NNAL, the ratios of free NNAL/total NNAL and NNAL-Gluc/total NNAL and UC risk were observed. In the future, large-scale studies will be required to verify the association between the single nucleotide polymorphisms of NNK metabolism-related enzymes and UC risk.
authors.affiliation: Department of Health Risk Management, College of Public Health, China Medical University, Taichung, Taiwan.
authors.forename: Chi-Jung
authors.initials: CJ
authors.lastname: Chung
authors.forename: Yeong-Shiau
authors.initials: YS
authors.lastname: Pu
authors.forename: Horng-Sheng
authors.initials: HS
authors.lastname: Shiue
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Lee
authors.forename: Pinpin
authors.initials: P
authors.lastname: Lin
authors.forename: Hsiu-Yuan
authors.initials: HY
authors.lastname: Yang
authors.forename: Chien-Tien
authors.initials: CT
authors.lastname: Su
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Hsueh
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009602:Nitrosamines / Q000737:chemistry / Q000378:metabolism*; D010865:Pilot Projects; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D014571:Urologic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D019459:Urothelium / Q000473:pathology
chemical_list: D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D001189:Aryl Hydrocarbon Hydroxylases; C414206:CYP2A13 protein, human; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase