title: Genetic determinants of cytochrome P450 2A6 activity and biomarkers of tobacco smoke exposure in relation to risk of lung cancer development in the Shanghai cohort study.
abstract: Cytochrome P450 2A6 (CYP2A6) catalyzes nicotine metabolism and contributes to the metabolism of the tobacco-specific lung carcinogen, NNK. Genetic variation in CYP2A6 may affect smoking behavior and contribute to lung cancer risk. A nested case-control study of 325 lung cancer cases and 356 controls was conducted within a prospective cohort of 18,244 Chinese men in Shanghai, China. Quantified were 4 allelic variants of CYP2A6 [*1(+51A), *4, *7, and *9] and urinary total nicotine, total cotinine, total trans-3'-hydroxycotinine (3HC) and total NNAL (an NNK metabolite). Calculated were total nicotine equivalents (TNE), the sum of total nicotine, total cotinine and total 3HC and the total 3HC:total cotinine ratio as a measure of CYP2A6 activity. The nicotine metabolizer status (normal, intermediate, slow and poor) was determined by CYP2A6 genotypes. The smoking-adjusted odds ratios (95% confidence intervals) of lung cancer for the highest vs lowest quartile of total nicotine, total cotinine, total 3HC, TNE and total NNAL were 3.03 (1.80-5.10), 4.70 (2.61-8.46), 4.26 (2.37-7.68), 4.71 (2.61-8.52), and 3.15 (1.86-5.33) (all Ptrend  < 0.001), respectively. Among controls CYP2A6 poor metabolizers had a 78% lower total 3HC:total cotinine ratio and 72% higher total nicotine (Ptrend ≤ 0.002). Poor metabolizers had an odds ratio of 0.64 (95% confidence interval = 0.43-0.97) for lung cancer, which was statistically nonsignificant (odds ratio = 0.74, 95% confidence interval = 0.48-1.15) after adjustment for urinary TNE and smoking intensity and duration. The lower lung cancer risk observed in CYP2A6 poor metabolizers is partially explained by the strong influence of CYP2A6 genetic polymorphisms on nicotine uptake and metabolism.
authors.affiliation: Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA.|Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Yuan
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN.|Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN.
authors.forename: Heather H
authors.initials: HH
authors.lastname: Nelson
authors.affiliation: Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA.|Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Lesley M
authors.initials: LM
authors.lastname: Butler
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Carmella
authors.affiliation: Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA.
authors.forename: Renwei
authors.initials: R
authors.lastname: Wang
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN.
authors.forename: Jacquelyn K
authors.initials: JK
authors.lastname: Kuriger-Laber
authors.affiliation: Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Adams-Haduch
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Hecht
authors.affiliation: Department of Epidemiology, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Yu-Tang
authors.initials: YT
authors.lastname: Gao
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN.|Department of Biochemistry, Molecular Biology and BioPhysics, University of Minnesota, Minneapolis, MN.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Murphy
mesh_terms: D044466:Asian People / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000032:analysis; D016022:Case-Control Studies; D002681:China; D015331:Cohort Studies; D003367:Cotinine / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000235:genetics / Q000378:metabolism*; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D009538:Nicotine; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D003367:Cotinine
keywords: CYP2A6; Chinese; lung cancer; tobacco exposure biomarkers; total nicotine equivalents