CYP2A6 genetic polymorphisms and biomarkers of tobacco smoke constituents in relation to risk of lung cancer in the Singapore Chinese Health Study.
Cytochrome P450 2A6 (CYP2A6) catalyzes the metabolism of nicotine and the tobacco-specific lung carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Genetic variation in CYP2A6 may affect smoking behavior and contribute to lung cancer risk. A nested case-control study of 197 lung cancer cases and 197 matched controls was conducted within a prospective cohort of 63 257 Chinese men and women in Singapore. Quantified were five genetic variants of CYP2A6 (*1A, *4, *7, *9 and *12) and urinary metabolites of nicotine [total nicotine, total cotinine, total trans-3'-hydroxycotinine (3HC)] and NNK (total NNAL, free NNAL, NNAL-glucuronide, NNAL-N-glucuronide, and NNAL-O-glucuronide). Higher urinary metabolites of nicotine and NNK were significantly associated with a 2- to 3-fold increased risk of lung cancer after adjustment for smoking intensity and duration. Lower CYP2A6-determined nicotine metabolizer status was significantly associated with a lower ratio of total 3HC over total cotinine, lower total nicotine equivalent and reduced risk of developing lung cancer (all Ptrend < 0.001). Compared with normal metabolizers, odds ratios (95% confidence intervals) of developing lung cancer for intermediate, slow and poor metabolizers determined by CYP2A6 genotypes were 0.85 (0.41-1.77), 0.55 (0.28-1.08) and 0.32 (0.15-0.70), respectively, after adjustment for smoking intensity and duration and urinary total nicotine equivalents. Thus the reduced risk of lung cancer in smokers with lower CYP2A6 activity may be explained by lower consumption of cigarettes, less intense smoking and reduced CYP2A6-catalyzed activation of the tobacco-specific lung carcinogen NNK.
Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.|Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Jian-Min
JM
Yuan
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.|Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
Heather H
HH
Nelson
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Steven G
SG
Carmella
Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Renwei
R
Wang
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Jacquelyn
J
Kuriger-Laber
National Registry of Diseases Office, Health Promotion Board, Singapore, Singapore.
Aizhen
A
Jin
Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Jennifer
J
Adams-Haduch
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Stephen S
SS
Hecht
Duke-NUS Medical School Singapore, Singapore, Singapore.|Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore and.
Woon-Puay
WP
Koh
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.|Department of Biochemistry, Molecular Biology and BioPhysics, University of Minnesota, MN, USA.
Sharon E
SE
Murphy
D044466:Asian People / Q000235:genetics; D015415:Biomarkers / Q000737:chemistry*; D002273:Carcinogens / Q000737:chemistry; D016022:Case-Control Studies; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000009:adverse effects; D009602:Nitrosamines / Q000009:adverse effects; D011110:Polymorphism, Genetic / Q000235:genetics*; D011446:Prospective Studies; D012306:Risk; D012846:Singapore; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects / Q000235:genetics; D014026:Nicotiana
D015415:Biomarkers; D002273:Carcinogens; D009602:Nitrosamines; D012906:Smoke; D009538:Nicotine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6