title: Pilot study of CYP2B6 genetic variation to explore the contribution of nitrosamine activation to lung carcinogenesis.
abstract: We explored the contribution of nitrosamine metabolism to lung cancer in a pilot investigation of genetic variation in CYP2B6, a high-affinity enzymatic activator of tobacco-specific nitrosamines with a negligible role in nicotine metabolism. Previously we found that variation in CYP2A6 and CHRNA5-CHRNA3-CHRNB4 combined to increase lung cancer risk in a case-control study in European American ever-smokers (n = 860). However, these genes are involved in the pharmacology of both nicotine, through which they alter smoking behaviours, and carcinogenic nitrosamines. Herein, we separated participants by CYP2B6 genotype into a high- vs. low-risk group (*1/*1 + *1/*6 vs. *6/*6). Odds ratios estimated through logistic regression modeling were 1.25 (95% CI 0.68-2.30), 1.27 (95% CI 0.89-1.79) and 1.56 (95% CI 1.04-2.31) for CYP2B6, CYP2A6 and CHRNA5-CHRNA3-CHRNB4, respectively, with negligible differences when all genes were evaluated concurrently. Modeling the combined impact of high-risk genotypes yielded odds ratios that rose from 2.05 (95% CI 0.39-10.9) to 2.43 (95% CI 0.47-12.7) to 3.94 (95% CI 0.72-21.5) for those with 1, 2 and 3 vs. 0 high-risk genotypes, respectively. Findings from this pilot point to genetic variation in CYP2B6 as a lung cancer risk factor supporting a role for nitrosamine metabolic activation in the molecular mechanism of lung carcinogenesis.
authors.affiliation: Department of Pharmacology and Toxicology, The University of Toronto, Toronto, ON M5S 1A8, Canada. r.tyndale@utoronto.ca.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Wassenaar
authors.forename: Qiong
authors.initials: Q
authors.lastname: Dong
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Spitz
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
mesh_terms: D065767:Activation, Metabolic / Q000235:genetics; D000368:Aged; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics* / Q000378:metabolism*; D005240:Feasibility Studies; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D009602:Nitrosamines / Q000378:metabolism*; D016017:Odds Ratio; D010865:Pilot Projects; D011978:Receptors, Nicotinic / Q000235:genetics; D012307:Risk Factors
chemical_list: D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D009419:Nerve Tissue Proteins; D009602:Nitrosamines; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human; C585710:CYP2A6 protein, human; C585599:CYP2B6 protein, human