Pilot Study of CYP2B6 Genetic Variation to Explore the Contribution of Nitrosamine Activation to Lung Carcinogenesis

Catherine Wassenaar,Christopher Amos,Margaret Spitz,Rachel Tyndale,Qiong Dong

doi:10.3390/ijms14048381

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.

Highlights

Variation in genes participating in nicotine and nitrosamine pharmacology has been associated with lung cancer risk among smokers
We have reported that variation in the nicotine and nitrosamine metabolizing gene, CYP2A6, and the nicotinic receptor subunit gene cluster, CHRNA5-CHRNA3-CHRNB4 (CHRNA5-A3-B4), combined to increase cigarette consumption and lung cancer risk among European American cigarette smokers [1]
To explicitly explore the potential contribution of altered nitrosamine pharmacology to lung cancer risk among smokers, we have extended our investigation of gene variants to CYP2B6

Summary

Introduction

Variation in genes participating in nicotine and nitrosamine pharmacology has been associated with lung cancer risk among smokers. Owing to the contribution of these genes to nicotine pharmacology, CYP2A6 and CHRNA5-A3-B4 increase lung cancer risk indirectly through increased cigarette consumption and increased carcinogen exposure These genes could be contributing to lung cancer risk directly through altered nitrosamine pharmacology—the CYP2A6 enzyme metabolically activates tobacco specific nitrosamines (TSNA) [2] and the nicotinic receptors are high-affinity binding sites for nitrosamines [3]. Activators of TSNAs suggested a potential redundant role of CYP2B6 and CYP2A6 gene variants In this exploratory analysis, our main objectives were to estimate the effect size of CYP2B6 relative to CYP2A6 and CHRNA5-A3-B4 and to establish a probable independent contribution of CYP2B6 to the risk of lung cancer among smokers and in so doing implicate a role for altered nitrosamine activation in the molecular mechanism of lung carcinogenesis

Results and Discussion

Experimental Section

Conclusions