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Int. J. Mol. Sci. 2013, 14(4), 8381-8392; doi:10.3390/ijms14048381
Article

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

1
, 2
, 3
, 4
 and 5,*
1 Department of Pharmacology and Toxicology, The University of Toronto, Toronto, ON M5S 1A8, Canada 2 Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA 3 Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA 4 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA 5 Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Departments of Psychiatry, Pharmacology and Toxicology, the University of Toronto, Toronto, ON M5S 1A8, Canada
* Author to whom correspondence should be addressed.
Received: 14 March 2013 / Revised: 2 April 2013 / Accepted: 9 April 2013 / Published: 16 April 2013
(This article belongs to the Special Issue Molecular Research of Carcinogenesis)
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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
Keywords: CYP2B6; CYP2A6; CHRNA5-CHRNA3-CHRNB4; tobacco specific nitrosamines; lung cancer risk; genetic variation CYP2B6; CYP2A6; CHRNA5-CHRNA3-CHRNB4; tobacco specific nitrosamines; lung cancer risk; genetic variation
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Wassenaar, C.A.; Dong, Q.; Amos, C.I.; Spitz, M.R.; Tyndale, R.F. Pilot Study of CYP2B6 Genetic Variation to Explore the Contribution of Nitrosamine Activation to Lung Carcinogenesis. Int. J. Mol. Sci. 2013, 14, 8381-8392.

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