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.

Harmful effects of nicotine

“…A study relates lung carcinogenesis by nicotine due to genetic variation in CYP2B6. [ 44 ] Its simultaneous exposure with hyperoxia has been found to induce cancer in hamsters. [ 45 ] Cotinine has been found to promote lung tumorigenesis by inhibiting anti-apoptotic pathway.…”

Polymorphic Variants of Cytochrome P450

“…Despite the suggestion from the GWA study discussed above that CYP2B6 genotype could be relevant to nicotine intake, the overall contribution of this isoform to nicotine metabolism is low (Lee et al, 2007). In a recent pilot study, some evidence suggesting an additional contribution by CYP2B6 genotype to that of CYP2A6 to risk of lung cancer susceptibility has been obtained, though additional studies involving larger populations or ethnic groups where low activity CYP2B6 alleles are common are needed to confirm this (Wassenaar et al, 2013).…”

“…However, the efficiency of CYP2B6 as an activator of nitrosamines, especially NNK, is higher than its efficiency as an oxidiser of nicotine, which is the reverse of CYP2A6 (Wassenaar, Dong, Amos, Spitz, & Tyndale, 2013). Despite the suggestion from the GWA study discussed above that CYP2B6 genotype could be relevant to nicotine intake, the overall contribution of this isoform to nicotine metabolism is low (Lee et al, 2007).…”

Penetapan Kadar Nikotin dan Karakteristik Ekstrak Daun Tembakau (Nicotiana tabacum L.)

“…Bahaya dari nikotin antara lain dapat merangsang pembentukan kanker 1,2 karsinogenesis paru paru karena variasi genetik pada CYP2B6. 3 Lebih dari 80% nikotin yang diserap mengalami metabolisme di hati, terutama oleh CYP2A6, UDP-glucuronosyltransferase, dan monooxygenase yang mengandung flavin. Sebanyak 85--90% nikotin dimetabolisme sebelum eliminasimelalui ekskresi ginjal.…”