Epoxide hydrolase and CYP2C9 polymorphisms, cigarette smoking, and risk of colorectal carcinoma in the Nurses' Health Study and the Physicians' Health Study

Abstract

Microsomal epoxide hydrolase (mEH) and cytochrome P450 2C9 (CYP2C9) are involved in the bioactivation and detoxification of polycyclic aromatic hydrocarbons (PAHs) derived from tobacco smoke. Two coding-region mEH variants (Tyr113His, His139Arg) and CYP2C9 variants (Arg144Cys, Ile359Leu) have been described and affect enzyme specific activity. We investigated these polymorphisms and tested interactions with smoking in relationship to risk of colorectal carcinoma in two case-control studies nested in the Nurses' Health Study (NHS) and Physicians' Health Study (PHS) cohorts. mEH Tyr113His and His139Arg polymorphisms were not associated with the risk of cancer among 197 incident cases and 490 controls from the NHS. Among 273 incident cases and 453 controls from the PHS, carrying one or two copies of the 'rapid' 139Arg allele was associated with a significantly reduced risk of colorectal cancer (OR=0.70, 95% CI 0.49--0.99) when compared with His139 wild-type individuals. Risk of colorectal cancer was significantly reduced among men carrying the CYP2C9 *1/*2 genotype (OR=0.62, 95% CI 0.42--0.92) or at least one CYP2C9 variant allele (OR=0.72, 95% CI 0.52--1.00) when compared with *1/*1 wild-type individuals. For women, carrying at least one variant CYP2C9 allele was inversely associated with the risk of colorectal cancer (OR=0.85, 95% CI, 0.57--1.27) when compared with *1/*1 wild-type individuals. No statistically significant genotype-smoking or gene-gene interactions were found in this study. Our results indicate that individuals exposed to tobacco carcinogens were at increased risk of colorectal cancer and that overall risk is related to mEH and CYP2C9 genotype, although the results were not consistent between men and women.