Microsomal epoxide hydrolase (mEPHX) is a critical metabolic enzyme involved in the activation and subsequent detoxification of specific tobacco carcinogens. mEPHX harbors polymorphisms in exon 3 and exon 4 that modulate enzymatic activity. The exon 3 polymorphism decreases mEPHX metabolic activity, whereas the exon 4 polymorphism increases activity. We hypothesized that the mEPHX polymorphisms modulate lung cancer risk. Using a case-control study design and restriction fragment length polymorphism polymerase chain reaction assay, we determined the mEPHX polymorphic genotypes of 181 lung cancer cases among non-Hispanic whites and 163 controls (matched for age, sex, ethnicity, and smoking history). Our results showed that the variant allele of mEPHX exon 4 increased the overall lung cancer risk by 56% (odds ratio [OR]=1.56, 95% confidence interval [CI]=0.99-2.46). Additionally, the risk estimates were elevated significantly for younger people (<64 yr) (OR=2.27, 95% CI=1.15-4.50) and current smokers (OR=2.22, 95% CI=1.06-4.65). The variant allele of mEPHX exon 3 had no effect overall (OR=0.88, 95% CI=0.56-1.38), but there was a 53% protective effect (OR=0.47, 95% CI=0.22-0.99) in younger people. When we analyzed the exon 3 and exon 4 polymorphisms together, those people with the high enzymatic activity genotype had an elevated lung cancer risk of 1.72 (95% CI=0.90-3.29). This elevated risk was also evident only in younger people. These findings suggest that these variant alleles of exon 3 and exon 4 of mEPHX modulates lung cancer risk.
Copyright 2002 Wiley-Liss, Inc.