The effect of mEH activity on lung cancer risk was not significantly modified by smoking exposure, CYP1A1 genotype, or GSTM1 genotype. mEH may thus be an important genetic determinant of smoking-induced lung cancer.
Activity of microsomal epoxide hydrolase (HYL1) has also been associated with lung cancer, and 2 variant alleles causing amino acid substitutions have been described.
A combination of susceptible CYP1A1 and HYL1 genotypes was found to be highly associated with lung cancer, especially with SCC (OR 6.76; 95% CI 2.29-19.10).
Although the three published results for Caucasians are somewhat variable, the association among African-Americans in these data provides some support for the hypothesis that genetically reduced microsomal epoxide hydrolase activity may be protective against lung cancer.
Our results agree with these observations in vitro and suggest that a genetically determined combination of a high-activity mEH and a low-activity GSTpi may increase lung cancer risk among smokers.
These findings suggest that the presence of the exon 4 and exon 3 polymorphisms of mEPHX may be associated with an increased risk of lung cancer particularly among younger Mexican-Americans in this study.
To determine whether there is gene-environment interaction between NAT2 polymorphisms, alone or in combination with mEH polymorphisms, and cumulative smoking exposure in the development of lung cancer, we conducted a case control study of 1115 Caucasian lung cancer patients and 1250 spouse and friend controls.
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).
Among genetic polymorphisms reviewed here, myeloperoxidase gene (a G to A mutation) and microsomal epoxide hydrolase exon 4 polymorphism (substitution of Arg for His) were significantly associated with lung cancer risk.
In conclusion, the CA data provides evidence to support that susceptibility mEH alleles are significantly involved with the development of lung cancer from cigarette smoking.
Together with data from the present study on DNA repair genes, we did not observe significant associations between any single variant genotype for several DNA-repair and chemical-metabolizing genes (XPD [or ERCC2], XRCC1, XRCC3, GSTM1, GSTT1, MPO, and mEH [or EPHX1]) and lung cancer.
In white populations, the high-activity (variant) genotype of EPHX1 polymorphism at exon 4 was associated with a modest increase in risk of lung cancer (1.22; 0.79-1.90) and the predicted low activity was associated with a modest decrease in risk (0.72; 0.43-1.22).
In this review, we collect and discuss the evidence reported up to date on the association between lung cancer and genetic polymorphism of cytochromes P450, N-acetyltransferase, glutathione S-transferases, microsomal epoxide hydrolase, NAD(P)H:quinone oxidoreductase, myeloperoxidase and glutathione peroxidase.
However, only four of the previously reported associations with polymorphisms in the GSTP1 (Ala14Val), SOD2 (Val16Ala), EPHX1 (His139Arg) genes and the NAT1 fast acetylator phenotype remained significantly associated with lung cancer.
However, this study provides some support for the T-Allel of GPX1(Pro200Leu) and the C-Allele of EPHX1(His113Tyr) to play a protective role in early onset lung cancer susceptibility.
A genetic component of early-onset lung cancer has been suggested but variations in enzyme activity and polymorphisms in EPHX1 have seldom been studied in young patients with lung cancer.