Abstract
BackgroundEPHX1 is a key enzyme in metabolizing some exogenous carcinogens such as products of cigarette-smoking. Two functional polymorphisms in the EPHX1 gene, Tyr113His and His139Arg can alter the enzyme activity, suggesting their possible association with carcinogenesis risk, particularly of some tobacco-related cancers.Methodology/Principal FindingsA comprehensive systematic review and meta-analysis was performed of available studies on these two polymorphisms and cancer risk published up to November 2010, consisting of 84 studies (31144 cases and 42439 controls) for Tyr113His and 77 studies (28496 cases and 38506 controls) for His139Arg primarily focused on lung cancer, upper aerodigestive tract (UADT) cancers (including oral, pharynx, larynx and esophagus cancers), colorectal cancer or adenoma, bladder cancer and breast cancer. Results showed that Y113H low activity allele (H) was significantly associated with decreased risk of lung cancer (OR = 0.88, 95%CI = 0.80–0.96) and UADT cancers (OR = 0.86, 95%CI = 0.77–0.97) and H139R high activity allele (R) with increased risk of lung cancer (OR = 1.18, 95%CI = 1.04–1.33) but not of UADT cancers (OR = 1.05, 95%CI = 0.93–1.17). Pooled analysis of lung and UADT cancers revealed that low EPHX1 enzyme activity, predicted by the combination of Y113H and H139R showed decreased risk of these cancers (OR = 0.83, 95%CI = 0.75–0.93) whereas high EPHX1 activity increased risk of the cancers (OR = 1.20, 95%CI = 0.98–1.46). Furthermore, modest difference for the risk of lung and UADT cancers was found between cigarette smokers and nonsmokers both in single SNP analyses (low activity allele H: OR = 0.77/0.85 for smokers/nonsmokers; high activity allele R: OR = 1.20/1.09 for smokers/nonsmokers) and in combined double SNP analyses (putative low activity: OR = 0.73/0.88 for smokers/nonsmokers; putative high activity: OR = 1.02/0.93 for smokers/ nonsmokers).Conclusions/SignificancePutative low EPHX1 enzyme activity may have a potential protective effect on tobacco-related carcinogenesis of lung and UADT cancers, whereas putative high EPHX1 activity may have a harmful effect. Moreover, cigarette-smoking status may influence the association of EPHX1 enzyme activity and the related cancer risk.
Highlights
Human microsomal epoxide hydrolase (EPHX1 or mEH, EC 3.3.2.9) plays an important role during xenobiotic detoxification of exogenous chemicals such as polycyclic aromatic hydrocarbons (PAHs) which are produced during the use of coal tar, coke, bitumen, or during cigarette smoking [1,2,3]
Cigarette-smoking status may influence the association of EPHX1 enzyme activity and the related cancer risk
A previous meta-analysis of the association of these single nucleotide polymorphisms (SNPs) with lung cancer revealed that the low-activity genotype (HH) of EPHX1 polymorphism Y113H was associated with decreased risk of lung cancer while the high-activity genotype (RR) of polymorphism H139R was associated with a modest increase risk of lung cancer among Caucasians
Summary
Human microsomal epoxide hydrolase (EPHX1 or mEH, EC 3.3.2.9) plays an important role during xenobiotic detoxification of exogenous chemicals such as polycyclic aromatic hydrocarbons (PAHs) which are produced during the use of coal tar, coke, bitumen, or during cigarette smoking [1,2,3]. Based on the genotype combination of these two functional polymorphisms, Benhamou and colleagues [9] classified EPHX1 activity as putative low activity (113HH/ 139HH, 113HH/139HR and 113YH/139HH), intermediate activity (113HH/139RR, 113YY/139HH and 113YH/139HR) and high activity (113YH/139RR, 113YY/139HR and 113YY/ 139RR) They found a significant association with lung cancer risk between cases exhibiting putative high and intermediate EPHX1 activity compared to low activity cases in Caucasian cigarette smokers [9]. The predicted low activity by genotype combination of two polymorphisms was associated with a modest decrease of lung cancer risk [19]. Two functional polymorphisms in the EPHX1 gene, Tyr113His and His139Arg can alter the enzyme activity, suggesting their possible association with carcinogenesis risk, of some tobacco-related cancers
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
