Microsomal Epoxide Hydrolase Gene Research Articles

EPOXID HYDROLASE SINGLE GENE POLYMORPHISM (RS1051740) AND SEVERITY OF CHRONIC OBSTRUCTIVE DISEASE.

The aim: The aim of the present study was to establish a link between polymorphic variants of the microsomal epoxide hydrolase gene and the severity of COPD in patients with COPD and coronary heart disease. Materials and methods: The study included 128 patients with COPD and IHD, who were divided into two groups: group 1 included 72 patients with in¬frequent exacerbations of COPD (0-1 per year) and group 2 included 56 patients with frequent exacerbations of COPD (exacerbation of COPD ≥2 per year). The control groups consisted of 15 smokers without COPD and IHD, 11 practically healthy non-smokers and 11 patients with IHD who do not smoke. All patients underwent DNA isolation and purification, followed by determination of the Tyr113His polymorphism of the EPHX1 microsomal epoxide hydrolase gene (rs1051740). Results: There was a significant association of the carriage of the CC genotype of the EPHX1 gene in patients with COPD and IHD (RO = 21.326 [95.0% CI 4.217-107.846], p <0.001) with a more severe course of COPD compared with the TT genotype of the EPHX1 gene. Conclusions: Patients with COPD and coronary heart disease who were carriers of a homozygous variant СС of the EPHX1 gene have a reliable association with a more severe course of COPD with frequent exacerbations (higher class according to GOLD classification and more severe symptoms of COPD according to the СAT questionnaire).

Association of microsomal epoxide hydrolase gene (fast genotype) with lung functions impairment in wood workers.

Exposure to wood dust may lead to impairment of the lung functions. Microsomal epoxide hydrolase enzyme (EPHX1) was shown to take part in protection against oxidative stress. An alteration in enzyme activity might be associated with its gene polymorphisms. In vitro polymorphisms in exons 3 (His113Tyr) and 4 (Arg139His) lead to reduced activity (slow allele) and increased activity (fast allele). Macrophage inflammatory protein 2 (MIP-2) is produced in rat lung epithelial cells after exposure to fine particles. We aimed to investigate the associations between mEPHX1 polymorphisms (in exon 3 and 4) and lung function in furniture workers and assessment of MIP-2 effect. Our study was performed on 70 wood dust exposed male workers and 70 matched normal controls subjects. Ventilatory function tests were measured by spirometer, MIP-2 was performed by ELISA methods and EPHX gene was done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods for each participant. Significant reduction in forced vital capacity (FVC%) and forced expiratory volume in the first second (FEV1) levels in Tyr-Tyr and Tyr-Hist genotypes of EPHX (exon 3) was observed. Reduced peak expiratory flow (PEF) levels and significant rise in MIP-2 levels were detected in Tyr-Tyr genotype. While high significant reduction in FVC% and FEV1 levels were shown in different genotypes in exon 4. Significant rise was observed in MIP-2 levels in Hist-Hist genotype of exon 4. An increase in duration of exposure showed positive correlation with fall in ventilatory functions. It was concluded that in Hist139Arg of EPHX gene, fast genotype (Arg-Arg) was associated with impaired ventilatory functions.

Evaluation of clinical and genetic factors in the population pharmacokinetics of carbamazepine.

AimsCarbamazepine can cause hypersensitivity reactions in ~10% of patients. An immunogenic effect can be produced by the electrophilic 10,11‐epoxide metabolite but not by carbamazepine. Hypothetically, certain single nucleotide polymorphisms might increase the formation of immunogenic metabolites, leading ultimately to hypersensitivity reactions. This study explores the role of clinical and genetic factors in the pharmacokinetics (PK) of carbamazepine and 3 metabolites known to be chemically reactive or formed through reactive intermediates.MethodsA combination of rich and sparse PK samples were collected from healthy volunteers and epilepsy patients. All subjects were genotyped for 20 single nucleotide polymorphisms in 11 genes known to be involved in the metabolism or transport of carbamazepine and carbamazepine 10,11‐epoxide. Nonlinear mixed effects modelling was used to build a population‐PK model.ResultsIn total, 248 observations were collected from 80 subjects. A 1‐compartment PK model with first‐order absorption and elimination best described the parent carbamazepine data, with a total clearance of 1.96 L/h, central distribution volume of 164 L and absorption rate constant of 0.45 h−1. Total daily dose and coadministration of phenytoin were significant covariates for total clearance of carbamazepine. EPHX1‐416G/G genotype was a significant covariate for the clearance of carbamazepine 10,11‐epoxide.ConclusionOur data indicate that carbamazepine clearance was affected by total dose and phenytoin coadministration, but not by genetic factors, while carbamazepine 10,11‐epoxide clearance was affected by a variant in the microsomal epoxide hydrolase gene. A much larger sample size would be required to fully evaluate the role of genetic variation in carbamazepine pharmacokinetics, and thereby predisposition to carbamazepine hypersensitivity.

The effect on congenital heart diseases of maternal EPHX1 polymorphisms modified by polycyclic aromatic hydrocarbons exposure.

Polycyclic aromatic hydrocarbons (PAHs) may be 1 of etiologic factors responsible for congenital heart diseases (CHDs). Variations of the microsomal epoxide hydrolase (EPHX1) gene, as well as their possible interactions with PAHs exposure, may increase susceptibility to CHDs.This case-control study investigated the risk of CHDs in relation to the EPHX1 polymorphisms and assessed the interactions between these polymorphisms and PAHs exposure in 357 mothers of CHDs fetuses and 270 control mothers. Logistic regression models for the risk of CHDs were applied to determine the effect of genetic polymorphisms using additive, recessive, and dominant genetic models, as well as gene-exposure interactions. Multiple testing was adjusted by applying the false discovery rate (FDR).None of the maternal genetic polymorphisms of EPHX1 was associated with CHDs occurrence. Only the single nucleotide polymorphism rs1051740 was associated with an increased risk of right-sided obstructive malformations under the recessive model (adjusted odds ratio [aOR] = 1.852, 95% confidence interval [CI]: 1.065, 3.22) before FDR correction. A possible modifying effect of PAHs exposure on genetic polymorphisms of EPHX1 was found in susceptibility to CHDs, though no multiplicative-scale interactions between maternal exposure to PAHs and polymorphisms of EPHX1 gene were seento affect the risk of CHDs.The role of EPHX1 gene polymorphisms for CHDs need to be further evaluated, in particularly by interacting with PAHs exposure.

Polymorphisms in the microsomal epoxide hydrolase gene: role in lung cancer susceptibility and prognosis.

The aim of this study was to investigate the relationship between EPHXI exon 3 Tyr113His and exon 4 His139Arg polymorphisms, predicted microsomal epoxide hydrolase (mEH) activity, and lung cancer development. mEH is a protective enzyme involved in oxidative defences against a number of environmental chemicals and pollutants, but it is also responsible for the xenobiotic activation of carcinogens. We investigated the two polymorphisms of the mEH gene (EPHX1) in 58 lung cancer patients and 41 controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The exon 3 Tyr113His polymorphism was associated with lung cancer (P < 0.001). The frequency of the His113His homozygote genotype in exon 3 was significantly increased in patients compared with controls (P < 0.001). In contrast, there was no significant difference in exon 4 polymorphisms between patients and controls. When the exon 3 and 4 polymorphisms were considered together, the combined EPHX1 His113His113/His139His139 genotype (very low predicted enzyme activity) was found to be associated with an increased risk of lung cancer (P = 0.044, OR = 3.063, CI = 0.932-10.069). We observed that patients with T3 + T4 tumors had an approximately 3-fold higher risk of the Tyr113/His113 genotype than patients with T1 + T2 tumors. Lung cancer patients carrying a heterozygote Tyr113/His 113 genotype had a 2-fold increased risk of lymph node metastases (P = 0.051). These findings suggest that the exon 3 Tyr113His and exon 4 His139Arg polymorphisms of EPHXI may be associated with a increased risk of lung cancer and a worse prognosis.

The clinical relevance and prognostic significance of microsomal epoxide hydrolase gene polymorphisms and their susceptibility to acquired aplastic anemia: an Egyptian study

Background: Microsomal epoxide hydrolase enzyme (mEPHX) is involved in xenobiotics detoxification. Two variants of mEPHX, Tyr113His and His139Arg, have been described. Both may lead to acquired aplastic anemia (AA).Objectives: Assessing mEPHX genetic polymorphisms and detecting their impact on susceptibility and prognosis in Egyptian AA patients.Participants and methods: mEPHX 113 and 139 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 100 patients with AA and 100 control subjects.Results: Both mEPHX Tyr113His and His139Arg gene polymorphisms were associated with increased risk of developing AA, and have a significant impact of bad prognosis (p value < 0.01).Conclusions: These mEPHX gene polymorphisms can be considered as risk factors and predictive molecular markers for prognosis in AA patients.

Microsomal epoxide hydrolase gene polymorphisms and susceptibility to prostate cancer: A systematic review.

Microsomal epoxide hydrolase (mEH) is a crucial biotransformation enzyme that has capability to metabolize a large number of structurally divergent, highly reactive epoxides, and numerous environmentally exposed carcinogens. It catalyzes the conversion of xenobiotic epoxide compounds into more polar diol metabolites and may play important part of the enzymatic defense against adverse effects of foreign compounds. Most commonly, two functional polymorphisms affecting mEH enzyme activity have been identified: One in exon 3 and other in exon 4 of the mEH gene, which results in His113Tyr and Arg139His amino acid substitutions, respectively. Recent reports have shown that polymorphisms in mEH gene loci may an important risk factor for susceptibility of prostate cancers (PCs), worldwide, but inconsistent finding were also be illustrated. To the best of our knowledge, globally, there is no any systematic review has been published related to mEH gene polymorphisms and PC risk. Thus, in the current review, we have discussed the association between mEH gene polymorphisms, gene-environmental interaction, and PC risk.

Transcription of the Human Microsomal Epoxide Hydrolase Gene (EPHX1) Is Regulated by PARP-1 and Histone H1.2. Association with Sodium-Dependent Bile Acid Transport.

Microsomal epoxide hydrolase (mEH) is a bifunctional protein that plays a central role in the metabolism of numerous xenobiotics as well as mediating the sodium-dependent transport of bile acids into hepatocytes. These compounds are involved in cholesterol homeostasis, lipid digestion, excretion of xenobiotics and the regulation of several nuclear receptors and signaling transduction pathways. Previous studies have demonstrated the critical role of GATA-4, a C/EBPα-NF/Y complex and an HNF-4α/CAR/RXR/PSF complex in the transcriptional regulation of the mEH gene (EPHX1). Studies also identified heterozygous mutations in human EPHX1 that resulted in a 95% decrease in mEH expression levels which was associated with a decrease in bile acid transport and severe hypercholanemia. In the present investigation we demonstrate that EPHX1 transcription is significantly inhibited by two heterozygous mutations observed in the Old Order Amish population that present numerous hypercholanemic subjects in the absence of liver damage suggesting a defect in bile acid transport into the hepatocyte. The identity of the regulatory proteins binding to these sites, established using biotinylated oligonucleotides in conjunction with mass spectrometry was shown to be poly(ADP-ribose)polymerase-1 (PARP-1) bound to the EPHX1 proximal promoter and a linker histone complex, H1.2/Aly, bound to a regulatory intron 1 site. These sites exhibited 71% homology and may represent potential nucleosome positioning domains. The high frequency of the H1.2 site polymorphism in the Amish population results in a potential genetic predisposition to hypercholanemia and in conjunction with our previous studies, further supports the critical role of mEH in mediating bile acid transport into hepatocytes.

EPHX1 Tyr113His polymorphism contributes to hepatocellular carcinoma risk: evidfnce from a meta-analysis

To clarify the association between microsomal epoxide hydrolase gene (EPHX1) Tyr113His polymorphism and hepatocellular carcinoma (HCC) risk, a meta-analysis was performed. Overall, EPHX1 Tyr113His polymorphism was associated with increased risk of HCC. Subgroup analyses by status of Hardy-Weinberg equilibrium (HWE) in controls further confirmed this association. Through a literature search, 119 relevant records were identified, and 17 individual case-control studies from 13 publications were finally included, involving a total of 1,480 HCC cases and 2,564 controls. In subgroup analyses, increased associations were found in Asians, Caucasians, hepatitis B virus (HBV)- dominant areas, hepatitis C virus (HCV)-dominant areas, high-rate areas of HCC, and medium-rate areas of HCC, but not in Africans and low-rate areas of HCC, respectively. This meta-analysis suggests that EPHX1 Tyr113His polymorphism contributes to HCC risk.

Meta-analysis of microsomal epoxide hydrolase gene polymorphism and the risk of breast carcinoma.

Carcinogenesis of breast carcinoma is very complicated. Previous studies have suggested conflicting results regarding the association between Tyr113His and His139Arg microsomal epoxide hydrolase (mEH) gene polymorphisms and risk of breast carcinoma. We conducted a meta-analysis to examine the relationship between these polymorphisms and breast carcinoma risk. We searched the PubMed, EMBASE, and Google Scholar databases to identify relevant studies. After extracting relevant data, the association between mEH polymorphisms and susceptibility to breast carcinoma was examined by meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of the association. Seven studies were identified that included 6357 cases and 8090 controls. The mEH His-allele was not associated with the risk of breast carcinoma based on the allelic contrast model (OR = 0.99, 95%CI = 0.94-1.04, P = 0.58), dominant genetic model (OR = 1.14, 95%CI = 0.88-1.48, P = 0.33), or recessive genetic model (OR = 1.03, 95%CI = 0.96-1.10, P = 0.43). Similarly, the mEH Arg-allele was not associated with breast carcinoma risk based on the allelic contrast model (OR = 0.97, 95%CI = 0.91-1.04, P = 0.44), dominant genetic model (OR = 1.01, 95%CI = 0.84-1.21, P = 0.94), or recessive genetic model (OR = 1.04, 95%CI = 0.96-1.12, P = 0.35). Subgroup analysis based on ethnicity showed no association between the polymorphisms and risk of breast carcinoma. Thus, the Tyr113His and His139Arg mEH polymorphisms may not be risk factors for breast carcinoma.

1 Alleles polymorphism of microsomal epoxide hydrolase gene (mEPHX) as modifier factor in cystic fibrosis

1 Alleles polymorphism of microsomal epoxide hydrolase gene (mEPHX) as modifier factor in cystic fibrosis N. Rohovyk1,2, N. Vishtak3, H. Makuh3, L. Bober4, O. Lyha2. 1Danylo Halytsky Lviv National Medical University, Lviv, Ukraine; 2Western Ukrainian Specialized Children’s Medical Centre and Cystic Fibrosis Regional Centre, Lviv, Ukraine; 3Institute of Hereditary Pathology of National Academy of Medical Sciences of Ukraine, Lviv, Ukraine; 4Western Ukrainian Specialized Children’s Medical Centre and Cystic Fibrosis regional centre, Lviv, Ukraine

Try113His and His139Arg polymorphisms in the microsomal epoxide hydrolase gene are not associated with risk of breast cancer

Breast cancer may be caused by several factors, including polymorphisms in the microsomal epoxide hydrolase (mEH) gene. Previous work suggested an association between mEH polymorphism and risk of breast cancer, but the results have been inconsistent. PubMed, EMBASE, Google Scholar, and the Chinese National Knowledge Infrastructure database were systematically searched to identify relevant studies. A meta-analysis was performed to examine the association between Tyr113His and His139Arg mEH polymorphisms and susceptibility to breast cancer. Odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated to assess the strength of the association. Seven studies involving 6,357 cases and 8,089 controls were included in this study. The Tyr113His mEH polymorphism did not affect breast cancer risk in the allelic contrast model (OR = 0.99, 95 % CI = 0.94-1.04, P = 0.58), the dominant genetic model (OR = 1.14, 95 % CI = 0.88-1.48, P = 0.33), or the recessive genetic model (OR = 1.03, 95 % CI = 0.96-1.10, P = 0.43). Similarly, the His139Arg mEH polymorphism was not associated with breast cancer risk in the allelic contrast model (OR = 0.97, 95 % CI = 0.91-1.04, P = 0.44), the dominant genetic model (OR = 1.01, 95 % CI = 0.84-1.21, P = 0.94), or the recessive genetic model (OR = 1.04, 95 % CI = 0.96-1.12, P = 0.35). The mEH polymorphisms Tyr113His and His139Arg are not risk factors for breast cancer. Further, large and well-designed studies are required to confirm this conclusion.

Intronic DNA elements regulate Nrf2 chemical responsiveness of the human microsomal epoxide hydrolase gene (EPHX1) through a far upstream alternative promoter

In humans, microsomal epoxide hydrolase (mEH) contributes important biological functions that underlie both detoxification and bioactivation fates arising from exposures to foreign chemicals. Previously, we discovered that human mEH gene transcription is initiated from alternative promoters. The respective transcripts are programmed with tissue specificity and the upstream E1b promoter contributes predominantly to mEH expression. The results presented demonstrate that exposures to the Nrf2 activators, sulforaphane (SFN) and tert-butylhydroquinone (tBHQ), markedly activate E1b transcription in human lung and liver cells. Genomic analyses identified two major DNase I hypersensitive regions (HS-1 and HS-2) within the ~15kb intervening sequence separating E1b from the downstream E1 promoter. In BEAS-2B cells, the Nrf2 effectors, SFN and tBHQ, selectively activated the more distal HS-2 through an antioxidant response element (ARE). An activator protein 1/12-O-tetradecanoylphorbol-13-acetate interaction was further identified within the HS-2 enhancer that functioned to additionally contribute to ARE-mediated induction responsiveness of the E1b promoter. The results demonstrate that ARE modulation, integrated with additional transcriptional complexes, regulates the tissue-specific expression of mEH and that these processes likely coordinate both the protective and bioactivation functions contributed by mEH activities in human tissues.

Transcription of the human microsomal epoxide hydrolase gene (EPHX1) is regulated by an HNF-4α/CAR/RXR/PSF complex

Microsomal epoxide hydrolase (mEH) is a bifunctional protein that plays a central role in the metabolism of numerous xenobiotics as well as mediating the sodium-dependent transport of bile acids into hepatocytes where they are involved in cholesterol excretion and metabolism, lipid digestion and regulating numerous signaling pathways. Previous studies have demonstrated the critical role of GATA-4 and a C/EBPα–NF/Y complex in the regulation of the mEH gene (EPHX1). In this study we show that HNF-4α and CAR/RXR also bind to the proximal promoter region and regulate EPHX1 expression. Bile acids, which inhibit the expression of HNF-4α also decrease the expression of EPHX1. Studies also established that the binding of HNF-4α was essential for the activation of EPHX1 activity by CAR suggesting the formation of a complex between these adjacent factors. The nature of this regulatory complex was further explored using a biotinylated oligonucleotide of this region in conjunction with BioMag beads and mass spectrometric analysis which demonstrated the presence of an additional inhibitory factor (PSF), confirmed by co-immunoprecipitation and ChIP analyses, which interacted with DNA-bound CAR/RXR/HNF-4α forming a 4-component regulatory complex.

MEH Tyr113His polymorphism and the risk of ovarian cancer development

BackgroundThe causes of ovarian cancer are complex and may be influenced by many factors, including polymorphism in the microsomal epoxide hydrolase (mEH) gene. Previous work suggests an association between the Tyr113His mEH polymorphism rs1051740 and susceptibility to ovarian cancer, but the results have been inconsistent.MethodsPubMed, EMBASE, Google Scholar, and Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. A meta-analysis was performed to examine the association between Tyr113His mEH polymorphism and susceptibility to ovarian cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.ResultsFive studies involving 2,566 cases and 2,839 controls were included. Although the polymorphism did not affect ovarian cancer risk in the allelic contrast model (OR = 0.99, 95% CI = 0.83-1.17, P = 0.86), the mutant CC genotype was significantly associated with increased risk in the homozygote comparison (OR = 1.20, 95% CI = 1.01-1.43, P = 0.04) and recessive genetic models (OR = 1.20, 95% CI = 1.01-1.41, P = 0.03). The wild-type TT genotype was not associated with higher or lower ovarian cancer risk in the dominant genetic model (OR = 1.04, 95% CI = 0.83-1.29, P = 0.74). These results were robust to sensitivity analysis.ConclusionsThe CC genotype of Tyr113His mEH may confer increased risk of ovarian cancer. These conclusions should be verified in large and well-designed studies.

Microsomal epoxide hydrolase gene polymorphisms and risk of chronic obstructive pulmonary disease: A comprehensive meta-analysis

Microsomal epoxide hydrolase (EPHX1) is an enzyme involved in the detoxification the products of smoking and is proposed to be a genetic factor for the development of chronic obstructive pulmonary disease (COPD). Two functional polymorphisms of EPHX1, T113C and A139G, have been analyzed in numerous studies to assess the COPD risk attributed to these variants. However, the conclusions were controversial. We performed a comprehensive meta-analysis to clarify these findings. A total of 24 studies comprising 8,259 COPD patients and 42,883 controls were included. The overall results showed that the EPHX1 113 mutant homozygote was significantly associated with an increased risk of COPD (OR, 1.33; 95% CI, 1.06–1.69). The subgroup analyses demonstrated this association in Caucasian individuals (OR, 1.61; 95% CI, 1.12–2.31) but not in Asian individuals. The 139 mutant heterozygote was significantly associated with a decreased risk of COPD in Asian populations (OR, 0.82; 95% CI, 0.68–0.99) but not in Caucasian populations. Pooled analyses revealed that the extremely slow (OR, 1.77; 95% CI, 1.23–2.55) and slow EPHX1 enzyme activity (OR, 1.44; 95% CI, 1.13–1.85) were associated with an increased risk of COPD, while the fast enzyme activity was not associated with a decreased risk of COPD. The stratified analysis demonstrated this association in Caucasian but not in Asian individuals. Furthermore, a modest difference in the risk of COPD was observed between the subgroups by using the cigarette smokers or the non-smokers as controls. A significant correlation between the two functional polymorphisms, T113C and A139G, of the EPHX1 gene and the enzyme activity and the individual’s susceptibility to COPD was noted. In addition, the results supported a contribution of EPHX1 to the aetiology of COPD.

Possible role of microsomal epoxide hydrolase gene polymorphism as a risk factor for developing insulin resistance and type 2 diabetes mellitus

The purpose of this study was to investigate the effects of mEPHX1 polymorphisms on risk of type 2 diabetes mellitus (T2DM) and insulin resistance (IR). One hundred and twelve patients with the diagnosis of T2DM and 150 control subjects were enrolled in the study. We investigated the two polymorphisms of the mEPHX1 gene (exon 3 Tyr113His and exon 4 His139Arg) using PCR-RFLP. Among diabetics, the frequencies obtained for the exon 3 mEPHX1 Tyr113 and His113 alleles were 46.9 and 53.1 %, respectively. In the control group, the frequencies were 70.7 and 29.3 %, respectively (P = 0.0001, OR = 2.73, 95 % CI = 1.9-3.91). The prevalence of mEPHX1 exon 3 Tyr/His and His/His was statistically significant (P = 0.004; 0.0001, respectively) when compared with the mEPHX1 exon 3 Tyr/Tyr homozygous carriers in both T2DM patients and in controls. We found that the His113 allele carriers had higher fasting insulin level, HOMA-IR, β cell activity, and lower insulin sensitivity compared to the wild type (P = 0.0001, 0.029, 0.0001, and 0.001, respectively). In contrast, there was no significant difference in exon 4 polymorphisms between patients and controls. However, our data revealed that the His139/His139 genotype carriers had higher fasting insulin level, and lower insulin sensitivity compared to Arg139 allele carriers (P = 0.02, and 0.001, respectively). Our study has shown for the first time that minor Tyr113 allele of mEPHX1 polymorphism had a higher risk of T2DM and IR occurrence with lower insulin sensitivity, while mEPHX1 exon 4 polymorphism had no significant association with T2DM and IR.

EPHX1 polymorphisms do not modify esophageal carcinoma susceptibility in Dutch Caucasians

Esophageal cancer (EC) has a globally increasing incidence with poor curative treatment options and survival rates. Crucial risk factors are exposure to toxins or carcinogens. Microsomal epoxide hydrolase (mEH) is a biotransformation enzyme essential for the detoxification of xenobiotics. Polymorphisms in exon 3 and exon 4 of the microsomal epoxide hydrolase gene (EPHX1) modify catalytic activity of this enzyme and subsequently may play a role in EC etiology. This case-control study investigated whether these polymorphisms in the EPHX1 gene influence esophageal cancer susceptibility in a Dutch Caucasian population. A case-control study including 349 Caucasian EC patients and 581 Caucasian healthy controls was conducted and the polymorphisms Tyr113His (exon 3) and His139Arg (exon 4) in the EPHX1 gene were determined, using polymerase chain reaction. The distribution of exon 3 and exon 4 genotypes were compared between cases and controls. Analyses included a stratification according to tumor histology; esophageal adenocarcinoma (EAC) or squamous cell carcinoma (ESCC). Furthermore, on the basis of allelic in vitro enzyme activity assays, exon 3 and 4 genotypes were combined and categorized according to their predicted high, medium or low enzyme activity. Homozygosity and heterozygosity for both exon 3 and 4 polymorphisms were correlated with a decreased esophageal squamous cell carcinoma risk. Heterozygosity and homozygosity for both polymorphisms correlated with an increased and a decreased esophageal adenocarcinoma risk, respectively. Predicted intermediate and high activity genotypes were risk and protective factors for esophageal squamous cell carcinoma and esophageal adenocarcinoma, respectively. However, none of these associations were statistically significant. In conclusion, the polymorphisms in exon 3 and exon 4 of the EPHX1 gene do not seem to be modifiers of esophageal squamous cell carcinoma or esophageal adenocarcinoma risk in Dutch Caucasians.

Genetically Lowered Microsomal Epoxide Hydrolase Activity and Tobacco-Related Cancer in 47,000 Individuals

Two functional polymorphisms of the microsomal epoxide hydrolase (mEH) gene (EPHX1), Tyr113His (rs1051740) and His139Arg (rs2234922), have variably been found to influence susceptibility to various cancer forms. We tested whether genetically lowered mEH activity affects risk of developing cancer in the general population. We genotyped 47,089 individuals from the Danish general population for the Tyr113His and His139Arg polymorphisms in the EPHX1 gene and divided them into groups with predicted fast, intermediate, and slow mEH activity. Using Cox proportional hazards models, we calculated HRs for 26 individual cancer diagnoses and for groups of any cancer, tobacco-related cancers, estrogen-related female cancers, and other cancers. Of the 47,089 individuals, 7,590 experienced a cancer event, and of these, 1,466 were tobacco-related. After multifactorial adjustment, the HRs (95% CI) for tobacco-related cancer were 1.1 (0.8-1.5) and 1.5 (1.1-2.0) in individuals with intermediate and slow mEH activity versus individuals with the fast phenotype (P(trend) = 0.003). The corresponding HRs among ever-smokers were 1.1 (0.8-1.5) and 1.5 (1.1-2.0; P(trend) = 0.003), whereas HRs among never-smokers did not differ from 1.0. Our results indicate that genetically lowered mEH activity is associated with increased risk of developing tobacco-related cancer among smokers in the general population; however, additional studies are needed to confirm our findings. To our knowledge, this is the largest study to investigate the association of mEH phenotype and genotype with tobacco-related cancers combined in the general population.

Association of Functionally Important Polymorphism of Microsomal Epoxide Hydrolase Gene (EPHX1) With Lung Cancer Susceptibility

Distribution and gene–environment interaction of EPHX1 polymorphism was evaluated in 175 lung cancer patients and 322 controls from north India. Two novel non-synonymous, Lys117Arg and Leu263Phe, and twelve single nucleotide polymorphisms were identified in the present study. Binary logistic regression analysis showed association of polymorphism Tyr113His with increased risk of lung cancer (OR = 2.2, 95% CI = 1.2–4.0, p < .05). Gene–environment interaction revealed that patients with His113His and smoking habit had significantly greater risk of lung cancer (OR = 4.52, 95% CI = 0.93–43.05, p < .05). Present study provided evidence that EPHX1 polymorphism is associated with lung cancer susceptibility in Indian population.