Search

Abstract Pancreatic cancer (PC) progresses rapidly, and gemcitabine‐based chemotherapy has brought only limited efficacy. Identifying key drivers and therapeutic targets holds significant clinical value. In this study, through comprehensive analysis of multiple PC databases, this work identifies TRIM21 as a promising driver mediator. This work further performs loss‐ and gain‐of‐function assays for TRIM21, revealing that TRIM21 knockout inhibits tumor proliferation and gemcitabine resistance both in vitro and vivo. Lipidomics reveal that silencing TRIM21 reduce the arachidonic acid production, and inhibit ferroptosis. Mechanically, through proteomics, ubiquitomics, and liquid chromatography‐tandem mass spectrometry analysis, the key metabolic enzyme of arachidonic acid ‐EPHX1 is identified as a downstream substrate of TRIM21. TRIM21 interacts with EPHX1 through its SPRY domain and promotes ubiquitin‐mediated degradation of EPHX1 via K33‐ and K48‐linked ubiquitination at the K105 site. Given the targeting potential, this work screens Bezafibrate to block the interaction between TRIM21 and EPHX1 and validates its sensitizing effect. In summary, TRIM21 promotes tumour growth and gemcitabine resistance in PC by inhibiting EPHX1‐mediated arachidonic acid metabolism. This provides a novel and promising target for clinical treatment of PC.

Epoxide hydrolases (EHs) regulate cellular homeostasis through hydrolysis of epoxides to less-reactive diols. The first discovered EH was EPHX1, also known as mEH. EH functions remain partly unknown, and no pathogenic variants have been reported in humans. We identified two de novo variants located in EPHX1 catalytic site in patients with a lipoatrophic diabetes characterized by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analyses revealed that these variants led to the protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response. This KO also promoted oxidative stress and cellular senescence, an observation confirmed in patient-derived fibroblasts. Metreleptin therapy had a beneficial effect in one patient. This translational study highlights the importance of epoxide regulation for adipocyte function and provides new insights into the physiological roles of EHs in humans.

Background: Chronic obstructive pulmonary disease (COPD) affects approximately 400 million people worldwide and is associated with high mortality and morbidity. The effect of EPHX1 and GSTP1 gene polymorphisms on COPD risk has not been fully characterized. Objective: To investigate the association of EPHX1 and GSTP1 gene polymorphisms with COPD risk. Methods: A systematic search was conducted on 9 databases to identify studies published in English and Chinese. The analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines (PRISMA). The pooled OR and 95% CI were calculated to evaluate the association of EPHX1 and GSTP1 gene polymorphisms with COPD risk. The I2 test, Q test, Egger's test, and Begg's test were conducted to determine the level of heterogeneity and publication bias of the included studies. Results: In total, 857 articles were retrieved, among which 59 met the inclusion criteria. The EPHX1 rs1051740 polymorphism (homozygote, heterozygote, dominant, recessives, and allele model) was significantly associated with high risk of COPD risk. Subgroup analysis revealed that the EPHX1 rs1051740 polymorphism was significantly associated with COPD risk among Asians (homozygote, heterozygote, dominant, and allele model) and Caucasians (homozygote, dominant, recessives, and allele model). The EPHX1 rs2234922 polymorphism (heterozygote, dominant, and allele model) was significantly associated with a low risk of COPD. Subgroup analysis showed that the EPHX1 rs2234922 polymorphism (heterozygote, dominant, and allele model) was significantly associated with COPD risk among Asians. The GSTP1 rs1695 polymorphism (homozygote and recessives model) was significantly associated with COPD risk. Subgroup analysis showed that the GSTP1 rs1695 polymorphism (homozygote and recessives model) was significantly associated with COPD risk among Caucasians. The GSTP1 rs1138272 polymorphism (heterozygote and dominant model) was significantly associated with COPD risk. Subgroup analysis suggested that the GSTP1 rs1138272 polymorphism (heterozygote, dominant, and allele model) was significantly associated with COPD risk among Caucasians. Conclusion: The C allele in EPHX1 rs1051740 among Asians and the CC genotype among Caucasians may be risk factors for COPD. However, the GA genotype in EPHX1 rs2234922 may be a protective factor against COPD in Asians. The GG genotype in GSTP1 rs1695 and the TC genotype in GSTP1 rs1138272 may be risk factors for COPD, especially among Caucasians. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Carbamazepine (CBZ), an anti-seizure drug, is widely prescribed for the management of focal seizures. At a given therapeutic dose, CBZ exhibits marked interindividual variation in the plasma CBZ levels. The aim wasto study the influence of EPHX1 c.337 T>C and UGT2B7*2 genetic polymorphisms on plasma carbamazepine (CBZ) levels in persons with epilepsy (PWE) from South India. METHODS: 115 PWE belong to South India origin who are on carbamazepine monotherapy were recruited. Genotyping of the two variants weredone using RT-PCR method. PWE who had seizure freedom for one year and their last dose which was not changed for one year duration were included and their plasma levels of CBZ and its active metabolite CBZ 10,11 epoxide were analysed by reverse phase HPLC. RESULTS: In EPHX1 c. 337 (T>C) polymorphism, the PWE carrying CC had lower plasma CBZ levels when compared to CT genotype (2.45 µg/ml vs 3.15 µg/ml. In UGT2B7*2, PWE carrying homozygous mutant TT had higher levels when compared with CT (3.09 µg/ml vs 2.74 µg/ml) genotype but found no statistical significance. Mutant genotype of EPHX1 (CC) had higher metabolic ratio compared to TT genotype (1.33 vs 1.17) but not found to be statistically significant. Mutant genotype of UGT2B7*2 (TT) was found to be having lower metabolic ratio when compared with CC genotype (1.18 vs 1.35; p value =0.08). CONCLUSION: PWE carrying EPHX1 c.337 T>C (rs1051740) and UGT2B7*2 (rs7439366) genetic polymorphisms did not affect the plasma CBZ levels and metabolic ratio of PWE of South Indian origin. However, this finding should be confirmed in a larger sample size which may help in optimization and personalized CBZ therapy in South Indians. [ABSTRACT FROM AUTHOR]

Aims: Carbamazepine (CBZ) is one of the most common causative drugs of severe cutaneous adverse drug reactions (SCARs) including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reactions with eosinophilia and systemic symptoms. Although genetic polymorphisms of the human leucocyte antigens (HLA) are well recognized key elements for the susceptibility to CBZ‐induced SCARs, some evidence suggest that polymorphisms of microsomal epoxide hydrolase 1 (EPHX1) may also contribute to the risk of these SCARs. This study investigated the association between the HLA and EPHX1 polymorphisms on CBZ‐induced SCARs in large sample sizes and well‐defined SCARs patients. Methods: Ninety‐one CBZ‐induced SCARs Thai patients and 144 CBZ‐tolerant patients were enrolled in the study. The genotypes of HLA‐A, HLA‐B and EPHX1 were determined. Results: Only 2 HLA alleles including HLA‐B*15:02 and HLA‐A*24:07 were statistically significant association with CBZ‐induced SJS/TEN. The highest risk was observed in patients with HLA‐B*15:02 allele (OR = 44.33, 95% confidence interval = 20.24–97.09, corrected P‐value = 6.80 × 10−29). Moreover, HLA‐B75 serotypes were significantly associated with CBZ‐induced SJS/TEN groups with an odds ratio of 81.00 (95% confidence interval = 32.39–202.56, corrected P‐value = 3.84 × 10−34). There is no association between EPHX1 c.337 T > C polymorphism and all phenotypes of CBZ‐induced SCARs. Conclusion: The HLA‐B*15:02 allele is the strongest genetic marker for the prediction of SJS/TEN induced by CBZ in Thai population. Screening for other alleles in the HLA‐B75 serotype increases sensitivity for prediction of a life‐threatening SCARs caused by CBZ. [ABSTRACT FROM AUTHOR]

Epoxide hydrolase 1 (EPHX1) has been reported to be related to the development of several tumors. However, the regulation of castration-resistant prostate cancer (CRPC) development by EPHX1 has not been reported. We used proteomic technology and found that the EPHX1 protein was highly expressed in CRPC tissues and the CRPC cell line C4-2. We performed screening and found that EPHX1 is a direct target of miR-491-5p. High miR-491-5p expression significantly reduced the EPHX1 level in C4-2 cells and inhibited C4-2 cell proliferation and migration. Zeolite imidazolate framework-8 (ZIF-8) has good thermal stability, a simple synthesis method, tumor site stability, and specific acid responsiveness. We synthesized ZIF-8 nanodrug vectors to deliver miR-491-5p into C4-2 cells. After loading miR-491-5p into ZIF-8, we modified the ZIF-8 surface with folic acid (FA) as the target group (FA@ZIF-8). Our synthesized nanodrug carrier showed less cytotoxicity to C4-2 cells even at 200 μg/ml. Modified FA could increase the efficiency of nanomaterial entry into C4-2 cells. FA@miR-491-5p@ZIF-8 could stably release miR-491-5p for a long period in both phosphate-buffered saline (pH 7.4) and acetate buffer (pH 4.8), and miR-491-5p was released faster at the beginning of the experiment in acetate buffer (pH 4.8). FA@miR-491-5p@ZIF-8 significantly reduced C4-2 cell proliferation and migration, and FA@miR-491-5p@ZIF-8 had a better effect than miR-491-5p alone. In vivo, FA@miR-491-5p@ZIF-8 significantly inhibited CRPC growth in nude mice. Overall, we verified that miR-491-4p regulated CRPC development by targeting EPHX1. The drug nanocarrier FA@miR-491-5p@ZIF-8 not only significantly reduced C4-2 CRPC cell proliferation and migration but also significantly inhibited CRPC growth. Our research provides a theoretical basis for treatment and treatment strategies for CRPC.

Objective We carried out a meta-analysis of case-control studies to determine whether epoxide hydrolase 1 (EPHX1) gene polymorphism rs1051740 was related to the risk of ovarian cancer.Methods Electronic databases were searched for relevant articles published in English or Chinese language. We calculated crude odds ratios (ORs) with their 95% confidence intervals (95% CIs) to assess the relationship of EPHX1 polymorphism rs1051740 with ovarian cancer risk. In addition, subgroup analyses were also conducted based on ethnicity and control source. Between-study heterogeneity was inspected with Q test and I2 statistic.Results Five eligible studies with a total of 1919 ovarian cancer patients and 1829 controls were ultimately included in the present meta-analysis. Overall results demonstrated that the association between EPHX1 polymorphism rs1051740 and ovarian cancer risk had no statistical significance either in total analysis or in subgroup analyses by ethnicity and source of control.Conclusion EPHX1 polymorphism rs1051740 may have no independent effect on ovarian cancer susceptibility.

Epoxide hydrolases (EHs) regulate cellular homeostasis through hydrolysis of epoxides to less-reactive diols. The first discovered EH was EPHX1, also known as mEH. EH functions remain partly unknown, and no pathogenic variants have been reported in humans. We identified two de novo variants located in EPHX1 catalytic site in patients with a lipoatrophic diabetes characterized by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analyses revealed that these variants led to the protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response. This KO also promoted oxidative stress and cellular senescence, an observation confirmed in patient-derived fibroblasts. Metreleptin therapy had a beneficial effect in one patient. This translational study highlights the importance of epoxide regulation for adipocyte function and provides new insights into the physiological roles of EHs in humans.

• EPHX1 rs1051740 T>C & rs2234922 A>G are associated with plasma CBZ concentration. • The impact of EPHX1 on plasma CBZ concentration varied among ethnic groups. • EPHX1 rs2234922 is associated with increased plasma CBZ concentration in Asian. Carbamazepine (CBZ) is a wildly used anti-epileptic drug (AED). Increasing evidence suggested that polymorphisms in Epoxide Hydrolase1 (EPHX1) gene are associated with the pharmacokinetics (PK) and pharmacodynamics (PD) of CBZ, albeit the results were inconsistent. A literature search on PubMed, Embase, and Cochrane Library was conducted to identify eligible studies published between 1974 and 2020. A meta -analysis was performed and the standardized mean difference (SMD) and 95% confidence interval (95% CI) were estimated using a random-effects model. The heterogeneity and leave-one-study-out sensitivity analyses of each article and the publication bias were also performed. All the statistical analyses were performed using STATA 14.0. A total of 6 articles with 1746 subjects were included in this meta -analysis. A significant correlation was detected between EPHX1 rs1051740 T > C polymorphisms and decreased plasma concentration of CBZ (TT vs CC: SMD = 0.34, P < 0.001; TC vs CC: SMD = 0.35, P = 0.009). However, similar results were not detected in the comparison of TT vs. TC in the EPHX1 rs1051740 T > C variation (P = 0.637), while subgroup analyses showed an association with plasma CBZ concentration in the non-Asian group (P < 0.001 , I 2 = 0.0%, Ph = 0.400). Although the association of EPHX1 rs2234922 A > G polymorphisms with plasma CBZ concentration was not detected (AA vs GG:SMD = 0.54, P = 0.102; AA vs AG:SMD = −0.05, P = 0.670; AG vs GG: SMD = 0.86, P = 0.107), subgroup analyses showed that the GG genotype EPHX1 rs2234922 was associated with increased plasma CBZ concentration in the Asian group (P = 0.005, I 2 = 48.6%, Ph = 0.143). EPHX1 rs1051740 T > C and rs2234922 A > G are important genetic variants associated with plasma CBZ concentration. The role of EPHX1 polymorphisms in the interindividual variability of plasma CBZ concentration varied significantly among different ethnic groups, which should be considered during clinical validation and in future studies. [ABSTRACT FROM AUTHOR]

Several studies have shown that low expression of epoxide hydrolase 1 (EPHX1) is closely associated with varying human cancers, including hepatocellular carcinoma (HCC). This study aims to explore the potential mechanism of EPHX1 silencing and revealed a novel regulatory pathway in the pathogenesis of HCC. In this study, micro ribonucleic acid (miR)‐184 was predicted and validated to be a regulator of EPHX1 through experiments, and its expression was negatively correlated with the messenger RNA (mRNA) levels of EPHX1 in primary tumors. Elevation of EPHX1 suppressed cell proliferation and migration as well as cell cycle progression, and induced apoptosis, while downregulation of miR‐184 exhibited the opposite effect on cellular processes. Moreover, LINC00205 interacted with miR‐184 and was markedly downregulated in tumors. The effects of the miR‐184 inhibitor on cell proliferation, apoptosis, and migration were reversed in part by the transfection with LINC00205 small interfering RNAs. In addition, LINC00205 acted as a molecular sponge to positively regulate the mRNA and protein levels of EPHX1 via regulating miR‐184. The tumorigenicity of HCC cells was enhanced by LINC00205 shRNA but diminished by overexpression of EPHX1 in vivo. Clinically, the EPHX1 expression in patients with HCC was markedly downregulated. Taken together, the results of this study suggest that as a competing endogenous RNA, LINC00205 may regulate EPHX1 by inhibiting miR‐184 in the progression of HCC and that targeting the LINC00205/miR‐184/EPHX1 axis may provide a treatment protocol for patients. [ABSTRACT FROM AUTHOR]

BackgroundEPHX1 gene polymorphisms were recently acknowledged as an important source of individual variability in carbamazepine metabolism, but the result of that association still remains controversial. Aim of the review To obtain a more precise estimation of the associations between EPHX1 polymorphisms and carbamazepine metabolism and resistance. Methods The PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals Database, China Biology Medicine disc and Wan fang Database were searched for appropriate studies regarding the rs1051740 and rs2234922 polymorphisms of EPHX1 up to September 2019. The meta-analysis was carried out using the Review Manager 5.3 software. The mean difference and 95% confidence interval were applied to assess the strength of the relationship. Results A total of 7 studies involving 1118 related epilepsy patients were included. EPHX1 rs1051740 polymorphism was significantly associated with adjusted concentrations of both carbamazepine (CC vs. TT: P = 0.02; CC vs. CT + TT: P = 0.005) and carbamazepine-10,11-epoxide (CC vs. CT + TT: P = 0.03). Furthermore, EPHX1 rs2234922 polymorphism was also observed to be significantly associated with decreased adjusted concentrations of carbamazepine-10,11-trans dihydrodiol (GG vs. GA + AA: P = 0.04) and CBZD:CBZE ratio (GG vs. AA: P = 0.008; GG vs. GA + AA: P = 0.0008). Nevertheless, the pooled analysis showed that the EPHX1 polymorphisms had no significant effect on CBZ resistance. Conclusion EPHX1 rs1051740 and rs2234922 polymorphisms may affect the carbamazepine metabolism; but carbamazepine resistance was not related to any of the single nucleotide polymorphisms investigated. These findings provided further evidence for individualized therapy of epilepsy patients in clinics. [ABSTRACT FROM AUTHOR]

Experimental and epidemiological data have shown that acute myeloid leukemia in early-age (i-AML) originates prenatally. The risk association between transplacental exposure to benzene metabolites and i-AML might be influenced by genetic susceptibility. In this study, we investigated the relationship between genetic polymorphisms in CYP2E1, EPHX1, MPO, NQO1, GSTM1 and GSTT1 genes, and i-AML risk. The study included 101 i-AMLs and 416 healthy controls. Genomic DNA from study subjects was purified from bone marrow or peripheral blood aspirates and genotyped for genetic polymorphisms by real-time PCR allelic discrimination, Sanger sequencing and multiplex PCR. Crude and adjusted odds ratios (OR, adjOR, respectively) with 95% confidence intervals (95% CI) were assessed using unconditional logistic regression to estimate the magnitude of risk associations. EPHX1 rs1051740 T>C was associated with i-AML risk under the co-dominant (adjOR 3.04, P = 0.003) and recessive (adjOR 2.99, P = 0.002) models. In stratified analysis, EPHX1 rs1051740 was associated with increased risk for i-AML with KMT2A rearrangement (adjOR 3.06, P = 0.045), i-AML with megakaryocytic differentiation (adjOR 5.10, P = 0.008), and i-AML with type I mutation (adjOR 2.02, P = 0.037). EPHX1 rs1051740-rs2234922 C-G haplotype was also associated with increased risk for i-AML (adjOR 2.55, P = 0.043), and for i-AML with KMT2A rearrangement (adjOR 3.23, P = 0.034). Since EPHX1 enzyme is essential in cellular defense against epoxides, the diminished enzymatic activity conferred by the variant allele C could explain the risk associations found for i-AML. In conclusion, EPHX1 rs1051740 plays an important role in i-AML’s genetic susceptibility by modulating the carcinogenic effects of epoxide exposures in the bone marrow. [ABSTRACT FROM AUTHOR]

In this study, we scrutinized the effects of curcumin and AFB 1 supplemented diet alone or in combination on phase-ӀӀ enzymes. Histopathological examination showed that after 28 days, AFB1 (5.0 mg/kg diet) induced liver injury in broilers, but curcumin supplementation partially ameliorated liver injury in a dose-dependent manner. RT-PCR data revealed that AFB 1 significantly (p < 0.01) down-regulated Nrf2 and its downstream genes mRNA expression level. Moreover, Western blot analysis showed that Nrf2, GSTM2, and GSTA3 protein expression level was markedly (p < 0.01) reduced in AFB 1 -fed group. However, curcumin supplementation ameliorated AFB 1 -induced liver injury via enhancing phase-ӀӀ enzymes expressions and activity. HPLC results showed that curcumin increased AFB 1 -GSH conjugation in-vitro in liver cytosol. Surprisingly, similar trends were noted in mRNA, protein expression level of Nrf2 and its downstream genes at day 35, one week after the withdrawal of AFB 1 and curcumin from the diet, showing the preventive effects of curcumin. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a type of obstructive lung disease characterized by long term poor airflow which worsens over time. It is considered to be one of the top five chronic diseases of the world in terms of morbidity and mortality. Genetic variability has been found to contribute to the development of COPD. Although association between gene polymorphisms in EPHX1 and TNF-a genes and chronic obstructive pulmonary disease (COPD) have been found but till date no genetic association studies have been done in the COPD affected Kazakhstan population. The aim of the present work was to investigate the association between the Y113H polymorphism (rs1051740) in EPHX1 gene and −308G/A polymorphism (rs1800629) in TNF-a gene and COPD in Kazakhstan population. A case-control study was conducted in Astana and Akmola regions of Kazakhstan, involving 55 cases with COPD and 52 healthy individuals who served as the controls. The polymorphisms were determined using conventional PCR and Sanger sequencing method. Results show that for the EPHX1 gene Y113H polymorphism, the presence of an “C” allele (TC/CC genotype) was significantly overrepresented in the COPD patients compared to the controls. For the TNF-a gene −308G/A polymorphism, no significant difference was found between the two groups. Thus we found that, Y113H polymorphism in EPHX1 gene contributed to increased susceptibility to COPD in the Kazakhstan population. [ABSTRACT FROM AUTHOR]

The aim of our study was to analyze the presence of 5-methyl-cytosine (5-mC) and 5-hydroxymethyl-cytosine (5-hmC) in the genome of crustacean Daphnia pulex. First, the presence of 5-mC and 5-hmC in genomic DNA was demonstrated by using antibodies specific to either 5-mC or 5-hmC. Then, analysis of 5-mC and 5-hmC using pairs of restriction enzymes with different sensitivity to methylation and hydroxymethylation confirmed the presence of both modifications in selected regions of three genes (Cox4, Cand2 and Ephx1). To get a detailed picture of 5-hmC distribution over the D. pulex genome, we performed 5-hmC enrichment and sequenced the enriched fraction using next generation sequencing and non-enriched library (input) as a control. Comparison of input and enriched libraries showed that 5-hmC in exons is twice as frequent as in introns. Functional analysis indicated that 5-hmC abundance is associated with genes that are involved in the adenylate cyclase-activating G-protein-coupled receptor signaling pathway, molting cycles, morphogenesis and cell fate determination. Genes that lack 5-hmC tend to be involved in the regulation of the transforming growth factor beta receptor signaling pathway and in many mRNA-related processes. Our results suggest that epigenetic modifications are present in the genome of D. pulex and most likely are involved in the regulation of gene expression of this crustacean. [ABSTRACT FROM AUTHOR]

Microsomal epoxide hydrolase (EPHX1) is an evolutionarily highly conserved biotransformation enzyme for converting epoxides to diols. Notably, the enzyme is able to either detoxify or bioactivate a wide range of substrates. Mutations and polymorphic variants in the EPHX1 gene have been associated with susceptibility to several human diseases including cancer. This review summarizes the key knowledge concerning EPHX1 gene and protein structure, expression pattern and regulation, and substrate specificity. The relevance of EPHX1 for human pathology is especially discussed. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the association between the major genetic variants involved in the pharmacokinetic/pharmacodynamic (PK/PD) properties of carbamazepine (CBZ) and its maintenance doses and concentrations. Patients & methods: The genotypes of 166 patients receiving CBZ monotherapy were detected using high-resolution melting curve (HRM) and TaqMan methods. Results: Both univariate and multiple regression analyses revealed that carriers of the SCN1A IVS5-91G>A or EPHX1 c.337T>C allele tended to require a higher CBZ dose and a lower CBZ natural logarithmic concentration-dose ratio (lnCDR) than noncarriers (p < 0.05). Furthermore, two interactions between these genes were associated with the lnCDR and the maintenance dosage of CBZ, respectively. Conclusion: SCN1A IVS5-91G>A gene polymorphism is potential genetic biomarker associated with the PK of CBZ. [ABSTRACT FROM AUTHOR]

Objectives: Carbamazepine (CBZ) is a first-line antiseizure drug used for focal onset seizures. It exhibits inter-individual variability in plasma carbamazepine levels and there are both genetic and non-genetic factors having a role in the requirement of CBZ maintenance dose. The aim was to study the influence of EPHX1 c.337 T>C and UGT2B7*2 genetic polymorphisms on CBZ maintenance dose requirement in persons with epilepsy., Methods: Persons with epilepsy (PWE) of both gender of age 15-65 years on carbamazepine monotherapy who had been taking same maintenance dose for one year were eligible. Five milliliter of venous blood was collected in 10% EDTA under aseptic precautions. After centrifugation, the cellular component was used for DNA extraction and genotyping. For three genotypes of EPHX1 c.337 T>C and UGT2B7*2 , the differences in mean carbamazepine dose were analyzed using Analysis of Variance (ANOVA). An unpaired t-test was used to draw a comparison between the genotypes and CBZ maintenance dose requirement for dominant and recessive models of EPHX1 c.337 T>C and  UGT2B7*2 . A value of p<0.05 was considered to be statistically significant., Results: For UGT2B7*2 (rs 7439366), CT required a higher dose (CT 626 mg/day and TT 523 mg/day) but not found to be significant (p-value 0.167). PWE carrying CT genotype of  EPHX1 c.337 T>C had 62 mg higher dose when compared to homozygous mutant CC (590 mg/day for CT and 528 mg/day for CC) but p-value was not found to be significant (p-value 0.835)., Conclusions: The results of our study done in 115 PWE showed there was a lack of association between SNPs of EPHX1 c.337 T>C, UGT2B7*2 and CBZ maintenance dose requirement in Southern part of India and this finding has to be confirmed in a larger sample size., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Styrene exposure is still present in different occupational settings including manufacture of synthetic rubber, resins, polyesters and plastic. The aim of this work was to investigate the effects of polymorphic genes CYP2E1, EPHX1, GSTT1, and GSTM1 on the urinary concentrations of the styrene metabolites mandelic acid (MA), phenylglyoxylic acid (PGA) and on the concentration ratios between (MA + PGA) and urinary styrene (U-Sty) and airborne styrene (A-Sty), in 30 workers from two fiberglass-reinforced plastic manufacturing plants and 26 unexposed controls. Personal air sampling and biological monitoring results revealed that sometimes exposure levels exceeded both the threshold limit value (TLV) and the biological exposure index (BEI) suggested by the American Conference of Governmental Industrial Hygienists. A significantly reduced excretion of styrene metabolites (MA + PGA) in individuals carrying the CYP2E1*5B and CYP2E1*6 heterozygote alleles, with respect to the homozygote wild type, was observed only in the exposed group. A reduction was also detected, in the same group, in subjects carrying the slow allele EPHX1 (codon 113), through the lowering of (MA + PGA)/urinary styrene concentration ratio. In addition, the ratio between MA + PGA and the personal airborne styrene concentration appeared to be modulated by the predicted mEH activity, in the exposed group, as evidenced by univariate linear regression analysis. Our results confirm some previous hypotheses about the role of the polymorphism of genes coding for enzymes involved in the styrene detoxification pathway: this may significantly reduce the levels of excreted metabolites and therefore it must be taken into account in the interpretation of the biological monitoring results for occupational exposure. [ABSTRACT FROM AUTHOR]

The microsomal epoxide hydrolase 1 ( EPHX1) Tyr113 His and His139 Arg polymorphisms have been reported to be associated with esophageal cancer ( EC) risk, yet the results of these previous results have been inconsistent or controversial. The objective of this study was to explore whether the EPHX1 Tyr113 His and His139 Arg polymorphisms confer risk to EC. The relevant studies were identified through a search of PubMed, Excerpta Medica Database (Embase), Elsevier Science Direct, and Chinese Biomedical Literature Database until May 2013. The association between the EPHX1 Tyr113 His and His139 Arg polymorphisms and EC risk was pooled by odds ratios ( ORs) together with their 95% confidence intervals (95% CIs). A total of eight case-control studies with 1163 EC patients and 1868 controls (seven studies for both Tyr113 His and His139 Arg polymorphisms, one study only for Tyr113 His polymorphism) were eventually identified. We found no association between EPHX1 Tyr113 His and His139 Arg polymorphisms and EC risk in overall population (For Tyr113 His: His vs. Tyr: OR = 1.05, 95% CI = 0.95-1.15, P = 0.379; His/ His vs. Tyr/ Tyr: OR = 1.04, 95% CI = 0.88-1.22, P = 0.208; His/ Tyr vs. Tyr/ Tyr: OR = 0.96, 95% CI = 0.80-1.15, P = 0.577; His/ His vs. His/ Tyr + Tyr/ Tyr: OR = 1.10, 95% CI = 0.96-1.26, P = 0.164; His/ His + His/ Tyr vs. Tyr/ Tyr: OR = 1.01, 95% CI = 0.90-1.12, P = 0.543. For His139 Arg: Arg vs. His: OR = 1.04, 95% CI = 0.94-1.14, P = 0.465; Arg/ Arg vs. His/ His: OR = 1.06, 95% CI = 0.91-1.24, P = 0.470; Arg/ His vs. His/ His: OR = 1.03, 95% CI = 0.91-1.16, P = 0.673; Arg/ Arg vs. Arg/ His + His/His: OR = 1.04, 95% CI = 0.85-1.27, P = 0.708; Arg/ Arg + Arg/ His vs. His/ His: OR = 1.02, 95% CI = 0.93-1.13, P = 0.617). In subgroup analysis based on ethnicity, significant association has been found in neither EPHX1 Tyr113 His nor His139 Arg polymorphism. The current meta-analysis suggests no evidence of association between the EPHX1 polymorphism and EC risk. [ABSTRACT FROM AUTHOR]

Objective This study explored the association between the risk of carbamazepine ( CBZ)-induced Stevens- Johnson syndrome ( SJS)/toxic epidermal necrolysis ( TEN) and CBZ dose, dose-adjusted concentration, and ABCB1 , CYP3A4 , EPHX1 , FAS , SCN1A , MICA, and BAG6 polymorphisms in patients of Han ethnicity with epilepsy who were living in northeastern China. Materials and methods We determined the genotypes of patients with CBZ- SJS/ TEN and CBZ-tolerant patients, who were used as controls, for ABCB1 , CYP3A4 , EPHX1 , FAS , SCN1A , MICA, and BAG6 polymorphisms by polymerase chain reaction ( PCR) amplification and direct sequencing. We measured the steady-state serum CBZ concentrations using fluorescence polarization immunoassay for the control patients. Results We observed statistically significant differences in EPHX1 c.337T>C polymorphisms between patients with CBZ- SJS/ TEN and CBZ-tolerant controls in terms of allelic and genotypic frequencies (p = 0.011 and p = 0.007, respectively). The C allele and the C- G diplotype of EPHX1 may play important roles in increasing the risk of CBZ- SJS/ TEN development (odds ratio [ OR] 0.478, 95% confidence interval [ CI] = 0.267-0.855, p = 0.011; OR = 0.213, 95% CI = 0.049-0.930, p = 0.025, respectively). We did not observe any significant associations between ABCB1 , CYP3A4 , EPHX1 , FAS , SCN1A , MICA or BAG6 genes and CBZ dose or dose-adjusted concentration in CBZ-tolerant patients. Significance We found a significant association between EPHX1 c.337T>C polymorphisms and the development of CBZ- SJS/ TEN in patients of Han ethnicity living in northeastern China. EPHX1 c.337T>C polymorphisms may contribute to the risk of severe CBZ- SJS/ TEN by increasing the concentration of a CBZ metabolite, CBZ-10,11-epoxide, in patients with epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section . [ABSTRACT FROM AUTHOR]

Abstract: Microsomal epoxide hydrolase (mEH, EPHX1) is a critical biotransformation enzyme, catalyzing the metabolism of many xenobiotics. Human mEH is transcribed using alternative promoters. The upstream E1 promoter is active in liver while the far upstream E1b promoter drives the expression of mEH in all tissues, including liver. Although several liver-specific transcription factors have been identified in the regulation of E1 transcription, little is known regarding the mechanisms of E1b transcriptional regulation. Genome-wide mapping of DNase I hypersensitive sites revealed an open chromatin region between nucleotide −300 upstream and +400 downstream of E1b. This area coincides with a previously described promoter region responsible for maintaining high basal promoter activity. In silico analysis of this location revealed several Sp1/Sp3 binding sites. Site-directed mutagenesis of these motifs suppressed the transactivation activity of the E1b proximal promoter, indicating their importance as contributors to E1b promoter regulation. Further, E1b promoter activities were increased significantly following Sp1 and Sp3 overexpression, while Mithramycin A, a selective Sp1 inhibitor, reduced the promoter activities. EMSA studies demonstrated that Sp1 bound to two putative Sp1/Sp3 binding sites. ChIP analysis confirmed that both endogenous Sp1 and Sp3 were bound to the proximal promoter region of E1b. Knockdown of Sp1 expression using siRNA did not alter the endogenous E1b transcriptional level, while knockdown of Sp3 greatly decreased E1b expression in different human cell lines. Taken together, these results support the concept that Sp1 and Sp3 are functionally involved as transcriptional integrators regulating the basal expression of the derived mEH E1b variant transcript. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Microsomal epoxide hydrolase is a smooth endoplasmic reticulum enzyme and is expressed relatively ubiquitously in most tissues and in many species. The microsomal epoxide hydrolase (mEH) encoded by EPHX1 is a biotransformation enzyme that metabolizes numerous reactive epoxide intermediates to more water-soluble trans-dihydrodiol derivatives. In the present study, we genotyped two SNPs of the EPHX1 gene [(Exon 3: Tyr113His; rs1051740) and (Exon 4: His139 Arg; rs2234922)], using TaqMan allelic discrimination among 212 individuals of six major south Indian populations, and compared with other available world populations data. Both polymorphisms followed Hardy-Weinberg equilibrium and were highly polymorphic in the studied populations. The haplotype based analysis revealed remarkable variation among the study populations. Linkage disequilibrium (LD) between Tyr113 His and His139Arg loci was not significant in any of the population studied. Calculation of LD in the 20kb up and downstream regions from Tyr113His and His 139Arg loci in HapMap populations revealed no significant LD between these markers in all the populations. Analysis of predicted EPHX1 activity status of all samples revealed that the prevalence of low activity samples is more than the intermediate and high activity samples in all populations studied. Screening of additional populations and computation of genetic distances between populations at SNP sites may help in understanding the population genetic and evolutionary aspects of this gene. [ABSTRACT FROM AUTHOR]

Microsomal epoxide hydrolase 1 (EPHX1) plays an important role in the detoxification of carcinogenic polycyclic aromatic hydrocarbons. EPHX1 Tyr113His and His139Arg polymorphisms have been reported to have some impacts on the EPHX1 activity. Previous case-control studies assessing the associations between EPHX1 polymorphisms and esophageal cancer risk reported conflicting results. To quantitatively summarize the associations of EPHX1 Tyr113His and His139Arg polymorphisms with esophageal cancer risk, a systemic review and meta-analysis of published studies were performed. Published literatures from PubMed, Embase, and China National Knowledge Infrastructure databases were searched. The strength of the associations between EPHX1 polymorphisms and esophageal cancer risk was estimated by the pooled odds ratios (ORs) with its 95 % confidence interval (95 %CI). This meta-analysis yielded nine case-control studies, which included nine studies for Tyr113His polymorphism (1,291 cases and 2,120 controls) and seven studies for His139Arg polymorphism (899 cases and 1,615 controls). Overall, meta-analysis showed that EPHX1 Tyr113His polymorphism was not associated with esophageal cancer risk under all genetic models. Meta-analysis of these seven studies for EPHX1 His139Arg polymorphism showed that EPHX1 His139Arg polymorphism was also not associated with esophageal cancer risk under all genetic models. However, subgroup analysis by ethnicity further showed that there was an obvious association between EPHX1 His139Arg polymorphism and decreased risk of esophageal cancer in Caucasians (ArgArg versus HisArg/HisHis: OR = 0.52, 95 %CI 0.27-0.97, P = 0.041). This meta-analysis suggests that EPHX1 His139Arg polymorphism is associated with decreased risk of esophageal cancer in Caucasians. In addition, more studies with large samples are needed to get a more precise estimation on the associations mentioned above. [ABSTRACT FROM AUTHOR]

Background: The interplay between genetic susceptibility and carcinogenic exposure is important in the development of haematopoietic malignancies. EPHX1, NQO1 and PON1 are three genes encoding proteins directly involved in the detoxification of potential carcinogens. Methods: We have studied the prevalence of three functional polymorphisms affecting these genes rs1051740 EPHX1, rs1800566 NQO1 and rs662 PON1 in 215 patients with lymphoma and 214 healthy controls. Results: Genotype frequencies for EPHX and NQO1 polymorphisms did not show any correlation with disease. In contrast, the GG genotype in the PON1 polymorphism was found to be strongly associated with the disease (15.3% vs. 4.7%; OR = 3.7 CI (95%): 1.8-7.7; p < 0.001). According to the pathological diagnosis this association was related to follicular (p = 0.004) and diffuse large B-cell (p = 0.016) lymphomas. Conclusions: Despite the fact that further confirmation is needed, this study shows that the PON1 GG genotype in rs662 polymorphism could be a risk factor for B-cell lymphomas [ABSTRACT FROM AUTHOR]

Background: The microsomal epoxide hydrolase is a phase II enzyme of the biotransformation. The human epoxide hydrolase 1 ( EPHX1) gene lies in the chromosomal region 1q42.1 and exhibits polymorphism. Two single nucleotide polymorphisms (SNPs) have been described in the coding region of the EPHX1 gene that produces two protein variants. Subjects and methods: A total of 604 samples belonging to 13 Indian populations were included in this study. Based on the DSM -IV criteria, 184 individuals from Kota population were classified into alcoholism cases (100) and controls (84). Genotypes of Tyr113His and His139Arg polymorphisms in the EPHX1 gene were determined using PCR and sequencing. Associations were tested using Pearson's χ2 test and haplotype analyses. Results: We found significant association between EPHX1 gene Tyr113His polymorphism and alcoholism in the Kota population (T vs. C: OR = .615, 95% CI = .399-.949, p = .027; TT vs. CC + CT: OR = .536, 95% CI = .297-.969, p = .038). The very slow activity haplotype CA (113His-139His) was also found to be associated with alcohol dependence ( p = .048). Analysis of additional populations demonstrated that the Tyr113His polymorphism significantly deviated from Hardy-Weinberg equilibrium in four populations but only one population deviated for the His139Arg locus. All populations shared the four possible two-site haplotypes. Linkage disequilibrium between these two loci was not significant in any of the population studied. Conclusion: EPHX1 gene polymorphisms and haplotypes are associated with an increased risk for alcoholism in the Kota population. This is the first report from India that will serve as a template for future investigations of the prevalence of EPHX1 alleles in association with various clinical entities. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Epoxide hydrolases are involved in detoxifying and excreting the environmental chemicals, which are associated with decreased semen quality and male infertility. We hypothesized that polymorphisms in epoxide hydrolases may be associated with risk of oligozoospermia and asthenospermia. Design and methods: In this study, 468 fertile controls and 672 idiopathic male infertile patients were recruited. SNPstream and TaqMan assay were used to genotype four single nucleotide polymorphisms in EPHX1 and EPHX2. The semen analysis was performed by computer-assisted semen analysis system. Results: Our results demonstrated that rs1042064 of EPHX2 was significantly associated with decreased risk of oligozoospermia (OR=0.65, 95% CI: 0.44–0.98) and asthenospermia (OR=0.66, 95% CI: 0.46–0.94). Conclusions: Our results provided evidence that genetic variants in epoxide hydrolases may modify the risk of oligozoospermia and asthenospermia in Han-Chinese population. [Copyright &y& Elsevier]