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Background 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. Methods 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. Results 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 C variation (P = 0.637), while subgroup analyses showed an association with plasma CBZ concentration in the non-Asian group (P 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, I2 = 48.6%, Ph = 0.143). Conclusion 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.

There is evidence that polycyclic aromatic hydrocarbons (PAHs) are consistently the predominant organic contaminants in concentration found in loggerhead sea turtles (Caretta caretta) from the North and Central Adriatic Sea. Hence this study investigates the PAH toxicity to loggerheads by using a particular set of genes [i.e. CYP1B, CAT, GPX, GSTT1, SOD3, DNMT1, Epoxide hydrolase 1 (EPHX1), Poly (ADP-ribose) polymerase 1 (PARP1), Lamin-A/C isoform 3 (LMNA), Talin 1 (TLN1), Annexin A1 (ANXA1)] whose altered expression is potentially dependent on and specific for the PAH-related mechanism of action. Twenty healthy juvenile loggerheads were thus divided into high and low exposure groups (mean of ΣPAHs: 80.34 ng mL−1 vs. 8.84 ng mL−1, P

Objectives Crizotinib is a standard treatment for advanced anaplastic lymphoma kinase (ALK)- or ROS1-fusion-gene-positive non-small cell lung cancer; however, serious adverse events (AEs), including elevated alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and interstitial lung disease (ILD), develop occasionally. Here, we evaluated relationships between clinically significant crizotinib-associated AEs and germline variations. Materials and Methods DNA obtained from 75 patients allowed selection of 147 genes according to function, exon identification and sequencing, and determination of germline single nucleotide variants (SNVs). Correlations between clinically significant AEs and presence of germline variants were estimated by Fisher’s exact test. Results We defined clinically significant AEs as grade 4 hematological toxicity, grade ≥3 non-hematological toxicity, and any grade of ILD. These AEs were observed in 26 patients (35%), with elevated AST/ALT (15%) the most common, followed by neutropenia (5%), ILD (4%), and thromboembolic events (4%). Nonsynonymous SNVs in epoxide hydrolase 1 (EPHX1) [odds ratio (OR): 3.86; p = 0.0009) and transcription factor 7-like 2 (TCF7L2) (OR: 2.51; p = 0.025) were associated with the presence of clinically significant AEs. Conclusion Nonsynonymous EPHX1 and TCF7L2 SNVs might be associated with clinically significant crizotinib-associated AEs. These data indicated that target-gene sequencing could be feasible for predicting anticancer-agent toxicity, and that germline multi-gene information might be useful for predicting patient-specific AEs to promote precision medicine.

Although the effects of prenatal passive smoking on birth weight have been reported, the effects of metabolic gene polymorphisms on passive smoking have not been studied. Therefore, we investigated the effects of maternal passive smoking and metabolic gene polymorphisms on child growth up to 3years of age using cotinine as a biomarker. We included 1356 Japanese participants in a prospective cohort between 2003 and 2007 (cotinine levels at the third trimester≤0.21ng/mL and 0.22 to 11.48ng/mL for non-passive and passive smokers, respectively), and measured child outcomes such as weight, length, head circumference, and Kaup index. Additionally, we analyzed cytochrome P450 1A1 (CYP1A1), epoxide hydrolase 1 (EPHX1), and two N-acetyltransferase 2 (NAT2) genotypes using real-time polymerase chain reaction methods. Associations were investigated using multiple regression models. Kaup index gain from birth up to 3years of age was significantly smaller in children born to passive smokers than in those born to non-passive smokers (-0.34kg/m2; 95% confidence interval: -0.67, -0.01). Maternal CYP1A1 genotype was not associated with prenatal passive smoking and Kaup index gain, but was significantly associated with prenatal passive smoking and head circumference gain from birth up to 3years of age (-0.75cm; 95% confidence interval: -1.39, -0.12). Thus, this study suggests that prenatal passive smoking may have potent effects on postnatal growth from birth up to 3years of age. Moreover, children with maternal CYP1A1 genotype may be more susceptible to the effects of prenatal passive smoking.

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.

Non-obese, spontaneous, and genetically predisposed type 2 diabetic Chinese hamsters exhibit metabolic abnormalities similar to those observed in human T2DM. Here, tandem mass tag (TMT)-based quantitative proteomics technology was used to screen and identify differentially abundant proteins in the liver that are associated with diabetes in Chinese hamsters. GO and KEGG pathway enrichment analysis were conducted to validate the findings, as well as qRT-PCR and western blotting. In total, 103 proteins were identified in the livers of diabetic hamsters, of which 48 were up-regulated and 55 were down-regulated. KEGG pathway enrichment analysis further demonstrated that linoleic acid metabolism, arachidonic acid metabolism, bile secretion, and other pathways were affected. Moreover, AQP9 and EPHX1 were significantly down-regulated in the bile secretion pathway, whereas PTGES2, Cyp2c27, and Cyp2c70 were associated with the arachidonic acid metabolic pathway. Serum levels of bile acid (BA) and arachidonic acid (AA) in diabetic Chinese hamsters were significantly higher than those in control hamsters. Cumulatively, our findings indicate that the five candidate proteins may be associated with abnormal BA and AA metabolism, suggesting their involvement in pathological changes in the livers of Chinese hamsters with T2DM. SIGNIFICANCE: The liver proteomics of Chinese hamsters describes differentially abundant proteins associated with T2DM, while promoting this animal model as an appropriate and ideal platform for investigating underlying molecular mechanisms of T2DM. This study reveals abnormal bile acid and arachidonic acid metabolism in T2DM hamsters, which may provide insights for studying the relationship between candidate proteins and KEGG pathways to elucidate the underlying molecular mechanism associated with T2DM.

Some studies suggested oxidative stress as a possible mechanism for the relation between exposure to bisphenol A (BPA) and liver damage. Therefore, we evaluated modification of genetic polymorphisms of cyclooxygenase 2 (COX2 or PTGS2), epoxide hydrolase 1 (EPHX1), catalase (CAT), and superoxide dismutase 2 (SOD2 or MnSOD), which are oxidative stress-related genes, on the relation between exposure to BPA and liver function in the elderly. We assessed the association of visit-to-visit variations in BPA exposure with abnormal liver function by each genotype or haplotype after controlling for age, sex, BMI, alcohol consumption, exercise, urinary cotinine levels, and low density lipoprotein cholesterol using a GLIMMIX model. A significant association of BPA with abnormal liver function was observed only in participants with COX2 GG genotype at rs5277 (odds ratio (OR)=3.04 and p=0.0231), CAT genotype at rs769218 (OR=4.16 and p=0.0356), CAT CT genotype at rs769217 (OR=4.19 and p=0.0348), SOD2 TT genotype at rs4880 (OR=2.59 and p=0.0438), or SOD2 GG genotype at rs2758331 (OR=2.57 and p=0.0457). Moreover, we also found higher OR values in participants with a pair of G-G haplotypes for COX2 (OR=2.81 and p=0.0384), G-C-A haplotype for EPHX1 (OR=4.63 and p=0.0654), A-T haplotype for CAT (OR=4.48 and p=0.0245), or T-G-A haplotype for SOD2 (OR=2.91 and p=0.0491) compared with those with the other pair of haplotypes for each gene. Furthermore, the risk score composed of 4 risky pair of haplotypes showed interactive effect with BPA on abnormal liver function (p=0.0057). Our study results suggest that genetic polymorphisms of COX2, EPHX1, CAT, and SOD2 modify the association of BPA with liver function.

The mammalian epoxide hydrolase (EPHX)3 is known from in vitro experiments to efficiently hydrolyze the linoleate epoxides 9,10-epoxyoctadecamonoenoic acid (EpOME) and epoxyalcohol 9R,10R-trans-epoxy-11E-13R-hydroxy-octadecenoate to corresponding diols and triols, respectively. Herein we examined the physiological relevance of EPHX3 to hydrolysis of both substrates in vivo. Ephx3−/− mice show no deficiency in EpOME-derived plasma diols, discounting a role for EPHX3 in their formation, whereas epoxyalcohol-derived triols esterified in acylceramides of the epidermal 12R-lipoxygenase pathway are reduced. Although the Ephx3−/− pups appear normal, measurements of transepidermal water loss detected a modest and statistically significant increase compared with the wild-type or heterozygote mice, reflecting a skin barrier impairment that was not evident in the knockouts of mouse microsomal (EPHX1/microsomal epoxide hydrolase) or soluble (EPHX2/sEH). This barrier phenotype in the Ephx3−/− pups was associated with a significant decrease in the covalently bound ceramides in the epidermis (40% reduction, p < 0.05), indicating a corresponding structural impairment in the integrity of the water barrier. Quantitative LC-MS analysis of the esterified linoleate-derived triols in the murine epidermis revealed a marked and isomer-specific reduction (∼85%) in the Ephx3−/− epidermis of the major trihydroxy isomer 9R,10S,13R-trihydroxy-11E-octadecenoate. We conclude that EPHX3 (and not EPHX1 or EPHX2) catalyzes hydrolysis of the 12R-LOX/eLOX3-derived epoxyalcohol esterified in acylceramide and may function to control flux through the alternative and crucial route of metabolism via the dehydrogenation pathway of SDR9C7. Importantly, our findings also identify a functional role for EPHX3 in transformation of a naturally esterified epoxide substrate, pointing to its potential contribution in other tissues.

Introduction Warfarin is the most commonly used oral anticoagulant, however, there are large interindividual variations in dose responses. Genetic polymorphisms in CYP2C9 , VKORC1 and CYP4F2 have been shown to play an important role in variations in the warfarin maintenance dose in adults, but their effects in children remain unclear. We aimed to investigate the effect of VKORC1 polymorphism on warfarin dosage in pediatric patients by meta-analysis. Materials and methods Using strict inclusion and exclusion criteria, we searched PubMed, EMBASE, Cochrane library, Chinese Biomedical Literature Database, CNKI and ChainInfo from 2004 to Mach 17th, 2015. The relationship between warfarin dose and two single nucleotide polymorphisms of the VKORC1 gene (at positions −1639 and 1173) were analyzed using Revman version 5.2.3 software. Results and conclusions Eight studies were included in the meta-analysis, involving 610 pediatric patients. Patients that were VKORC1 −1639 GA, AA or A carriers required significantly lower warfarin dosage than GG carriers (the weighted mean difference in warfarin dose ranged from −26% to −50%). Additionally, the age of the patient and indication of warfarin (i.e. Fontan procedure) significantly affected warfarin dosage, but changes in the target international normalized ratio range had no effect. On the other hand, VKORC1 1173 polymorphisms showed no significant effect on warfarin dosage, which differs from adult patients. In conclusion, we found that VKORC1 −1639 gene polymorphisms have a moderate effect on warfarin dosage in pediatric patients, but clinical characteristics such as age and indication of warfarin also play an important role.

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.

Background Xenobiotic metabolizing enzymes (XME) comprising epoxide hydrolase (EPHX1), NAD(P)H quinone-oxidoreductase 1 (NQO1) and paraoxonase 1 (PON1) are considered crucial for homeostasis and clearance of xenobiotics which involve external as well as internal carcinogens. Polymorphisms of xenobiotic-metabolizing genes are suggested to be implicated in the pathogenesis of various types of cancers. Aim of the work The aim of the current study was to investigate the influence of inherited genetic polymorphisms of the xenobiotic metabolizing enzymes EPHX1, NQO1 and PON1 on the susceptibility and development of Non-Hodgkin's Lymphomas in a cohort of Egyptian population. Patients and methods A total of 100 patients with B-non Hodgkin's lymphoma (B-NHL) with mean age of 52 years, together with 75 age and sex matched healthy controls were enrolled in the study for evaluation of Inherited genetic polymorphisms in the xenobiotic metabolizing enzymes EPHX1 (Tyr-His, rs 1,051,740), NQO1 (C609T rs 1,800,566) and PON1 (Codon 192) A-G, Gly (A)-Arg (B), re662 (Q192R) using Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR- RFLP) assay. Results The comparison between the distribution of the different genotypes of EPHX1 (T/C), NQO1 (C/T), PON1 (A/G) revealed no statistically significant difference between the patient and control groups except for the PON1 GG homozygote phenotype (p = 0.016). Further analysis of the influence of the studied genetic polymorphisms on the characteristics of the disease showed that there was no statistical difference between B-NHL patients harboring the wild or the polymorphic genotypes regarding their clinical status and laboratory data. Conclusion The study suggests that there is no correlation between (EPHX1 and NQO1, PON1) genetic polymorphisms and the risk of B-NHL. However, In PON1 polymorphism, the homozygosity (GG) was significantly higher in the control group (13.3%) compared to B-NHL patients (3%) with a P-value = 0.016. So, better understanding of the functional consequences of EPHX1, NQO1 and PON1 genetic polymorphisms as well as involvement of larger cohort would provide a foundation for future studies of these genes in the pathogenesis of different types of NHL.

Background Studies have reported gene-by-environment interaction for chronic respiratory conditions but none on acute illnesses in children. We investigated, longitudinally, whether genotype modifies the relationship of environmental exposures (second-hand tobacco smoke, polycyclic aromatic hydrocarbons, particulate matter 2.5 )) with acute bronchitis in children below two years. Methods A random sample of 1133 children, born between 1994 and 1998, in two districts of the Czech Republic, was followed-up from birth, of which 793 were genotyped. Pediatric records were abstracted for respiratory illnesses. Second-hand tobacco smoke exposure from household members was obtained through questionnaires and verified using urine cotinine. Air monitoring provided estimates of ambient polycyclic aromatic hydrocarbons and PM 2.5 . Additionally, we collected information on a range of potential confounders including breastfeeding history, indoor fuel use, other children in household, maternal characteristics, ambient temperature etc. DNA was extracted from tissues taken from the middle of the placenta, opposite the umbilical cord. We examined six single nucleotide polymorphisms (GSTM1, GSTP1, GSTT1, CYP1A1 MspI, EPHX1 exon 3 and 4) and one (EPHX1) diplotype. To investigate effect measure modification we constructed logistic regression models using generalized estimating equations (for repeated observations) stratified by genotypes. Results The EPHX1 low activity diplotype consistently imparts greater susceptibility to bronchitis from second-hand tobacco smoke, polyclic aromatic hydrocarbons (PAH) and PM2.5. Each of these three classes of exposure also showed elevated risk for bronchitis in the presence of either one or two histidines at exon 3 and exon 4 of EPHX1. Additional effect modifiers include CYP1A1 and GSTT1. Conclusion Several xenobiotic metabolizing genes may modify the impact of second-hand tobacco smoke and ambient air pollutants, polycyclic aromatic hydrocarbons and PM 2.5 , on acute bronchitis in preschool children.

Discovering genetic predictors of childhood acute lymphoblastic leukemia (ALL) necessitates the evaluation of novel factors including maternal genetic effects, which are a proxy for the intrauterine environment, and robust epidemiologic study designs. Therefore, we evaluated five maternal and offspring xenobiotic metabolism haplotypes and the risk of childhood ALL among 120 case-parent triads. Two of the five haplotypes were significantly associated with risk: GSTM3/GSTM4 (P = 0.01) and GSTP1 (P = 0.02). The EPHX1 haplotype was marginally associated with risk (P = 0.05), whereas haplotypes in CYP1B1 and GSTA4 were not. Our results suggest genetic variation in xenobiotic metabolism is important in childhood ALL etiology.

Inter-individual variation in the metabolism of xenobiotics, caused by factors such as cigarette smoking or inorganic arsenic exposure, is hypothesized to be a susceptibility factor for urothelial carcinoma (UC). Therefore, our study aimed to evaluate the role of gene–environment interaction in the carcinogenesis of UC. A hospital-based case–control study was conducted. Urinary arsenic profiles were measured using high-performance liquid chromatography–hydride generator-atomic absorption spectrometry. Genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism technique. Information about cigarette smoking exposure was acquired from a lifestyle questionnaire. Multivariate logistic regression was applied to estimate the UC risk associated with certain risk factors. We found that UC patients had higher urinary levels of total arsenic, higher percentages of inorganic arsenic (InAs%) and monomethylarsonic acid (MMA%) and lower percentages of dimethylarsinic acid (DMA%) compared to controls. Subjects carrying the GSTM1 null genotype had significantly increased UC risk. However, no association was observed between gene polymorphisms of CYP1A1, EPHX1, SULT1A1 and GSTT1 and UC risk after adjustment for age and sex. Significant gene–environment interactions among urinary arsenic profile, cigarette smoking, and GSTM1 wild/null polymorphism and UC risk were observed after adjustment for potential risk factors. Overall, gene–environment interactions simultaneously played an important role in UC carcinogenesis. In the future, large-scale studies should be conducted using tag-SNPs of xenobiotic-metabolism-related enzymes for gene determination.

In the present study, nsSNPs in EPHX1, GSTT1, GSTM1 and GSTP1 genes were screened for their functional impact on concerned proteins and their plausible role in breast cancer susceptibility. Initially, SNPs were retrieved from dbSNP, followed by identification of potentially deleterious nsSNPs using PolyPhen and SIFT. Functional analysis was done with SNPs3D, SNPs&GO and MutPred methods. Prediction and evaluation of the functional impact on the 3D structure of proteins were performed with Swiss PDB viewer and NOMAD-Ref servers. On analysis, 13 nsSNPs were found to be highly deleterious and damaging to the protein structure, of which 6 nsSNPs, rs45549733, rs45506591 and rs4986949 of GSTP1, rs72549341 and rs148240980 of EPHX1 and rs17856199 of GSTT1 were predicted to be potentially polymorphic. It is therefore hypothesized that the 6 identified nsSNPs may alter the detoxification process and elevate carcinogenic metabolite accumulation thus modifies the risk of breast cancer susceptibility in a group of women.

Metabolic bioactivation is widely considered an undesirable event and a likely prerequisite step in the expression of drug-induced hepatotoxicity and hypersensitivity. Reducing bioactivation risk early in drug discovery, therefore, may help reduce compound attrition and provide safer drug therapies. In vitro bioactivation data and clinical dose for a large set of marketed drugs were analysed for their concordance with clinical hepatotoxicity and the data used to develop an early reactive metabolite strategy. A contingency table analysis of cytochrome P450 metabolism-dependent inhibition (CYP MDI), glutathione trapping data, and dose for >200 marketed drugs with or without a clinical hepatotoxic signal; and microsomal covalent binding data and dose for ∼60 marketed compounds obtained from literature publications was performed to assess concordance with hepatotoxicity. Clinical daily dose ≥100mg or glutathione adduct formation was strongly associated with hepatotoxicity (p

Background Epidemiologic studies indicate that exposure to air pollution caused by traffic may have an association with an increased risk of childhood asthma. Some studies report an association between the polymorphisms of the microsomal epoxide hydroxylase ( EPHX1 ) gene and enzyme activity. We investigated the associations of EPHX1 Tyr113His and His139Arg polymorphisms with asthma and wheezing outcomes, and focused on the functional genetic change in different ambient nitrogen dioxide (NO 2 ) levels on glutathione S-transferase p1 ( GSTP1 ) and glutathione S-transferase m1 ( GSTM1 ) genotypes. Methods A total of 3,741 children were enrolled in the Taiwan Children Health Study from 14 communities. We examined the associations of EPHX1 Tyr113His and His139Arg genotypes and diplotypes with asthma and wheezing outcomes under different ambient NO 2 exposures. Results Children with the EPHX1 Arg/His or Arg/Arg genotypes at codon 139 were significantly associated with increased risks of lifetime asthma (adjusted OR [aOR] = 1.3; 95% CI, 1.1-1.7; and aOR=1.5; 95% CI, 1.1-2.1, respectively). The EPHX1 diplotypes showed significant associations with lifetime asthma (global P value=.01) and early-onset asthma (global P value=.01). The risk of EPHX1 139Arg allele and 113Tyr-139Arg diplotype were of greater magnitude in higher compared with lower NO 2 communities. The increase of the effect from the EPHX1 139Arg allele with higher NO 2 exposure was most marked in the GSTP1 Val allele and GSTM1 present genotype. Conclusions Children with high EPHX1 activity may have increase risk of asthma and wheezing outcomes, and can be mediated through airway oxidative stress generation.

Background : We examined risk of multiple myeloma (MM) associated with variants in genes involved in metabolism and response to exogenous chemicals [cytochrome P450 enzymes ( CYP1B1 , CYP2C9 ), epoxide hydrolase ( EPHX1 ), paraoxonase 1 ( PON1 ), arylhydrocarbon hydroxylase receptor ( AHR ), and NAD(P)H:quinone oxidoreductase ( NQO1 )]. Methods : This study included 279 MM cases and 782 controls in a pooled analysis of two population-based case–control studies. One common variant from each candidate gene was genotyped using DNA from blood or buccal cells. We estimated risk of MM associated with each genotype, controlling for race, gender, study site, and age, using odds ratios (OR) and 95% confidence intervals (CI). Results : Evaluations of the CYP1B1 V432L variant (rs1056836) suggested increased risk of MM among persons with the CG and GG genotypes compared to the CC genotype [OR (95% CI)=1.4 (1.0–2.0)]. Similar results were seen in analyses stratified by race and gender. We did not find any associations between MM and the CYP2C9 , EPHX1 , NQO1 , or PON1 genes. Conclusions : CYP1B1 activates chemicals such as polycyclic aromatic hydrocarbons and dioxins to create oxidized, reactive intermediates, and higher gene activity has been shown for the G allele. We conducted the largest analysis to date on MM and these genetic variants and our results provide preliminary evidence that variation in CYP1B1 may influence susceptibility to MM.

The interindividual variation in the activity of xenobiotic metabolizing enzymes and DNA repair genes could modify an individual's risk of recurrent malignancy and response to therapy. We investigated whether ALL outcome was related to polymorphisms in genes CYP2D6, MPO, EPHX1, NQO1, TS, XPD and XRCC1 in 95 consecutive ALL children by PCR or PCR-FRLP techniques. Polymorphisms in genes NQO1 and TS were associated with a significantly slow response to induction chemotherapy and NQO1 was also associated with a lower five-year event-free survival. This study suggests that polymorphisms of NQO1 and TS could be important for patient response to induction therapy and for treatment outcome.

Summary Airflow limitation in COPD patients is not fully reversible. However, there may be large variability in bronchodilator responsiveness (BDR) among COPD patients, and familial aggregation of BDR suggests a genetic component. Therefore, we investigated the association between six candidate genes and BDR in subjects with severe COPD. A total of 389 subjects from the National Emphysema Treatment Trial (NETT) were analyzed. Bronchodilator responsiveness to albuterol was expressed in three ways: absolute change in FEV 1 , change in FEV 1 as a percent of baseline FEV 1 , and change in FEV 1 as a percent of predicted FEV 1 . Genotyping was completed for 122 single nucleotide polymorphisms (SNPs) in six candidate genes ( EPHX1 , SFTPB , TGFB1 , SERPINE2 , GSTP1 , ADRB2 ). Associations between BDR phenotypes and SNP genotypes were tested using linear regression, adjusting for age, sex, pack-years of smoking, and height. Genes associated with BDR phenotypes in the NETT subjects were assessed for replication in 127 pedigrees from the Boston Early-Onset COPD (EOCOPD) Study. Three SNPs in EPHX1 ( p =0.009–0.04), three SNPs in SERPINE2 ( p =0.004–0.05) and two SNPs in ADRB2 (0.04–0.05) were significantly associated with BDR phenotypes in NETT subjects. One SNP in EPHX1 (rs1009668, p =0.04) was significantly replicated in EOCOPD subjects. SNPs in SFTPB , TGFB1 , and GSTP1 genes were not associated with BDR. In conclusion, a polymorphism of EPHX1 was associated with bronchodilator responsiveness phenotypes in subjects with severe COPD.

Summary Microsomal epoxide hydrolase gene ( EPHX1 ) is polymorphic and encodes an enzyme involved in both the activation and detoxification of several tobacco carcinogens. Therefore, a contribution of EPHX1 enzymatic activity on lung cancer risk is possible. 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. Primary lung cancer cases of both sexes and under age 45 at diagnosis were considered for this study. Controls fulfilled the following criteria: over 60 years old, smoking history of at least 40 years, no malignancies. Because of these criteria, they are referred to as super controls. The polymorphisms at exons 3 (Tyr113His) and 4 (His139Arg) as well as at the 5′-UTR-290T/G of the EPHX1 gene were genotyped by minisequencing. The association of these three polymorphisms with the development of early-onset lung cancer and the group of the super controls was evaluated by means of 2×2 tables using Yate's X 2 test or Fisher's exact test. Overall, data were obtained from 42 cases and 72 super controls. There was a significant association between early-onset lung cancer and the presence of the EPHX1 exon 4 variant (OR=3.33, 95% CI=1.50–7.41). This was confirmed at the phenotypic level when the data of both patients and super controls were stratified according to the predicted enzymatic activity ( X 2 for linear trend=7.23, p =0.007). This analysis of lung cancer in subjects under age 45 supports the hypothesis that EPHX1 polymorphisms may have a role in cancer susceptibility in this age group.

We investigated the roles of EPHX1 Tyr 113 His and His 139 Arg polymorphisms in lung cancer susceptibility in a Finnish study population comprising of 230 lung cancer cases and a large control group ( n =2105). The controls were distributed into five age strata, which enabled us to examine the potential age-related changes in the putative EPHX1 at-risk genotypes in the cancer free population. Although the exon 3 slow activity associated allele ( His 113 ) containing genotypes posed a decreased lung cancer risk compared with the homozygous wild-type Tyr 113 / Tyr 113 genotype (OR, 0.68; 95% CI, 0.49–0.94), no association was seen for the EPHX1 phenotypes interpreted from the combined exons 3 and 4 genotype data. Neither was any difference seen in the prevalence of the EPHX1 Tyr 113 His genotypes or interpreted EPHX1 phenotypes in the different age groups.

1,3-Butadiene (BD) is an important industrial chemical and pollutant. Its ability to induce genetic damage and cause hematological malignancies in humans is controversial. We have examined chromosome damage by fluorescence in situ hybridization (FISH) and mutations in the HPRT gene in the blood of Chinese workers exposed to BD. Peripheral blood samples were collected and cultured from 39 workers exposed to BD (median level 2 ppm, 6 h time-weighted average) and 38 matched controls in Yanshan, China. No difference in the level of aneuploidy or structural changes in chromosomes 1, 7, 8, and 12 was detected in metaphase cells from exposed subjects in comparison with matched controls, nor was there an increase in the frequency of HPRT mutations in the BD-exposed workers. Because genetic polymorphisms in glutathione S-transferase (GST) enzymes and microsomal epoxide hydrolase (EPHX1) may affect the genotoxic effects of BD and its metabolites, we also related chromosome alterations and gene mutations to GSTT1, GSTM1 and EPHX1 genotypes. Overall, there was no effect of variants in these genotypes on numerical or structural changes in chromosomes 1, 7, 8 and 12 or on HPRT mutant frequency in relation to BD exposure, but the GST genotypes did influence background levels of both hyperdiploidy and HPRT mutant frequency. In conclusion, our data show no increase in chromosomal aberrations or HPRT mutations among workers exposed to BD, even in potentially susceptible genetic subgroups. The study is, however, quite small and the levels of BD exposure are not extremely high, but our findings in China do support those from a similar study conducted in the Czech Republic. Together, these studies suggest that low levels of occupational BD exposure do not pose a significant risk of genetic damage.

Styrene is widely used in the production of various plastics, synthetic rubber and resins. The aim of this study was to evaluate if individual polymorphisms in xenobiotic metabolizing enzymes, related with the metabolic fate of styrene, could modify individual susceptibility to the possible genotoxic effects of the styrene exposure. Twenty-eight reinforced plastic workers and 28 control subjects were studied. In the selected population the urinary styrene metabolites mandelic (MA) and phenylglyoxylic (PGA) acids were quantified, sister chromatid exchanges (SCE) and micronuclei (MN) were assessed in peripheral lymphocytes and all the subjects were genotyped for GSTM1 , GSTT1 (gene deletions), GSTP1 (codon 105 ile ⇒ val), EPHX1 (codons 113 tyr ⇒ his and 139 his ⇒ arg) and CYP2E1 ( Dra I polymorphism in intron 6). The results obtained showed a significant difference between the levels of SCE, but not in MN levels, in exposed workers as compared with the control group. The GSTP1 and CYP2E1 individual genotypes modulate the baseline levels of SCE that are lower in non-wild type individuals for both polymorphisms. The GSTM1 null individuals with low levels of exposure have significantly higher urinary levels of MA+PGA. The present data seem to suggest that apart from the methodology usually used for monitoring populations occupationally exposed to styrene (urinary metabolites and biomarkers of early biological effects) the analysis of individual genotypes associated with the metabolic fate of styrene should also be carried out in order to evaluate the individual genetic susceptibility of exposed populations.

Objective. The objective was to determine the prevalence of the polymorphisms of the microsomal epoxide hydrolase (Ephx1), glutathione S-transferase µ1 (GSTM1), θ1 (GSTT1), and π1 (GSTP1) genes in patients with oropharyngeal carcinoma. Study design. Gene polymorphisms in 137 patients with oropharyngeal carcinoma were determined by polymerase chain reaction and restriction enzyme digestion for xenobiotic metabolizing enzymes that have been implicated in the carcinogenesis of tobacco-related neoplasias and compared with a population sample of 99 persons. Results. At Ephx1 (microsomal epoxide hydrolase) codon 113, an overrepresentation of the greater activity genotype (Tyr/Tyr) was observed for male ever-smokers alone, both male and female ever-smokers, female never-smokers alone, and in both male and female never-smokers, compared with a control population sample. At codon 139, Ephx1 showed no differences. There was an overrepresentation of homozygosity for the GSTT1 (glutathione S-transferase θ1) null allele [but not for the GSTM1 (glutathione S-transferase µ1) null allele] in ever-smokers, when compared with controls. Polymorphisms at the GSTP1 (glutathione S-transferase π1) locus did not show differences versus controls, although in the never-smoker cancer sample there was a higher prevalence of the B/B genotype compared with ever-smokers. Conclusion. The Ephx1 codon 113 Tyr/Tyr variant, as well as homozygosity for the GSTT1 null allele, is associated with oropharyngeal carcinogenesis. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;93:440-5)

NAD(P)H:quinone oxidoreductase (NQO1) catalyzes the two- or four-electron reduction of numerous endogenous and environmental quinones (e.g., the vitamin E alpha-tocopherol quinone, menadione, benzene quinones). In laboratory animals treated with various environmental chemicals, inhibition of NQO1 metabolism has long been known to increase the risk of toxicity or cancer. Currently, there are 22 reported single-nucleotide polymorphisms (SNPs) in the NQO1 gene. Compared with the human consensus (reference, "wild-type") NQO1*1 allele coding for normal NQO1 enzyme and activity, the NQO1*2 allele encodes a nonsynonymous mutation (P187S) that has negligible NQO1 activity. The NQO1*2 allelic frequency ranges between 0.22 (Caucasian) and 0.45 (Asian) in various ethnic populations. A large epidemiologic investigation of a benzene-exposed population has shown that NQO1*2 homozygotes exhibit as much as a 7-fold greater risk of bone marrow toxicity, leading to diseases such as aplastic anemia and leukemia. The extent of the contribution of polymorphisms in other genes involved in the metabolism of benzene and related compounds-such as the P450 2E1 (CYP2E1), myeloperoxidase (MPO), glutathione-S-transferase (GSTM1, GSTT1), microsomal epoxide hydrolase (EPHX1), and other genes-should also be considered. However, it now seems clear that a lowered or absent NQO1 activity can increase one's risk of bone marrow toxicity, after environmental exposure to benzene and benzene-like compounds. In cancer patients, the NQO1*2 allele appears to be associated with increased risk of chemotherapy-related myeloid leukemia. Many other epidemiological studies, attempting to find an association between the NQO1 polymorphism and one or another human disease, have now begun to appear in the medical literature.

Human microsomal epoxide hydrolase (mEH) catalyzes a key step in the biotransformation of benzo[a]pyrene that yields the highly mutagenic (+)-anti-7,8-diol-9,10 epoxide (BPDE). Two polymorphisms have been described in the coding region of the mEH gene (EPHX1) that produce two protein variants: 113Tyr-->113His (exon 3) and 139His-->139Arg (exon 4). We performed a case-control study among Northwestern Mediterranean Caucasians to investigate a possible association between these EPHX1 variants and lung cancer risk. Both EPHX1 polymorphisms were analyzed in a group of lung cancer patients (n=176) and in a control group of healthy smokers (n=187). The results showed a significantly decreased risk for the rare homozygous 113His/113His (adjusted odds ratio (OR): 0.44, 95% confidence interval (CI): 0.27-0.71) and 139Arg/139Arg (adjusted OR: 0.55, 95% CI: 0.33-0.91) compared with the major wild-types 113Tyr/113Tyr and 139His/139His, respectively, as the references. Thereafter, we analyzed the EPHX1 variants in combination with three glutathione S-transferase polymorphic genes (GSTM1, GSTT1, and GSTP1) and we found a significant overepresentation of cancer patients with a combination of exon 3 113Tyr/113Tyr EPHX1 and exon 5 105Ile/105Ile GSTP1 (adjusted OR: 2.34, 95% CI: 1.21-4.52). The polymorphic site within the exon 5 of GSTP1 results in a Ile-->Val substitution, and the isoleucine GSTpi isoform has been found in vitro to be less active than the valine isoform towards the conjugation of BPDE. The 113 Tyr/Tyr EPHX1 encodes for a high-activity mEH. 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.

Epoxides are organic three-membered oxygen compounds that arise from oxidative metabolism of endogenous, as well as xenobiotic compounds via chemical and enzymatic oxidation processes, including the cytochrome P450 monooxygenase system. The resultant epoxides are typically unstable in aqueous environments and chemically reactive. In the case of xenobiotics and certain endogenous substances, epoxide intermediates have been implicated as ultimate mutagenic and carcinogenic initiators Adams et al. (Chem. Biol. Interact. 95 (1995) 57-77) Guengrich (Properties and Metabolic roles 4 (1982) 5-30) Sayer et al. (J. Biol. Chem. 260 (1985) 1630-1640). Therefore, it is of vital importance for the biological organism to regulate levels of these reactive species. The epoxide hydrolases (E.C. 3.3.2. 3) belong to a sub-category of a broad group of hydrolytic enzymes that include esterases, proteases, dehalogenases, and lipases Beetham et al. (DNA Cell Biol. 14 (1995) 61-71). In particular, the epoxide hydrolases are a class of proteins that catalyze the hydration of chemically reactive epoxides to their corresponding dihydrodiol products. Simple epoxides are hydrated to their corresponding vicinal dihydrodiols, and arene oxides to trans-dihydrodiols. In general, this hydration leads to more stable and less reactive intermediates, however exceptions do exist. In mammalian species, there are at least five epoxide hydrolase forms, microsomal cholesterol 5,6-oxide hydrolase, hepoxilin A(3) hydrolase, leukotriene A(4) hydrolase, soluble, and microsomal epoxide hydrolase. Each of these enzymes is distinct chemically and immunologically. Table 1 illustrates some general properties for each of these classes of hydrolases. Fig. 1 provides an overview of selected model substrates for each class of epoxide hydrolase.

Summary Background The first-pass metabolism of foreign compounds in the lung is an important protective mechanism against oxidative stress. We investigated whether polymorphisms in the gene for microsomal epoxide hydrolase (mEPHX), an enzyme involved in this protective process, had any bearing on individual susceptibility to the development of chronic obstructive pulmonary disease (COPD) and emphysema. Methods We designed PCR-based genotyping assays to detect variant forms of mEPHX that confer slow and fast activity. We used these assays to screen 203 blood-donor controls and groups of patients with asthma (n=57), lung cancer (n=50), COPD (n=68), and emphysema (n=94), who were attending specialised clinics in Edinburgh, UK. Findings The proportion of individuals with innate slow mEPHX activity (homozygotes) was significantly higher in both the COPD group and the emphysema group than in the control group (COPD 13 [19%] vs control 13 [6%]; emphysema 21 [22%] vs 13 [6%]). The odds ratios for homozygous slow activity versus all other phenotypes were 4·1 (95% CI 1·8–9·7) for COPD and 5·0 (2·3–10·9) for emphysema. Interpretation Genetic polymorphisms in xenobiotic enzymes may have a role in individual susceptibility to oxidant-related lung disease. Epoxide derivatives of cigarette-smoke components may be the cause of some of the lung damage characteristic of these diseases.

Objectives Clinical studies have documented a familiar tendency to develop preeclampsia and patients with impaired endothelial health are at increased risk. We studied genetic polymorphisms associated to cardiovascular disease and impaired endothelial function in women with and without preeclampsia. Methods 241 African and 279 Caucasian women were recruited for genetic testing of the polymorphisms epoxide hydrolase 1 (EPXH1), endothelial nitric oxide synthase (NOS3) on exon 7 and variable nucleotide tandem repeats in intron 4 (NOS3I4a/b), angiotensinogen and the estrogen receptor1 polymorphism in intron 1. Results Of 241 African women, 95 developed preeclampsia and out of the 279 Caucasian women 81 had preeclampsia. Carriers of the NOS3I4a/b polymorphism had a 1.7-fold increased risk to develop preeclampsia. There was no difference in distribution of the other tested polymorphism. Furthermore we could show a fourfold reduction to encounter severe course of preeclampsia (defined as occurrence of HELLP-syndrome or eclampsia) in carriers of the EPHX1 polymorphism encoding histidine. Conclusions Our data reveal a highly significant association of the NOS3I4a/b polymorphism with increased risk to develop preeclampsia in pregnancy. The shown association of EPXH1 polymorphism with the severity of preeclampsia strengthen the concept, that individual susceptibility determines the capability of the maternal organism to deal with the pregnancy derived agents causing preeclampsia.