Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Maternal cigarette smoking during the first trimester of pregnancy is associated with an increased risk of having a child with an oral cleft. Compounds present in cigarette smoke undergo bioactivation and/or detoxication. Phase I of this process results in the formation of reactive epoxides, which can form DNA adducts initiating and promoting mutagenesis, carcinogenesis, or teratogenesis. Microsomal epoxide hydrolase (mEH; gene symbol EPHX1) catalyzes hydrolysis of epoxides. Phase II involves attachment of a moiety (e.g., glutathione) to the compound mediated by a variety of enzymes, including glutathione S-transferase, generally resulting in a decreased reactivity. Recent studies suggest an association between the EPHX1 codon 113 polymorphism or homozygous null GSTM1 allele and the risk of carcinogenesis, emphysema, phenytoin-associated oral clefting, and the risk of spontaneous abortion. This study explores the association between EPHX1 codon 113 and homozygous null GSTM1 genotypes and oral clefting among infants whose mothers smoked during pregnancy. Case infants were diagnosed with isolated cleft lip with or without cleft palate (CL/P). EPHX1 codon 113 allelotyping was performed on 195 samples (85 cases, 110 controls) by PCR/RFLP analysis. 130 samples (79 cases, 51 controls) were tested for the GSTM1 homozygous null genotype using PCR. Using the odds ratio as a measure of association, we did not observe elevated risks of CL/P associated with either allelic comparison. This suggests that when mothers smoke periconceptionally, their infants having these alleles at either (or both) loci were not at substantially increased risk for CL/P compared to infants with the wild-type alleles.
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PMID:Analysis of the EPHX1 113 polymorphism and GSTM1 homozygous null polymorphism and oral clefting associated with maternal smoking. 1147 Nov 67

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.
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PMID:Lung cancer susceptibility in relation to combined polymorphisms of microsomal epoxide hydrolase and glutathione S-transferase P1. 1159 90

Two polymorphic sites of the microsomal epoxide hydrolase gene (EPHX1, 113Tyr-->113His, 139His-->139Arg) and four glutathione S-transferase genes (GSTM1, GSTM3, GSTP1, GSTT1) were genotyped in a group of patients with larynx cancer (N=204) and in a group of healthy controls (N=203), all Spanish caucasians. After adjusting for gender, age, and tobacco smoking, none of the polymorphisms alone were found to be associated with larynx cancer risk. The analysis of EPHX1/GST combinations, however, showed a significant over-representation of patients with a combination of 113Tyr/113Tyr EPHX1 and 105Ile/105Ile GSTP1 (adjusted odds ratio (OR): 1.95; 95% confidence interval (CI): 1.02-3.78). The calculation of the predicted epoxide hydrolase (EH) activity also showed an increased risk for the individuals with both predicted high activity EH and 105Ile/105Ile GSTP1 (OR: 2.90; 95% CI: 1.10-7.67). These results on larynx cancer tend to confirm a former study on lung cancer (Cancer Lett. 173 (2001) 155) suggesting the existence of an interaction between variants of EH and GSTpi, both enzymes being involved in the metabolism of aromatic hydrocarbons, that may increase susceptibility to tobacco-related cancers.
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PMID:Microsomal epoxide hydrolase and glutathione S-transferase polymorphisms in relation to laryngeal carcinoma risk. 1235 56

Susceptibility to colorectal cancer, one of the most common forms of cancer in the Western world, has been associated with several environmental and dietary risk factors. Dietary exposure to food derived heterocyclic amine carcinogens and polycyclic aromatic hydrocarbons have been proposed as specific risk factors. Many polymorphic Phase I and Phase II drug metabolizing enzymes are responsible for the metabolism and disposition of these compounds and it is therefore possible that inheritance of specific allelic variants of these enzymes may influence colorectal cancer susceptibility. In a multicenter case-control study, 490 colorectal cancer patients and 593 controls (433 matched case-control pairs) were genotyped for common polymorphisms in the cytochrome P450 (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C9, CYP2C19 and CYP2D6), glutathione S-transferase (GSTM1, GSTP1 and GSTT1), sulfotransferase (SULT1A1 and SULT1A2), N-acetyl transferase 2 (NAT2), NAD(P)H:quinone oxidoreductase (NQO1), methylenetetrahydrofolate reductase (MTHFR), and microsomal epoxide hydrolase (EPHX1) genes. Matched case-control analysis identified alleles associated with higher colorectal cancer risk as carriage of CYP1A1*2C (OR = 2.15, 95% CI 1.36-3.39) and homozygosity for GSTM1*2/*2 (OR = 1.53, 95% CI 1.16-2.02). In contrast, inheritance of the CYP2A6*2 (OR = 0.51, 95% CI 0.28-1.06), CYP2C19*2 (OR = 0.72, 95% CI 0.52-0.98) and the EPHX1(His113) alleles were associated with reduced cancer risk. We found no association with colorectal cancer risk with NAT2 genotype or any of the other polymorphic genes associated with the metabolism and disposition of heterocyclic amine carcinogens. This data suggests that heterocyclic amines do not play an important role in the aetiology of colorectal cancer but that exposure to other carcinogens such as polycyclic aromatic hydrocarbons may be important determinants of cancer risk.
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PMID:A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer. 1241 32

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.
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PMID:Lack of increased genetic damage in 1,3-butadiene-exposed Chinese workers studied in relation to EPHX1 and GST genotypes. 1503 20

Microsomal epoxide hydrolase (mEH) plays a central role in xenobiotic metabolism as well as mediating the sodium-dependent uptake of bile acids into the liver, where these compounds regulate numerous biological processes such as cholesterol metabolism and hepatocyte signaling pathways. Little is known, however, about the factors that control the constitutive and inducible expression of the mEH gene (EPHX1) that is altered during development and in response to numerous xenobiotics. In previous studies we have established that GATA-4 binding to the EPHX1 core promoter is critical for EPHX1 expression. The -80/+25 bp core promoter also contained a reversed CCAAT box (-5/-1 bp), integrity of which was required for maximal basal EPHX1 transcription in HepG2 cells. Transient transfection of CCAAT/enhancer-binding protein alpha (C/EBPalpha) substantially stimulated EPHX1 promoter activity. Electrophoretic mobility shift assays, however, revealed that nuclear factor Y (NF-Y), but not C/EBPalpha, directly bound to this site although increased expression of NF-Y had no effect on EPHX1 promoter activity. These results suggested that C/EBPalpha activated EPHX1 expression through its interaction with NF-Y bound to the CCAAT box. The existence of a C/EBPalpha[NF-Y] complex was supported by electrophoretic mobility shift assays using antibodies against NF-Y and C/EBPalpha as well as by the ability of a dominant-negative NF-Y expression vector to inhibit promoter activity. The interaction between these transcription factors was established by co-immunoprecipitation analysis and glutathione S-transferase pull-down assays, whereas the association of the two factors and the interaction of NF-Y with the CCAAT box in vivo was confirmed by chromatin immunoprecipitation assays. C/EBPalpha-dependent EPHX1 activation was also supported by reconstitution studies in HeLa cells that lack this protein. These results establish that EPHX1 expression is regulated by C/EBPalpha interacting with DNA-bound NF-Y.
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PMID:CCAAT/enhancer-binding protein alpha (C/EBPalpha) activates transcription of the human microsomal epoxide hydrolase gene (EPHX1) through the interaction with DNA-bound NF-Y. 1515 Feb 64

Synthetic triterpenoid analogues of oleanolic acid are potent inducers of the phase 2 response as well as inhibitors of inflammation. We show that the triterpenoid, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), is a highly potent chemopreventive agent that inhibits aflatoxin-induced tumorigenesis in rat liver. The chemopreventive potency of CDDO-Im was evaluated by measuring inhibition of formation of putative preneoplastic lesions (glutathione S-transferase P positive foci) in the liver of rats exposed to aflatoxin B1. CDDO-Im produces an 85% reduction in the hepatic focal burden of preneoplastic lesions at 1 micromol/kg body weight and a >99% reduction at 100 micromol/kg body weight. CDDO-Im treatment reduces levels of aflatoxin-DNA adducts by approximately 40% to 90% over the range of 1 to 100 micromol/kg body weight. Additionally, changes in mRNA levels of genes involved in aflatoxin metabolism were measured in rat liver following a single dose of CDDO-Im. GSTA2, GSTA5, AFAR, and EPHX1 transcripts are elevated 6 hours following a 1 micromol/kg body weight dose of CDDO-Im. Microarray analysis using wild-type and Nrf2 knockout mice confirms that many phase 2 and antioxidant genes are induced in an Nrf2-dependent manner in mouse liver following treatment with CDDO-Im. Thus, low-micromole doses of CDDO-Im induce cytoprotective genes, inhibit DNA adduct formation, and dramatically block hepatic tumorigenesis. As a point of reference, oltipraz, an established modulator of aflatoxin metabolism in humans, is 100-fold weaker than CDDO-Im in this rat antitumorigenesis model. The unparalleled potency of CDDO-Im in vivo highlights the chemopreventive promise of targeting Nrf2 pathways with triterpenoids.
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PMID:Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole. 1648 57

Polymorphic genes encoding drug-metabolizing enzymes may account for interindividual differences in certain types of diseases especially cancer. In this study, microsomal epoxide hydrolase (EPHX1) and glutathione S-transferase P1 (GSTP1) gene polymorphisms were determined among 133 healthy males of a Turkish population. Frequencies of EPHX1 and GSTP1 gene polymorphisms were determined by using the polymerase chain reaction-restriction fragment length polymorphism (PCR/RFLP) method. The observed genotype frequencies of EPHX1 exon 3 were Tyr113Tyr:50.4%, Tyr113His: 42.1%, His113His: 7.5% and EPHX1 exon 4 were His139His: 69.2%, His139Arg: 28.6%, Arg133Arg: 2.2%. GSTP1 exon 5 genotype frequencies were Ile105Ile: 58.7%, Ile105Val: 35.3%, Val105Val: 6.0% and GSTP1 exon 6 genotype frequencies were Ala114Ala: 85.0%, Ala114Val: 14.3%, Val114Val: 0.7%. These results reveal that the frequencies of EPHX1 and GSTP1gene polymorphisms in a small sampling of males within a Turkish population are similar to European Caucasian populations.
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PMID:Polymorphisms of microsomal epoxide hydrolase and glutathione S-transferase P1 in a male Turkish population. 1736 45

Ethylene oxide is considered as a human carcinogen. A biomarker of exposure would be a useful instrument to assess the risk in occupationally exposed workers. This cross-sectional study aimed at examining (a) whether the urinary excretion of a metabolite of ethylene oxide, 2-hydroxyethyl mercapturic acid (HEMA), could be used for monitoring occupational exposure and (b) whether glutathione S-transferase (GST) and epoxide hydrolase genotypes influenced biological monitoring. Exposure to ethylene oxide was measured by personal sampling in 80 hospital workers (95% of those eligible). HEMA concentrations were determined in three urine samples (baseline, end of shift, and next morning) by liquid chromatography with tandem mass spectrometry. GSTs (GSTT1, GSTM1, and GSTP1) and epoxide hydrolase (EPHX1) were also genotyped. The influence of exposure, genotypes, and several other factors was examined in multiple regression analyses. Exposure was always <1 parts per million. On a group basis, exposure and a non-null GSTT1 genotype increased the HEMA concentrations in the urine sample collected at the end of the shift and these factors remained statistically significant after considering possible confounding or modifying factors.
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PMID:Exposure to ethylene oxide in hospitals: biological monitoring and influence of glutathione S-transferase and epoxide hydrolase polymorphisms. 1741 73

The HepG2 cell line is a valuable tool for screening for cytotoxicity in the early phase of pharmaceutical development. Some compounds which produce reactive and toxic metabolites, are classified as being toxic in HepG2 cells. In contrast, other compounds, which are toxic in primary human hepatocytes, are not toxic in HepG2 cells. A difference in metabolism between HepG2 cells and primary human hepatocytes might be the reason. To investigate this, cytochrome P450 and Phase II enzyme levels were characterized. In the present study the focus is on Phase II enzyme metabolism. Transcript levels of UDP-glucuronosyl transferases (UGTs), sulfotransferases (SULTs), glutathione S-transferases (GSTs), N-acetyltransferase-1 (NAT1) and epoxide hydrolase (EPHX1) were measured with quantitative PCR in HepG2 cells and cryopreserved primary human hepatocytes. Levels of SULT1A1, 1A2, 1E1, 1A2, and 2A1, microsomal GST 1, GST mu1, NAT1, and EPHX1 in HepG2 cells were almost similar to levels in primary human hepatocytes. In contrast, levels of UGT1A1 and 1A6 transcripts were between 10- and more than 1000-fold higher in the primary hepatocytes. The regulatory processes of Phase II enzymes by the aryl hydrocarbon receptor, pregnane X receptor and constitutive androstane receptor were studied in HepG2 cells and appeared quite similar to those in primary human hepatocytes. Due to the involvement of Phase II enzymes in the toxication of some compounds, HepG2 cells can be a valuable cellular system to predict toxicity for these compounds. On the other hand, the normal expression of most Phase II enzymes in combination with the lower expression of cytochrome P450 enzymes in HepG2 cells might result in an underestimation of toxicity for several compounds. Compared to primary human hepatocytes, HepG2 cells are a relatively easy-to-handle tool to study the up-regulation of Phase II enzymes.
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PMID:Phase II enzyme levels in HepG2 cells and cryopreserved primary human hepatocytes and their induction in HepG2 cells. 1771 55


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