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)

Estrogen has been shown to exert a modifying potential on carcinogenesis in various organs, and in particular the hormone-dependent tissues. The present experiments were carried out to determine the effects of post-initiation phase administration of ethinyl estradiol (EE) on tumor development in the liver, kidney, lung, thyroid, bladder and esophagus of male F344 rats. Animals were initiated by 2 weeks treatment with 0.05% N-bis(2-hydroxypropyl)nitrosamine (DHPN), 0.1% N-ethyl-N-hydroxyethylnitrosamine (EHEN), 0.03% N-nitrosopiperidine (NPD), 0.02% 2-acetylaminofluorene (2-AAF) or 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their diet or drinking water, and starting 1 week after initiation, they were given diet with or without a 0.001% EE supplement for 49 weeks, at which point the experiment was terminated. EE significantly increased the development of tumors of the liver (DHPN-, EHEN-, 2-AAF- and NPD-treated groups) and kidneys (EHEN-treated group) but inhibited their development in the lungs (DHPN-treated group) and urinary bladder (BBN-treated group). In the liver, EE also increased the development of glutathione S-transferase P type-positive lesions to various extents depending on the initiator used. EE administration was associated with a decreased incidence of esophageal hyperplasia in the EHEN-initiated group but an opposite increase in the NPD-initiated animals. No effect of EE was evident regarding thyroid lesions.
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PMID:Organ specific modifying potential of ethinyl estradiol on carcinogenesis initiated with different carcinogens. 380 86

The binding of fluorodifen, fenarimol, acifluorfen, 2,4-DES, methyl parathion, paraquat and pyrazophos by alpha, mu and pi class glutathione transferases (GST) was determined by the 2-p-toluidinylnaphthalene-6-sulphonate (TNS) binding fluorescence inhibition technique. Although all the 3 GST classes appear to be capable of binding the pesticides investigated, mu class exhibited somewhat higher affinity than the alpha and pi classes.
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PMID:Binding of pesticides to alpha, mu and pi class glutathione transferase. 772 48

The magnitude of health risks to workers associated with current and past exposures to butadiene has been the subject of considerable recent debate. Butadiene is metabolized in-vivo and in-vitro to the genotoxic intermediates 3,4-epoxybutene and diepoxybutane. Studies in animals and in-vitro systems have clearly demonstrated that 1,3-butadiene is a genotoxin and a potent inducer of sister-chromatid exchanges (SCEs). Data on the genotoxicity of butadiene in humans is, however, limited. Epidemiologic data indicate that butadiene is a probable human carcinogen. Recent work has further demonstrated that cultured lymphocytes from the approximately 20% of the Caucasian population that lack the glutathione S-transferase class theta gene (GSTT1) are relatively sensitive to the induction of cytogenetic damage by butadiene metabolites. In order to test whether butadiene exposure was associated with increases in SCE frequencies in peripheral blood lymphocytes and whether any increase observed could be affected by the DEB sensitivity-GSTT1 deletion, we studied 40 workers employed in the production of butadiene. In these workers baseline frequencies of SCEs, diepoxybutane-induced SCE frequencies and GSTT1 deletion status were assessed. Questionnaires were administered to each worker and exposure to 1,3-butadiene was determined using three separate approaches. Industrial hygiene personal sampling was used to measure breathing zone butadiene exposure and urine was collected to use in measurement of the urinary butadiene metabolite 1,2-dihydroxy-4-(N-acetylcysteinyl-S-)-butane (M1). Exposure to butadiene was generally below 2 ppm. The urinary metabolite M1 was found in all workers, but it did not correlate significantly with exposure. Six of 40 of the workers were GST theta-deleted DEB sensitive. No measure of acute or chronic exposure to butadiene was associated with an increase in SCE frequency. However, smoking and DEB sensitivity-GSTT1 null status were each significantly associated with elevations in baseline SCE frequency.
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PMID:Sister-chromatid exchanges, glutathione S-transferase theta deletion and cytogenetic sensitivity to diepoxybutane in lymphocytes from butadiene monomer production workers. 852 42

Estrogen receptor-related orphan receptor alpha 1 is a member of the steroid/thyroid nuclear receptor superfamily. We have previously cloned the human estrogen receptor-related orphan receptor alpha 1 (hERR alpha 1) cDNA and demonstrated that it enhances estrogen responsiveness of the lactoferrin gene promoter in transfected human endometrial carcinoma cells. In the present study, we used the hERR alpha 1 cDNA as a probe and isolated the mouse homologue of ERR alpha 1 from the cDNA libraries of the brain and kidney. Sequence comparison between human and mouse ERR alpha 1 (mERR alpha 1) revealed that the homologies are 89% in nucleotides and 97% in amino acids. By electrophoresis mobility shift assay, we showed that the glutathione S-transferase-mERR alpha 1 fusion protein produced in a bacterial system bound to the human ERR alpha 1 DNA-binding element. Mouse uterine nuclear extract also interacted with this DNA element and produced three complexes in the mobility shift assay, one of which was supershifted by the hERR alpha 1 antiserum. A 2.2 kbp transcript was detected by Northern analysis in all adult mouse tissues tested; however, large variations in the amount of ERR alpha 1 mRNA were found among them. Multiple immunoreactive forms of mouse ERR alpha 1 were detected by Western analysis in non-reproductive tissues, whereas a major 53 kDa protein was found in reproductive tissues such as uterus, cervix and vagina. Diethylstilbestrol (DES) stimulated the expression of ERR alpha 1 mRNA in the uterus of 19-day-old mouse. We showed that DES and estradiol, but not progesterone or dexamethasone, enhanced the level of immunoreactive ERR alpha 1 in the mouse uterus. These results demonstrated that the ERR alpha 1 is an estrogen-responsive gene in the mouse uterus and provides a model system with which to study the biological roles of this nuclear orphan receptor.
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PMID:The mouse estrogen receptor-related orphan receptor alpha 1: molecular cloning and estrogen responsiveness. 946 Jun 51

The risk factors for women developing breast and endometrium cancers are all associated with a lifetime of estrogen exposure. Estrogen replacement therapy (ERT) in particular has been correlated with a slight increased cancer risk, although the numerous benefits of ERT may negate this harmful side effect. Equilenin and equilin are equine estrogens which make up between 30% and 45% of the most widely prescribed estrogen replacement formulation, Premarin (Wyeth-Ayerst). In this study we have synthesized the catechol metabolites of equilenin [4-hydroxyequilenin (4-OHEN)] and equilin [4-hydroxyequilin (4-OHEQ)] and examined how changing unsaturation in the B ring affects the formation of o-quinone GSH conjugates and the ability of the o-quinones and/or GSH conjugates to inhibit glutathione S-transferase (GST). Interestingly, both 4-OHEN and 4-OHEQ autoxidized to o-quinones without the need of oxidative enzyme catalysis. 4-OHEN-o-quinone reacts with GSH to give two mono-GSH conjugates and one diadduct. The behavior of 4-OHEQ was found to be more complex than 4-OHEN as conjugates resulting from 4-OHEN were detected in addition to the 4-OHEQ GSH adducts. Both 4-OHEN and 4-OHEQ were found to be potent inhibitors of GST-catalyzed conjugation of GSH with 1-chloro-2,4-dinitrobenzene. In contrast, the endogenous catechol estrogens, 4-hydroxyestrone (4-OHE) and 2-hydroxyestrone (2-OHE), were without effect unless tyrosinase was present to convert the catechols to o-quinones. Scavengers of reactive oxygen species and metal chelators had no effect on GST inhibition by catechol estrogens with the exception of the catalase which protected GST activity. Kinetic studies showed that 4-OHEN was a potent irreversible inactivator of GST. Preincubation of the enzyme with 4-OHEN showed a time-dependent increase in inhibitory effect, and gel filtration did not restore GST activity confirming the irreversible nature of the enzyme inactivation. Analysis of the Kitz-Wilson plot gave a dissociation constant of the reversible enzyme-inhibitor complex (Ki = 620 microM) and a rate constant of conversion of the reversible enzyme-inhibitor complex to the irreversibly inhibited enzyme (k2 = 7.3 x 10(-)3 s-1). These data suggest that 4-OHEN is an irreversible inactivator with relatively low affinity for GST; however, once formed the 4-OHEN enzyme complex is rapidly converted to the irreversibly inhibited enzyme. The inhibition mechanism likely involves oxidation of the catechol estrogens to o-quinones and covalent modification and/or oxidation of critical amino acid residues on GST. In addition, hydrogen peroxide generated through redox cycling of the o-quinone and/or semiquinone radical and GSH could cause oxidative damage to GST.
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PMID:Inhibition of glutathione S-transferase activity by the quinoid metabolites of equine estrogens. 967 38

Estrogen-responsive genes are regulated by altering the balance of estrogen receptor (ER) interaction with transcription activators and inhibitors. Here we examined the role of ER ligand on ER interaction with the Chicken Ovalbumin Upstream Promoter Transcription Factor (COUP-TF) orphan nuclear receptor. COUP-TF binding to half-site estrogen response elements (EREs) was increased by the addition of estradiol (E2) -liganded ER (E2-ER), but not by ER liganded with the antiestrogens 4-hydroxytamoxifen (4-OHT-ER) or tamoxifen aziridine (TAz-ER). ER did not bind to single half-sites. Conversely, COUP-TF enhanced the ERE binding of purified E2-ER, but did not affect TAz-ER-ERE binding. In contrast, only antiestrogens enhanced direct interaction between ER and COUP-TF as assessed by GST pull-down assays. Identical results were obtained using either purified bovine or recombinant human ERalpha. Co-immunoprecipitation assays showed that ER and COUP-TF interact in extracts from MCF-7 and ERalpha-transfected MDA-MB-231 cells. Here we document that ER ligand impacts COUP-TF-ER interaction. COUP-TF interaction is mediated by the DNA binding and ligand-binding domains of ER. We suggest that changes in ER conformation induced by DNA binding reduce ER-COUP-TF interaction. Transient transfection of human MCF-7 breast cancer cells with a COUP-TFI expression vector repressed E2-induced luciferase reporter gene expression from single or multiple tandem copies of a consensus ERE. COUP-TFI stimulated 4-OHT-induced luciferase activity from a minimal ERE. Alone, COUP-TFI increased transcription from ERE half-sites or a single ERE in a sequence-dependent manner. These data provide evidence that the ERE sequence and its immediate flanking regions influence whether COUP-TF enhances, inhibits, or has no effect on ER ligand-induced ERE reporter gene expression and that COUP-TFI activates gene transcription from ERE half-sites. We suggest that COUP-TFI plays a role in mitigating estrogen-responsive gene expression.
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PMID:Role of estrogen receptor ligand and estrogen response element sequence on interaction with chicken ovalbumin upstream promoter transcription factor (COUP-TF). 1061 53

Estrogen receptors (ERs) are ligand-activated transcription factors that regulate gene expression and cell growth. Two ERs now have been identified: ERalpha and the more recently discovered ERbeta. The physiological function of ERbeta remains unclear, but evidence from vascular injury studies and from ERbeta knockout mice suggests that ERbeta may be involved in the regulation of cellular proliferation. Here we show a direct and specific interaction between ERbeta and the cell cycle mitotic spindle assembly checkpoint protein, MAD2 (mitosis arrest-deficient 2). The ERbeta-MAD2 interaction was identified by screening of a yeast two-hybrid system vascular endothelial cell library with ERbeta and confirmed with glutathione S-transferase-fusion protein interaction studies. In contrast, ERalpha did not interact with MAD2 in either the two-hybrid system or in the protein-protein interaction experiments. Amino acids 173-208 in the hinge region of ERbeta were sufficient to mediate the interaction with MAD2 in the two-hybrid system and in glutathione S-transferase-fusion protein studies. These data identify a link between ERbeta and MAD2 of potential importance to regulation of the cell cycle and support a function of ERbeta distinct from the established role of ERs as transcription factors.
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PMID:Specific association of estrogen receptor beta with the cell cycle spindle assembly checkpoint protein, MAD2. 1070 29

International scientific publications on the influence of metabolic genotypes on biological indicators of genotoxic risk in environmental or occupational exposure are reviewed. Biomarkers of exposure (substance or its metabolites in biological fluids, urinary mutagenicity, protein and DNA adducts) and of effects (chromosome aberrations (CAs), sister chromatid exchanges (SCEs), micronuclei (Mn), COMET assay, HPRT mutants) have been evaluated according to different genotypes (or phenotypes) of several activating/detoxifying metabolic activities. In less than half the studies (43 out of 95), the influence of genotype on the examined biological indicator was found, of which four report poorly reliable results (i.e., with scarce biological plausibility, because of the inconsistency of modulated effect with the type of enzymatic activity expressed). As regards urinary metabolites, the excretion of mercapturic acids (MA) is greater in subjects with high GST activity, that of 1-pyrenol and other PAH metabolites turns out to be significantly influenced by genotypes CYP1A1 or GSTM1 null, and that of exposure indicators to aromatic amines (AA) (acetylated and non-acetylated metabolites) is modulated by NAT2. In benzene exposure, preliminary results suggest an increase in urinary t, t-muconic acid (t,t-MA) in subjects with some genotypes. On urinary mutagenicity of PAH-exposed subjects, the effects of genotype GSTM1 null, alone or combined with NAT2 slow are reported. When DNA adduct levels are clearly increased in PAH-exposed group (18 out of 22), 7 out of 18 studies report the influence of GSTM1 null on this biomarker, and of the five studies which also examined genotype CYP1A1, four report the influence of genotype CYP1A1, alone or in combination with GSTM1 null. A total of 25 out of 41 publications (61%) evaluating the influence of metabolic polymorphisms on biomarkers of effect (cytogenetic markers, COMET assay, HPRT mutants) do not record any increase in the indicator due to exposure to the genotoxic agents studied, confirming the scarce sensitivity of these indicators (mainly HPRT mutants, Mn, COMET assay) for assessing environmental or occupational exposure to genotoxic substances. Concluding, in determining urinary metabolites for monitoring exposure to genotoxic substances, there is sufficient evidence that genetically-based metabolic polymorphisms must be taken into account in the future. The unfavourable association for the activating/detoxifying metabolism of PAH is also confirmed as a risk factor due to the formation of PAH-DNA adducts. The clearly protective role played by GSTT1 on DEB (and/or related compound)-induced sister chromatid exchanges (SCEs) should be noted. The modulating effects of genotypes on protein adduct levels in environmental and occupational exposure have not yet been documented, and most studies on the influence of genotype on biological indicators of early genotoxic effects report negative results.
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PMID:Biological indicators of genotoxic risk and metabolic polymorphisms. 1101 45

Estrogen is to thought to play a role in the pathogenesis of low grade but not high grade endometrial carcinomas. The dominant circulating estrogen in post menopausal women is estrone which is formed by aromatization of androstenedione. delta4-5 isomerase, active in the conversion of dehydroepiandrosterone to androstenedione, may be demonstrated immunohistochemically by the antibody to alpha glutathione S-transferase (alphaGST). Inhibin, normally acting to suppress FSH secretion, also has an LH-dependent paracrine stimulatory effect on ovarian stromal cells to produce androstenedione. The purpose of this study was to compare the distributions of alphaGST and alpha inhibin in the ovaries of patients with low grade and high grade endometrial carcinomas. The results show a statistically significant increase in intracytoplasmic alphaGST staining in patients with low grade endometrioid adenocarcinomas compared to high grade carcinomas. There was also a statistically significant correlation between the distribution of alphaGST and alpha inhibin. These findings lend some support to the hypothesis that estrogen plays a role in the pathogenesis of low grade carcinomas; that the increase in estrone is partly due to increased production of androstenedione by the ovary and that this increased production could be the consequence of increased inhibin paracrine activity.
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PMID:The distribution of alpha inhibin and alpha glutathione S-transferase (delta4-5 isomerase) in the ovaries of patients with endometrial carcinoma. 1124 Jul 97

Olefinic compounds are commercially valuable because they form useful polymeric substances. The same chemical property (presence of double bonds) that makes the olefins useful may also cause them to be toxic in the body. The double bonds of olefins can be oxidized by cytochrome P450 enzymes to epoxides, which are electrophiles that can react with DNA and may cause alterations in the genetic information carried by that macromolecule. Epoxides can be rendered inactive toward DNA by binding to proteins, by hydrolysis to diols through epoxide hydrolase enzymes (EHs), or by forming conjugates with glutathione via glutathione S-transferase (GST) activities. The balance between the oxidizing enzymatic activities and the hydrolyzing or conjugating enzymatic activities in the livers of different species can influence the potential toxicity of the olefins. The location of the enzymes and the potential for concerted reactions in which epoxides are inactivated immediately after formation will also influence the potential toxicity of the olefins. Cytochrome P450 enzymes and EHs are in microsomes located in the rough endoplasmic reticulum surrounding the nucleus where the DNA is located. GST is in the cytoplasm of the cell. In the case of 1,3-butadiene (BD), such enzymatic differences may strongly influence the toxicity in different species. The mouse, in which BD is a potent multi-site carcinogen, has the lowest microsomal EH activity of any species. This allows the monoepoxides formed in the microsomes by cytochrome P450 enzymes to be further oxidized to the highly genotoxic diepoxide (DEB), and both epoxides can either be released into the blood for distribution throughout the body or can react with DNA in the nucleus. The rat, in which BD is a weak carcinogen, has much higher levels of microsomal EH, and only trace amounts of DEB enter the bloodstream. Major BD metabolites in primates suggest that the hydrolysis pathway is even more prominent in primates than in rats. Data suggest that BD will be much less toxic in primates than in mice. Considering these quantitative differences in metabolism may help to reduce the uncertainties in extrapolating animal data on olefin toxicity to health risk assessments for humans exposed to the compounds.
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PMID:Species differences in the metabolism of olefins: implications for risk assessment. 1139 81


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