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)

Pharmaceuticals are ubiquitous pollutants in the aquatic environment where their potential effects on non-target species like fish has only recently become subject of systematic investigations. In the present study, experiments were undertaken to examine the effects of a synthetic pharmaceutical endocrine disruptor, ethynylestradiol (EE2), given in water at 5 or 50 ng/L and sampled at days 0 (control), 3 and 7 after exposure, on hepatic phase I and II biotransformation and hormonal pathways of juvenile salmon using quantitative (real-time) polymerase chain reaction (qPCR), Vtg ELISA and 7-ethoxyresorufin O-deethylase (EROD) catalytic activity. Our data show that EE2 produced time- and concentration-specific modulation of estrogen receptor isoforms (ERalpha, ERbeta) and androgen receptor-beta (ARbeta). EE2 produced a concentration-specific induction of vitellogenin (Vtg) and zona radiata protein (Zr-protein) at day 3 after exposure. At day 7, Vtg and Zr-protein mRNA (and plasma Vtg protein) expression were significantly decreased in the group given 5 ng EE2/L, compared to dimethyl sulfoxide (DMSO) control group. In the xenobiotic biotransformation pathway, EE2 produced a significant increase of aryl hydrocarbon receptor-alpha (AhRalpha) at day 3 in the group given 5 ng EE2/L and AhRbeta was decreased at the same concentration at day 7. While CYP3A was not significantly affected by EE2 exposure, the CYP1A1, AhR nuclear translocator (Arnt) and AhR repressor (AhRR) mRNA showed an apparent EE2 concentration and time-dependent decrease. The expression of uridine diphosphoglucuronosyl transferase (UGT) and glutathione S-transferase class pi-like (GSTpi-like) mRNA were decreased after exposure to 50ng EE2/L at both day 3 and 7 after exposure. The effect of EE2 on the CYP1A1 gene expressions paralleled effect on EROD and AhRR mRNA, suggesting a direct role of EE2 in controlling cellular detoxification machinery. Interestingly, the carrier vehicle, DMSO produced significant time-dependent induction of estrogenic (ERalpha, Vtg and Zr-protein) responses, compared with blank (i.e. without DMSO) controls at day 7 post-exposure. The effect of DMSO totally underscored the observed EE2 effect at day 7 after exposure. In general, these findings support previous reports on the endocrine effects of EE2, in addition to effects on hepatic biotransformation system. In view of the data presented here and our recent studies, the use of DMSO as carrier vehicle in endocrine toxicological experimental studies should be re-evaluated.
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PMID:Effects of 17alpha-ethynylestradiol on hormonal responses and xenobiotic biotransformation system of Atlantic salmon (Salmo salar). 1787 31

There is a clear association between the excessive exposure to estrogens and the development of cancer in hormone-sensitive tissues (breast, endometrium). It has become clear that there are likely multiple overlapping mechanisms of estrogen carcinogenesis. One major pathway is the extensively studied hormonal pathway, by which estrogen stimulates cell proliferation through nuclear estrogen receptor (ER)-mediated signaling, thus resulting in an increased risk of genomic mutations during DNA replication. A similar "nongenomic pathway", potentially involving newly discovered membrane-associated ERs, also appears to regulate extranuclear estrogen signaling pathways. This perspective is focused on a third pathway involving the metabolism of estrogens to catechols mediated by cytochrome P450 and further oxidation of these catechols to estrogen o-quinones. Oxidative enzymes, metal ions, and in some cases molecular oxygen can catalyze o-quinone formation, so that these electrophilic/redox-active quinones can cause damage within cells by alkylation and/or oxidation of cellular proteins and DNA in many tissues. It appears that the endogenous estrogen quinones primarily form unstable N3-adenine or N7-guanine DNA adducts, ultimately resulting in mutagenic apurinic sites. In contrast, equine estrogen quinones, formed from estrogens present in popular hormone replacement therapy prescriptions, generate a variety of DNA lesions, including bulky stable adducts, apurinic sites, DNA strand cleavage, and oxidation of DNA bases. DNA damage induced by these equine quinones is significantly increased in cells containing ERs, leading us to hypothesize a mechanism involving ER binding/alkylation by the catchol/quinone, resulting in a "Trojan horse". The "Trojan horse" carries the highly redox-active catechol to estrogen -sensitive genes, where high amounts of reactive oxygen species are generated, causing selective DNA damage. Our data further suggest that other key protein targets for estrogen o-quinones could be redox-sensitive enzymes (i.e, GST P1-1, QR). These proteins are involved in stress response cascades that are known to contribute to the regulation of cell proliferation and apoptosis. Finally, it has been shown that catechol estrogens can transform breast epithelial cells into a tumorigenic phenotype and that these transformed cells had differential gene expression of several genes involved in oxidative stress. Given the direct link between excessive exposure to estrogens, metabolism of estrogens, and increased risk of breast cancer, it is crucial that factors that affect the formation, reactivity, and cellular targets of estrogen quinoids be thoroughly explored.
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PMID:Potential mechanisms of estrogen quinone carcinogenesis. 1805 5

New World primates exhibit a form of resistance to estrogens that is associated with overexpression of an estrogen response element (ERE)-binding protein (ERE-BP) and an intracellular estradiol (E(2))-binding protein (IEBP). Both proteins suppress E(2)-mediated transcription when overexpressed in estrogen receptor-alpha (ERalpha)-positive cells. Although ERE-BP acts as a competitor for ERE occupancy by liganded ERalpha, the function of IEBP and its human homolog, heat-shock protein 27 (hsp27), is less clear. In data presented here, we have used E(2)-responsive human MCF-7 breast cancer cells to show that IEBP/hsp27 can regulate estrogen signaling as a cytosolic decoy for E(2) and as a protein chaperone for ERalpha. Furthermore, co-immunoprecipitation, colocalization, yeast two-hybrid, and glutathione S-transferase pull-down analyses indicate that IEBP/hsp27 also interacts with ERE-BP to form a dynamic complex that appears to cycle between the cytoplasm and nucleus during normal estrogen signaling. Overexpression of either IEBP/hsp27 or ERE-BP in MCF-7 cells resulted in abnormal subcellular distribution of the IEBP/hsp27 and ERE-BP, with concomitant dysregulation of ERE occupancy as determined by chromatin immunoprecipitation. We hypothesize that IEBP/hsp27 and ERE-BP not only cause hormone resistance in New World primates but are also crucial to normal estrogen signaling in human cells. This appears to involve a physical association between the two proteins to form a complex that is able to interact with both E(2) and ERalpha in cytosolic and nuclear compartments.
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PMID:Control of estradiol-directed gene transactivation by an intracellular estrogen-binding protein and an estrogen response element-binding protein. 1809 92

ERRalpha (estrogen receptor-related receptor alpha) is a member of the nuclear receptor superfamily. To further our understanding of the detailed molecular mechanism of transcriptional regulation by ERRalpha, we searched for ERRalpha-interacting proteins using a yeast two-hybrid system by screening a human mammary gland cDNA expression library with the ligand-binding domain (LBD) of ERRalpha as the "bait". Fast skeletal muscle troponin I (TNNI2), along with several known nuclear receptor co-activators, were isolated. We demonstrated that TNNI2 localizes to the cell nucleus and interacts with ERRalpha in co-immunoprecipitation experiments. GST pull-down assays also revealed that TNNI2 interacts directly with ERRalpha. Through luciferase reporter gene assays, TNNI2 was found to enhance the transactivity of ERRalpha. Combining mutagenesis and yeast two-hybrid assays, we mapped the ERRalpha-interacting domain on TNNI2 to a region encompassing amino acids 1-128. These findings reveal a new function for TNNI2 as a co-activator of ERRalpha.
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PMID:Fast skeletal muscle troponin I is a co-activator of estrogen receptor-related receptor alpha. 1833 30

Endocrine disrupting compounds (EDCs), including both natural estrogens and estrogenic chemicals, are almost ubiquitous in the aquatic environment. In the marine bivalve Mytilus galloprovincialis different estrogenic compounds, both individually and in mixtures, were shown to affect the immune function both in vitro and in vivo. Moreover, individual estrogens, the natural estrogen 17beta-estradiol (E(2)) and the xenoestrogen bisphenol A (BPA), have been recently demonstrated to alter functional parameters and gene expression in mussel digestive gland, a tissue that plays a central role in metabolism and in nutrient distribution to the gonad during gamete maturation, with possible consequences on gametogenesis. In this work, the possible effects of a synthetic mixture of EDCs on the digestive gland were evaluated. The mixture contained seven estrogenic chemicals (17beta-estradiol, 17alpha-ethynyl estradiol, mestranol (MES), nonylphenol, nonylphenol monoethoxylate carboxylate (NP1EC), BPA, benzophenone (BP)), in proportions similar to those previously found in water samples of a coastal lagoon. Mussels were injected with different concentrations of the mixture (approximate nominal concentrations of total EDCs: 0.0177, 0.177, 1.77 and 177 ng/g dw) and tissues sampled 24 h post-injection. The mixture induced significant changes in lysosomal biomarkers (lysosomal membrane stability (LMS), neutral lipid (NL) and lipofuscin (LF) accumulation) as well as in the activities of catalase, glutathione transferase (GST), and of the glycolytic enzymes phosphofructokinase (PFK) and pyruvate kinase (PK). Moreover, downregulation of the gene transcription for the Mytilus estrogen receptor MeER1 isoform and for catalase, as evaluated by quantitative RT-PCR, were observed. Significant changes in lysosomal biomarkers, enzyme activities and gene transcription were also recorded at 72 h post-injection. The results demonstrate that short-term exposure to environmentally relevant concentrations of EDC mixtures can interfere with the lysosomal function, redox-related enzyme activities and gene transcription of mussel digestive gland.
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PMID:Short-term effects of environmentally relevant concentrations of EDC mixtures on Mytilus galloprovincialis digestive gland. 1837 27

The glutathione S-transferase (GST) family of enzymes is involved in the protection of the cell against foreign compounds and may consequently play a role in the development of cancer. Two of the family members, GSTA1 and GSTO1, have only been considered in a very limited number of studies. The objective of this study was to evaluate the potential relationships between GSTA1 and GSTO1 polymorphisms and breast cancer, taking into account the estrogen receptor statuses of the tumors and potential interactions with smoking, and intake of fruits and vegetables. The basis for the study was a nested case-control study including 396 postmenopausal pairs. Genetic polymorphisms were determined by restriction-fragment length polymorphism-polymerase chain reaction methods, and risks for breast cancer were estimated using conditional logistic regression. No association between GSTA1 polymorphism and breast cancer was found whereas carriers of the GSTO1 *B/*B genotype had higher risks of breast cancer when compared with carriers of the GSTO1 *A/*A genotype (incidence rate ratio 1.62, 95% confidence interval: 1.01-2.61). This association was strongest with regard to estrogen receptor positive breast cancer (incidence rate ratio 2.16, 95% confidence interval: 1.21-3.84). No signs of interaction with smoking or intake of fruits and vegetables were found for either GSTA1 or GSTO1 polymorphism. The study suggests that postmenopausal carriers of the GSTO1 *B/*B genotype may be at increased risk of especially estrogen receptor positive breast cancer. The finding of a higher risk with this genotype is in accordance with the only previous study. Further research is needed to confirm the finding.
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PMID:Polymorphisms of glutathione S-transferase A1 and O1 and breast cancer among postmenopausal Danish women. 1841 93

The CpG island spanning the transcription start of the glutathione S-transferase P1 becomes methylated in a variety of human cancers including breast cancer. To study the effect of sequence variation on hypermethylation of the GSTP1 promoter, we analyzed the genetic and epigenetic variability in 90 tumors from patients with locally advanced breast cancer. High-resolution quantitative analysis revealed large variability in the DNA methylation levels. Lack of methylation was more often observed in the basal and normal-like estrogen receptor (ER)-negative tumors, and methylated GSTP1 was associated with better overall survival (P = 0.00063). Studies of the genetic variation identified 14 different haplotypes. The distribution of methylation levels of tumors homozygous for the most frequent haplotype was significantly different from other haplotype combinations (P = 0.011), the difference being more pronounced in ER-positive (P = 0.005) and progesterone receptor-positive (P = 0.008) tumors. Regression modeling identified the ER status and haplotype as the main determinants of DNA methylation variability. We identified a putative c-Myb response element (MRE) that was present in one of two minimal promoter haplotypes. In vitro analysis showed that c-Myb binds to the MRE, but binding was weakened by the two polymorphisms. Transient cotransfections in luminal-type and basal-like breast cancer cell lines confirmed cell-specific differential binding of c-Myb to the polymorphic sites, leading to a change in the expression from the GSTP1 promoter in vivo. GSTP1 expression was moderately but significantly (P = 0.01) reduced after siRNA-mediated knockdown of c-Myb. Our results indicate that haplotype structure of a promoter is important for the extent of DNA methylation.
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PMID:GSTP1 promoter haplotypes affect DNA methylation levels and promoter activity in breast carcinomas. 1863 8

The herbicide atrazine (ATZ) is one of the most widely used pesticides in the world and is now under scrutiny for its alleged capacity to disrupt the endocrine system. Exhibiting negligible interaction with the estrogen receptor (ER), ATZ's mode of action remains to be elucidated. ATZ may act as an inducer of the enzyme aromatase, which converts androgens to estrogens, although other mechanisms should also be taken into consideration such as impairment of hepatic metabolism. Therefore we administered juvenile rainbow trout (Oncorhynchus mykiss) a dose of either 2 or 200 microg ATZ/kg, or of carrier control phosphate buffered saline (PBS) and we measured plasma concentrations of testosterone (T), 17beta-estradiol (E2) and vitellogenin (Vtg) 6 days after exposure. Simultaneously we analyzed hepatic gene expression of cytochrome P450 (CYP) 1A and pi-class glutathione S-transferase (GST-P), and catalase (CAT) activity. Although sex steroid levels showed no significant alterations, we found a dose-dependent increase in Vtg and a concomitant decrease in CYP1A. There was no effect of ATZ on GST-P mRNA levels but GST-P was positively correlated with CYP1A. Also, CYP1A was negatively correlated with liver CAT and E2, and varied with T concentrations in a hormetic manner. The results showed that ATZ can alter hepatic metabolism, induce estrogenic effects and oxidative stress in vivo, and that these effects are linked.
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PMID:Effects of atrazine on hepatic metabolism and endocrine homeostasis in rainbow trout (Oncorhynchus mykiss). 1897 69

The estrogen receptor (ER) is a key regulator of proliferation and differentiation in breast cancer cells. In the present study, the effect of steroid and xenobiotic receptor (SXR) on 17/beta-estradiol (E2)-induced transcription through ERalpha was studied. SXR augmented ER-mediated transcription in the presence of E2 in MCF-7 breast cancer-derived cells and CV-1 fibroblast-derived cells. On the other hand, SXR alone did not affect the estrogen response element (ERE)-containing promoter activity in CV-1 cells. SXR did not directly bind to ERalpha or ERE in vitro, indicating that SXR may affect ER-mediated transcription by altering cofactor binding to ER. Although SXR did not alter the binding between ERalpha and p300/CBP interacting protein (p/CIP), it decreased the binding of a specific corepressor, silencing mediator of retinoid and thyroid hormone receptors (SMRT) to liganded ERalpha as assessed by mammalian two-hybrid, glutathione S-transferase pull-down, immunoprecipitation and newly developed Liquid Chemiluminescent DNA Pull-Down Assays. These results indicate that SXR augmented ER-mediated transcription by dissociating SMRT from ERalpha. Thus, the expression of SXR in breast cancer cells may alter the ER signaling, which may play crucial role for growth and differentiation of breast cancer cells.
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PMID:Augmentation of estrogen receptor-mediated transcription by steroid and xenobiotic receptor. 1901 99

Human prostate cancer (PCa) and prostate epithelial cells predominantly express estrogen receptor (ER) beta, but not ERalpha. ERbeta might utilize various ER coregulators to mediate the E2-signaling pathway in PCa. Here, we identified coiled-coil domain containing 62 (CCDC62)/ERAP75 as a novel ER coactivator. CCDC62/ERAP75 is widely expressed in PCa cell lines and has low expression in MCF7 cells. Both in vitro and in vivo interaction assays using mammalian two-hybrid, glutathione S-transferase pull-down and coimmunoprecipitation methods proved that ERbeta can interact with the C-terminus of CCDC62/ERAP75 via the ligand-binding domain. The first LXXLL motif within CCDC62/ERAP75 is required for the interaction between ERbeta and CCDC62/ERAP75. Electrophoretic mobility shift assay showed that CCDC62/ERAP75 can be recruited by the estrogen response element-ER complex in the presence of ligand. Furthermore, a chromatin immunoprecipitation assay demonstrated the hormone-dependent recruitment of CCDC62/ERAP75 within the promoter of the estrogen-responsive gene cyclin D1. In addition, using silencing RNA (siRNA) against endogeneous CCDC62/ERAP75, we demonstrated that inhibition of endogenous CCDC62/ERAP75 results in the suppression of ERbeta-mediated transactivation as well as target gene expression in LNCaP cells. More importantly, using the tet-on overexpression system, we showed that induced expression of CCDC62/ERAP75 can enhance the E2-regulated cyclin D1 expression and cell growth in LNCaP cells. Together, our results revealed the role of CCDC62/ERAP75 as a novel coactivator in PCa cells that can modulate ERbeta transactivation and receptor function.
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PMID:CCDC62/ERAP75 functions as a coactivator to enhance estrogen receptor beta-mediated transactivation and target gene expression in prostate cancer cells. 1912 43


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