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)

Oxidative stress has been implicated in the pathogenesis of several neurodegenerative disorders including primary open-angle glaucoma (POAG) an optic neuropathy characterized by loss of retinal ganglion cell (RGC) axons and remodeling of the optic nerve head (ONH). Previous findings in glaucomatous astrocytes suggested increased oxidative stress and lipid peroxidation in human optic nerves. We studied the dose and time dependent effects of 4-hydroxynonenal (HNE), a by-product of lipid peroxidation, on the viability of primary cultures of human ONH astrocyte. A significant depletion of glutathione (GSH) level was observed in normal astrocytes after exposure to HNE for 1 h and 3 h. Untreated glaucomatous astrocytes exhibited depleted levels of GSH which increased slightly after exposure to HNE. Both normal and glaucomatous astrocytes recovered GSH levels after 24 h of removal of HNE. HNE caused significant increases in expression of antioxidant enzymes, glutamate cysteine ligase catalytic subunit (GCLC), aldo-keto reductase 1C family member 1 (AKR1C1) and glutathione S-transferase-alpha4 (GSTA4). HNE induced expression of the transcription factor Nrf2, which coordinates the upregulation of detoxification enzymes. In addition, ONH astrocytes responded to HNE by activation and transcription of cFOS and NFkB, which regulate physiological protective responses against oxidative stress. Our results indicate that ONH astrocytes exhibit a strong antioxidant response to HNE treatment by inducing the transcription factors cFOS, NFkB, and Nrf2, which upregulate the expression of GCLC, to produce more GSH in the cell. AKR1C1 was also upregulated after HNE treatment to inactivate HNE, independent of GSH availability in the cells. Collectively these data indicate that ONH astrocytes can efficiently counteract the neurotoxic effects of HNE offering protection in the optic nerve by releasing GSH and antioxidant enzymes to eliminate the products of chronic oxidative stress.
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PMID:4-Hydroxynonenal, a product of oxidative stress, leads to an antioxidant response in optic nerve head astrocytes. 1717 95

Placental glutathione transferase (GST-P) is specifically expressed during rat haptocarcinogenesis, and has been used as a reliable tumor marker for experimental hepatocarcinogenesis in the rat. The regulation of this tumor marker gene may be associated with the process of carcinogeneisis. By elucidating the mechanisms of such tumor marker gene expression, we may shed light on the molecular mechanisms of carcinogenesis. We analyzed the regulation of the GST-P gene and found that the strong enhancer element GPE1 (GST-P enhancer-1) specifically regulates the GST-P gene by interacting with specific transcription factors in normal liver and during hepatocarcinogenesis. In particular, C/EBPalpha was required for the suppression of GST-P gene in normal liver, whereas the Nrf2/MafK heterodimer was required for the activation of this gene during hepatocarcinogenesis. In this Mini-Review, we describe the positive and negative regulatory mechanisms in the pre-cancerous and normal liver, respectively.
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PMID:Regulation of glutathione transferase P: a tumor marker of hepatocarcinogenesis. 1743 54

Curcumin is a plant-derived diferuloylmethane compound extracted from Curcuma longa, possessing antioxidative and anticarcinogenic properties. Antioxidants and oxidative stress are known to induce the expression of certain classes of detoxification enzymes. Since the upregulation of detoxifying enzymes affects the drug metabolism and cell defense system, it is important to understand the gene regulation by such agents. In this study, we demonstrated that curcumin could induce the expression of human glutathione S-transferase P1 (GSTP1). In HepG2 cells treated with 20muM curcumin, the level of GSTP1 mRNA was significantly increased. In luciferase reporter assays, curcumin augmented the promoter activity of a reporter construct carrying 336bp upstream of the 5'-flanking region of the GSTP1 gene. Mutation analyses revealed that the region including antioxidant response element (ARE), which overlaps AP1 in sequence, was essential to the response to curcumin. While the introduction of a wild-type Nrf2 expression construct augmented the promoter activity of the GSTP1 gene, co-expression of a dominant-negative Nrf2 abolished the responsiveness to curcumin. In addition, curcumin activated the expression of the luciferase gene from a reporter construct carrying multiple ARE consensus sequences but not one with multiple AP1 sites. In a gel mobility shift assay with an oligonucleotide with GSTP1 ARE, an increase in the amount of the binding complex was observed in the nuclear extracts of curcumin-treated HepG2 cells. These results suggested that ARE is the primary sequence for the curcumin-induced transactivation of the GSTP1 gene. The induction of GSTP1 may be one of the mechanisms underlying the multiple actions of curcumin.
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PMID:Curcumin activates human glutathione S-transferase P1 expression through antioxidant response element. 1744 3

In rat liver, in addition to their intrinsic transferase activity, alpha-class GSTs have Se-independent glutathione peroxidase activity toward fatty acid hydroperoxides, cumene hydroperoxide and phospholipids hydroperoxides but not toward H(2)O(2.) We have previously shown that hepatic GST activity by these isoenzymes is significantly increased 24h after cadmium or manganese administration (Casalino et al., 2004). Here it is reported that Se-independent glutathione peroxidase activity by alpha-class GSTs is also stimulated in the liver of intoxicated rats. The stimulation is associated with a higher level of alpha-class GST proteins, whose induction is blocked by actinomycin D co-administration. The observed Se-independent glutathione peroxidase activity is due to alpha-class GST isoenzymes, as indicated by the studies with diethyldithiocarbamate which, at any concentration, equally inhibits both GST and Se-independent glutathione peroxidase and is an uncompetitive inhibitor of both enzymes. As for liver Se-GSPx, it is not at all affected under these toxic conditions. For comparison, we have evaluated the status of another important antioxidant enzyme, NAD(P)H:quinone reductase, 24h after cadmium or manganese administration. NQO1 too results strongly stimulated in the liver of the intoxicated rats. In these animals, a higher expression of Nrf2 protein is observed, actively translocated from the cytoplasm to the nucleus. The results with the transcription inhibitor, actinomycin D, and the effects on Nrf2 protein are the first clear indication that acute manganese intoxication, similarly to that of cadmium and other heavy metals, increases both the hepatic level of Nrf2 and its transfer from the cytoplasm to the nucleus where it actively regulates the induction of phase II enzymes.
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PMID:The Nrf2 transcription factor contributes to the induction of alpha-class GST isoenzymes in liver of acute cadmium or manganese intoxicated rats: comparison with the toxic effect on NAD(P)H:quinone reductase. 1757 73

Wild Panax ginseng C.A. Meyer (WG) is a well-known medicinal herb. In this study, the protective effects of a water extract from the root of WG on benzo[alpha]pyrene (BP)-induced hepatotoxicity and the mechanism of these effects were investigated for the first time. The effects of WG on liver toxicities induced by BP were assessed by blood biochemical and histopathological analyses. BP caused severe liver injury in rats, as indicated by elevated plasma ALT, AST and LPO levels. Pretreatment with WG for 4 weeks completely abrogated increases in the ALT, AST and LPO levels when challenged with BP. Reductions in GSH content and GST activity by BP were reversed by WG. These protective effects of WG against BP-induced toxicity were consistent with the results of histopathological examinations. We next examined the effects of WG on the gene expression of the enzymes that metabolize BP in H4IIE cells. CYP1A1 mRNA and protein expression were increased by BP. WG moderately inhibited BP-induced CYP1A1 gene expression. Moreover, GSTA2, GSTA3 and GSTM2 gene expressions were significantly increased by WG through the Nrf2/antioxidant responsive element pathway for enzyme induction. In summary, WG is efficacious in protecting against BP-induced hepatotoxicity as results of metabolic regulations through both the inhibition of metabolic enzyme activation and the enhancement of electrophilic detoxification, implying that WG should be considered a potential chemopreventive agent.
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PMID:The potent protective effect of wild ginseng (Panax ginseng C.A. Meyer) against benzo[alpha]pyrene-induced toxicity through metabolic regulation of CYP1A1 and GSTs. 1759 Feb 95

Mice fed diets containing 3% or 6% coffee for 5 days had increased levels of mRNA for NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione S-transferase class Alpha 1 (GSTA1) of between 4- and 20-fold in the liver and small intestine. Mice fed 6% coffee also had increased amounts of mRNA for UDP-glucuronosyl transferase 1A6 (UGT1A6) and the glutamate cysteine ligase catalytic (GCLC) subunit of between 3- and 10-fold in the small intestine. Up-regulation of these mRNAs was significantly greater in mice possessing Nrf2 (NF-E2 p45 subunit-related factor 2) than those lacking the transcription factor. Basal levels of mRNAs for NQO1, GSTA1, UGT1A6 and GCLC were lower in tissues from nrf2(-/-) mice than from nrf2(+/+) mice, but modest induction occurred in the mutant animals. Treatment of mouse embryonic fibroblasts (MEFs) from nrf2(+/+) mice with either coffee or the coffee-specific diterpenes cafestol and kahweol (C+K) increased NQO1 mRNA up to 9-fold. MEFs from nrf2(-/-) mice expressed less NQO1 mRNA than did wild-type MEFs, but NQO1 was induced modestly by coffee or C+K in the mutant fibroblasts. Transfection of MEFs with nqo1-luciferase reporter constructs showed that induction by C+K was mediated primarily by Nrf2 and required the presence of an antioxidant response element in the 5'-upstream region of the gene. Luciferase reporter activity did not increase following treatment of MEFs with 100 mumol/l furan, suggesting that this ring structure within C+K is insufficient for gene induction. Priming of nrf2(+/+) MEFs, but not nrf2(-/-) MEFs, with C+K conferred 2-fold resistance towards acrolein.
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PMID:Induction of cancer chemopreventive enzymes by coffee is mediated by transcription factor Nrf2. Evidence that the coffee-specific diterpenes cafestol and kahweol confer protection against acrolein. 1802 74

The selenocysteine tRNA (tRNA(Sec)) molecule is the sight of synthesis for the amino acid selenocysteine and the adaptor for its translational insertion into selenoprotein enzymes, the majority of which contribute to cellular redox homeostasis. To examine the consequences of selenoprotein depletion on the oxidative environment of the cell, we generated a conditional knock-out mouse for the tRNA(Sec) gene (Trsp). Deletion of Trsp in either macrophages or liver elevated oxidative stress and activated the transcriptional induction of cytoprotective antioxidant and detoxification enzyme genes, including glutathione S-transferase P1 and NAD(P)H:quinone oxidoreductase 1, and other well known target genes of the transcription factor Nrf2 (NF-E2-related factor 2). Simultaneous disruption of Trsp and Nrf2 severely compromised the cytoprotective response. Double knock-out macrophages displayed reduced viability, elevated oxidative stress, and increased susceptible to hydrogen peroxide treatment compared with deletion of either gene alone. Mice carrying a liver-specific deletion of Trsp on an Nrf2-null background experienced hepatocellular apoptosis and displayed a severely reduced survival rate compared with loss of Trsp alone. Our results thus demonstrate that reduced selenoprotein activity is counterbalanced by an Nrf2-mediated cytoprotective response, which is essential for maintaining cellular redox homeostasis and viability.
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PMID:Deletion of the selenocysteine tRNA gene in macrophages and liver results in compensatory gene induction of cytoprotective enzymes by Nrf2. 1803 55

Frequent consumption of green tea, one of the most popular and widely consumed beverages, has been known to protect against development of various cancers according to numerous experimental and several population-based studies. Molecular mechanisms underlying chemopreventive effects exerted by green tea and its components have been extensively investigated. (-)-Epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, has been shown to induce expression of glutathione S-transferase, glutathione peroxidase, glutamate cysteine ligase, hemeoxygenase-1, etc. that are involved in the elimination or inactivation of reactive oxygen species and electrophiles implicated in multi-stage carcinogenesis. The redox-sensitive transcription factor, nuclear factor erythroid 2 p45 (NF-E2)-related factor (Nrf2) plays a key role in regulating induction of phase II detoxifying or antioxidant enzymes. Thus, activation of Nrf2 is considered to be an important molecular target of many chemopreventive and chemoprotective agents. This review summarizes the molecular basis of chemoprevention and cytoprotection afforded by EGCG with emphasis on its ability to modulate Nrf2-mediated cellular events.
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PMID:Modulation of Nrf2-mediated antioxidant and detoxifying enzyme induction by the green tea polyphenol EGCG. 1808 23

Autophagy is a bulk protein degradation system for the entire organelles and cytoplasmic proteins. Previously, we have shown the liver dysfunction by autophagy deficiency. To examine the pathological effect of autophagy deficiency, we examined protein composition and their levels in autophagy-deficient liver by the proteomic analysis. While impaired autophagy led to an increase in total protein mass, the protein composition was largely unchanged, consistent with non-selective proteins/organelles degradation of autophagy. However, a series of oxidative stress-inducible proteins, including glutathione S-transferase families, protein disulfide isomerase and glucose-regulated proteins were specifically increased in autophagy-deficient liver, probably due to enhanced gene expression, which is induced by accumulation of Nrf2 in the nuclei of mutant hepatocytes. Our results suggest that autophagy deficiency causes oxidative stress, and such stress might be the main cause of liver injury in autophagy-deficient liver.
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PMID:Comprehensive proteomics analysis of autophagy-deficient mouse liver. 1824 91

Selenium (Se) and vitamin E are antioxidant micronutrients. Se functions through selenoproteins and vitamin E reacts with oxidizing molecules in membranes. The relationship of these micronutrients with the Nrf2-antioxidant response element (ARE) pathway was investigated using ARE-reporter mice and Nrf2-/- mice. Weanling males were fed Se-deficient (0 Se), vitamin E-deficient (0 E), or control diet for 16 or 22 weeks. The ARE reporter was elevated 450-fold in 0 Se liver but was not elevated in 0 E liver. Antioxidant enzymes induced by Nrf2-ARE (glutathione S-transferase (GST), NAD(P)H quinone oxidoreductase (NQOR), and heme oxygenase-1 (HO-1)) were elevated in 0 Se livers but not in 0 E livers. Deletion of Nrf2 had varying effects on the inductions, with GST induction being abolished by it but induction of NQOR and HO-1 still occurring. Thus, Se deficiency, but not vitamin E deficiency, induces a number of enzymes that protect against oxidative stress and modify xenobiotic metabolism through Nrf2-ARE and other stress-response pathways. We conclude that Se deficiency causes cytosolic oxidative stress but that vitamin E deficiency does not. This suggests that the oxidant defense mechanisms in which these antioxidant nutrients function are independent of one another.
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PMID:Selenium deficiency activates mouse liver Nrf2-ARE but vitamin E deficiency does not. 1827 78


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