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 and inflammation appear to play a critical role in the progression of Parkinson's disease. As a result, there has been growing interest in antioxidant pathways and how these pathways might be exploited to slow the progressive loss of dopamine neurons. One such pathway that has garnered attention recently is mediated by the transcription factor Nrf2 and is integral in orchestrating cells' antiinflammatory defense. Nrf2 controls the inducible expression of numerous antioxidant and phase 2 detoxification genes, such as glutathione S-transferase, heme oxygenase-1, and NAD(P)H:quinone oxidoreductase 1 (NQO1). Once activated, these genes work synergistically to maintain intracellular redox homeostasis. In this study, we test the hypothesis that Nrf2 activation can protect dopaminergic neurons against 6-hydroxydopamine (6-OHDA)-induced toxicity. Treatment of organotypic nigrostriatal cocultures with either tert-butylhydroquinone (tBHQ) or sulforaphane, known activators of Nrf2, mitigated dopaminergic cell loss. The observed protection appeared to be mediated, at least in part, by an increase in antioxidant activity. Simultaneous treatment of cultures with tBHQ and 6-OHDA increased NQO1 expression 17-fold compared with controls. Overall, these results suggest that Nrf2 may play an important role in cellular protection in neurodegenerative diseases and may be a viable therapeutic target in the future.
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PMID:Nrf2 activators provide neuroprotection against 6-hydroxydopamine toxicity in rat organotypic nigrostriatal cocultures. 1912 16

Previous studies have shown that nuclear factor erythroid 2-related factor 2 (Nrf2) plays a unique role in many physiological stress processes. The present study investigated the role of Nrf2 in modulating traumatic brain injury (TBI)-induced secondary brain injury. Wild-type Nrf2 (+/+) and Nrf2 (-/-)-deficient mice were subjected to a moderately severe weight-drop impact head injury. The absence of Nrf2 function in mice resulted in exacerbated brain injury as shown by the increased severity of neurological deficit, apoptosis, and brain edema at 24h after TBI. This exacerbation of brain injury in Nrf2-deficient mice was associated with increased mRNA and protein expression of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6), and with decreased mRNA expression and enzymatic activity of antioxidant and detoxifying enzymes including NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione S-transferase alpha-1 (GST-alpha1), compared with their wild-type counterparts after TBI. In combination, these results suggest that Nrf2 plays an important role in protecting TBI-induced secondary brain injury, possibly by regulating inflammatory cytokines and inducing antioxidant and detoxifying enzymes.
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PMID:Role of Nrf2 in protection against traumatic brain injury in mice. 1912 83

Naturally occurring coumarins possess anti-carcinogenic activities in part by inducing carcinogen-detoxifying enzymes glutathione S-transferase (GST) and/or NAD(P)H quinone oxidoreductase (NQO1). Our goal was to determine whether citrus coumarins induce hepatic GST and/or NQO1 via activation of Nrf2 and the antioxidant response element (ARE). First, HepG2 cells stably transfected with the ARE and a green fluorescent protein (GFP) reporter were treated with increasing concentrations of coumarins and compared to positive controls. tert-Butylhydroquinone (TBHQ) and oltipraz increased GFP fluorescence, as did coumarin, limettin, auraptene, imperatorin, and 7,8-benzoflavone, suggesting that they activate the ARE, whereas isopimpinellin did not increase GFP fluorescence. Next, the effects of orally administered coumarins and oltipraz on hepatic GST and NQO1 activities were compared in Nrf2 knockout mice or Nrf2 heterozygous mice exhibiting the wild-type phenotype. Oltipraz, auraptene, imperatorin, isopimpinellin, and auraptene all significantly increased liver cytosolic GST activities in Nrf2 heterozygous mice. This effect was abrogated in Nrf2(-/-) mice dosed with oltipraz, attenuated in mice Nrf2(-/-) mice treated with auraptene and imperatorin, and still significant in Nrf2(-/-) mice treated with isopimpinellin. Of these compounds, only isopimpinellin significantly increased liver cytosolic NQO1 activities, and this effect was not attenuated in Nrf2(-/-) mice. These results strongly suggest that imperatorin and auraptene induce murine liver cytosolic GST activities via the Nrf2/ARE mechanism. Although structurally similar, isopimpinellin did not appear to activate HepG2-ARE-GFP and the Nrf2 knockout mouse study suggests that isopimpinellin may induce GST and NQO1 via additional mechanisms.
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PMID:Comparison of citrus coumarins on carcinogen-detoxifying enzymes in Nrf2 knockout mice. 1915 Jun 46

Glutathione S-transferases (GSTs), superoxide dismutase 2 (SOD2) and NAD(P)H:quinone oxidoreductase 1 (NQO1) are anti-oxidant enzyme genes. Polymorphisms of GSTs, SOD2 and NQO1 have been reported to influence individual susceptibility to various diseases. In an earlier study, we obtained preliminary findings that a subset of glutathione S-transferase T1 (GSTT1)-wt patients with varicocele may exhibit good response to varicocelectomy. In this study, we extended the earlier study to determine the distribution of genotype of each gene in the infertile population and to evaluate whether polymorphism of these genes affects the results of surgical treatment of varicocele. We analyzed 72 infertile varicocele patients, 202 infertile patients without varicocele and 101 male controls. Genotypes of GSTs were determined by polymerase chain reaction (PCR). Genotyping of SOD2 and NQO1 was performed using the PCR-restriction fragment length polymorphism (PCR-RFLP) method. A significantly better response to varicocelectomy was found in patients with the GSTT1-wt genotype (63.2%) and NQO1-Ser/Ser genotype (80.0%) than in those with GSTT1-null genotype (35.3%) and NQO1-Pro/Pro or NQO1-Pro/Ser genotype (45.2%), respectively. The frequencies of glutathione S-transferase M1/T1, SOD2 and NQO1 genotypes did not differ significantly among the varicocele patients, idiopathic infertile patients and male controls. GSTT1 genotype is associated with improvement of semen parameters after varicocelectomy. As the number of patients with NQO1-Ser/Ser genotype was not sufficient to reach definite conclusions, the association of NQO1 genotype with varicocelectomy requires further investigation.
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PMID:Genetic polymorphisms in glutathione S-transferase T1 affect the surgical outcome of varicocelectomies in infertile patients. 1915 39

Previous studies have shown that nuclear factor erythroid 2-related factor 2 (Nrf2) plays a unique role in many physiological stress processes. The present study investigated the role of Nrf2 in the regulation of traumatic brain injury (TBI)-induced acute lung injury (ALI). Wild-type Nrf2 (+/+) and Nrf2 (-/-)-deficient mice were subjected to a moderately severe weight-drop impact head injury. Pulmonary capillary permeability (PCP), wet/dry weight ratio, apoptosis, inflammatory cytokines and antioxidant/detoxifying enzymes were measured at 24 h after TBI. Mice lacking Nrf2 were found to be more susceptible to TBI-induced ALI, as characterized by the higher increase in PCP, wet/dry weight ratio and alveolar cells apoptosis after TBI. This exacerbation of lung injury in Nrf2-deficient mice was associated with increased pulmonary mRNA and protein expression of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6); and with decreased pulmonary mRNA expression and enzymatic activities of antioxidant and detoxifying enzymes including NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione S-transferase alpha1 (GST-alpha1)--as compared with their wild-type Nrf2 (+/+) counterparts after TBI. The results of the present study suggest that Nrf2 reduces TBI-induced acute lung injury, possibly by decreasing pulmonary inflammation and inducing antioxidant and detoxifying enzymes.
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PMID:Genetic ablation of Nrf2 enhances susceptibility to acute lung injury after traumatic brain injury in mice. 1917 47

3H-1,2-dithiole-3-thione (D3T), a cruciferous organosulfur compound, induces cytoprotective enzymes in animal cardiovascular cells. However, it remains unknown if D3T also upregulates antioxidants and phase 2 enzymes in human cardiomyocytes, and protects against cell injury induced by oxidative/electrophilic species as well as doxorubicin. In this study, we found that D3T (10-50 muM) potently induced a series of antioxidants and phase 2 enzymes in primary cultured human cardiomyocytes, including superoxide dismutase (SOD), glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx) glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1 (NQO1), aldose reductase (AR), and heme oxygenase (HO). D3T treatment also caused elevation of SOD, GSH, GR, GPx and GST in the isolated mitochondria. We also observed a time-dependent induction by D3T of mRNA expression for Cu,ZnSOD, MnSOD, gamma-glutamylcysteine ligase, GR, GSTA1, GSTM1, NQO1, AR, and HO-1. Pretreatment with D3T conferred concentration-dependent protection against cell injury induced by xanthine oxidase (XO)/xanthine, H(2)O(2), 3-morpholinosydnonimine, 4-hydroxy-2-nonenal, and doxorubicin. Pretreatment with D3T also reduced the formation of intracellular reactive oxygen species by XO/xanthine, H(2)O(2), and doxorubicin. In conclusion, this study demonstrated that D3T potently upregulated many antioxidants and phase 2 enzymes in human cardiomyocytes, which was accompanied by increased resistance to oxidative/electrophilic stress and doxorubicin toxicity.
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PMID:Cruciferous dithiolethione-mediated coordinated induction of total cellular and mitochondrial antioxidants and phase 2 enzymes in human primary cardiomyocytes: cytoprotection against oxidative/electrophilic stress and doxorubicin toxicity. 1917 75

Isoflavones are thought to be biologically active components in soy that play a role in the prevention of chronic diseases including cancer. How isoflavones may mediate their beneficial effects has not yet been fully established. Potential mechanisms of cellular action of isoflavones may include their ability to modulate gene expression and the activity levels of enzymes involved in antioxidant defence and the metabolism of xenobiotics including NAD(P)H (Nicotinamide-adenine-dinucleotide-phosphate) quinone oxidoreductase 1 (NQO1) and glutathione S-transferase (GST). Although there is increasing evidence from cell culture studies that genistein, the major isoflavone present in soy, may regulate the expression of genes encoding for phase II and antioxidant enzymes, little is known about its effect in vivo. Feeding rats over 3 weeks with semisynthetic diets enriched with genistein (2 g/kg) significantly increased both the hepatic mRNA and activity levels of NQO1. The total GST activity did not change in response to dietary genistein supplementation, whereas the mRNA levels of individual GST isoenzymes were differentially modulated. The hepatic mRNA level of Gsta2 (class alpha 2) was significantly increased whereas the mRNA levels of Gstm2 (class mu 2) and Gstp1 (class pi 1) were significantly lowered due to genistein supplementation. The protein level of Nrf2 (Nuclear factor E2-related factor 2), a transcription factor involved in the regulation of phase II enzymes, was not altered by dietary genistein. Furthermore, genistein did not affect the hepatic enzyme activity of the antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) or liver lipid peroxidation and glutathione levels. The induction of NQO1 may be one mechanism by which dietary genistein improves the capacity of the liver to detoxify carcinogens.
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PMID:Effect of dietary genistein on Phase II and antioxidant enzymes in rat liver. 1945 Oct 92

Isothiocyanate up-regulation of hepatic NAD(P)H:quinone oxidoreductase (NQO1) and glutathione S-transferases (GSTs) is an integral mechanism of their chemoprevention. In this paper, for the first time, the potential of the isothiocyanates erucin and sulforaphane to modulate these enzymes was investigated in two human livers and compared to rat liver. Precision-cut liver slices were incubated with erucin or sulforaphane (1-50 microM). Both isothiocyanates elevated NQO1 activity in rat slices that was paralleled by a fourfold rise in protein levels. No change in activity was noted in human slices, and only a weak rise in protein levels, < 10% of that in rat, was observed in only one of the human livers, whereas the other was refractive. GST activity, assessed with three substrates, was elevated in rat slices treated with either isothiocyanate, and was accompanied by a rise in GSTalpha and GSTmicro, but not GSTpi, protein levels. A rise in activity and in GSTalpha and GSTmu protein levels was also noted in one of the human livers. It appears that erucin and sulforaphane elevate GST expression in isoform-specific manner in both rat and human liver, whereas NQO1 is inducible by these compounds only in rat liver and very poorly in human liver.
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PMID:The aliphatic isothiocyanates erucin and sulforaphane do not effectively up-regulate NAD(P)H:quinone oxidoreductase (NQO1) in human liver compared with rat. 1953 70

Nitric oxide (NO)-donating non-steroidal anti-inflammatory drugs (NSAIDs) represent a promising new class of drugs developed to provide a safer alternative than their conventional NSAID counterparts in chemoprevention. We tested the effects of NO-aspirin 2 on Phase I and Phase II carcinogen-metabolizing enzymes. In HepG2 human hepatoma cells and in LS180 colonic adenocarcinoma cells, NO-aspirin 2 inhibited 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD)-induced cytochrome P450 (CYP) enzyme activity and CYP1A1 and CYP1A2 mRNA expression. These effects were further characterized as being mediated through transcriptional regulation: NO-aspirin 2 inhibited binding of ligand (TCDD)-activated aryl hydrocarbon receptor to the CYP1A1 enhancer sequence; additionally, NO-aspirin 2 suppressed carcinogen-induced expression of CYP1A heterogeneous nuclear RNA. The fate of carcinogen metabolites depends not only on activation by CYP enzymes but also detoxification by Phase II enzymes. Both HepG2 and LS180 cells treated with NO-aspirin 2 showed an increase in glutathione S-transferase-P1 (GST-P1), glutamate-cysteine ligase (GCL), and NAD(P)H:quinone oxidoreductase-1 (NQO1) expression. Compared with two other NO-releasing compounds, diethylenetriamine-NO and the organic nitrate, isosorbide dinitrate, the inhibitory effects of NO-aspirin 2 on TCDD-induced CYP activity and mRNA expression were considerably more potent. Furthermore, aspirin alone had no inhibitory effect on TCDD-induced CYP activity, nor did aspirin up-regulate GCL, GST-P1, or NQO1 expression. Consequent to the effects on carcinogen-metabolizing enzymes, NO-aspirin 2 inhibited [3H]benzo[a]pyrene-DNA adduct formation and DNA damage elicited by TCDD or benzo[a]pyrene. Our results demonstrate that NO-aspirin 2 may be an effective chemopreventive agent by favorably affecting the inhibitory and enhancing effects of Phase I and Phase II carcinogen metabolism, thereby protecting DNA from carcinogenic insult.
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PMID:Modulation of carcinogen metabolism by nitric oxide-aspirin 2 is associated with suppression of DNA damage and DNA adduct formation. 1954 25

Environmental tobacco smoke (ETS) exposure might increase the risk for childhood asthma, and we hypothesized the effect may be modified by the phase II genes NAD(P)H: quinone oxidoreductase 1 (NQO1) and glutathione S-transferase (GST) M1. To investigate the genetic and environmental associations with asthma, GSTM1 and NQO1 functional polymorphisms and ETS were analyzed in a two-staged cross-sectional study among elementary schoolchildren in Taiwan. Multiple logistic regression analysis revealed a significant association between the Ser allele of the NQO1 Pro187Ser polymorphism and asthma (OR=1.6, 95% CI 1.3-1.8). Although GSTM1 genotype itself was not significantly associated with asthma (OR=1.0, 95% CI 0.8-1.1), the GSTM1 genotype modified the association between the NQO1 polymorphism and asthma in children exposed to ETS (p=0.0002). The NQO1 gene might be involved in the development of asthma, especially in children carrying the GSTM1 null genotype who are exposed to ETS.
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PMID:NAD(P)H: Quinone oxidoreductase 1, glutathione S-transferase M1, environmental tobacco smoke exposure, and childhood asthma. 1959 59


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