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)

In myocardial preparations isolated from guinea pigs, 2-methyl-1, 4-naphthoquinone (menadione) causes an increase in contractility that is strictly related to the generation of reactive oxygen species (ROS) as a consequence of quinone metabolism. In heart, menadione undergoes one-electron reduction to semiquinone, a reaction mainly catalysed by mitochondrial NADH: ubiquinone oxidoreductase. It is also converted to hydroquinone by the soluble two-electron reductase, DT-diaphorase, and is conjugated with GSH by glutathione S-transferase. In order to assess the role of DT-diaphorase in cardiac responses to menadione, we examined the effects of both a specific inhibitor (dicoumarol) and an inducer (beta-naphthoflavone) of the enzyme on the inotropic action of the quinone. In electrically driven left atria of guinea pig, 4 microM dicoumarol significantly enhanced the positive inotropic effect of menadione, especially at the lower concentrations of the quinone. In myocardial preparations isolated from guinea pigs treated with beta-naphthoflavone (80 mg/kg i.p.for 2 days), DT-diaphorase activity was enhanced (+36% with respect to control animals, P < 0. 01), whereas the activities of the other enzymes involved in menadione metabolism were not modified. In these preparations, menadione caused a significantly lower increase in the force of contraction than in atria from untreated animals; moreover, pretreatment with beta-naphthoflavone caused a significant decrease in the menadione-induced oxidative stress, as evaluated from the GSH redox index. Taken together, these results demonstrate that cardiac DT-diaphorase does not contribute to ROS generation, but represents a detoxification system.
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PMID:Protective action of cardiac DT-diaphorase against menadione toxicity in guinea pig isolated atria. 1087 36

The effect of hydroalcoholic (80% ethanol, 20% water) extract of leaves of Aegle marmelos was examined on carcinogen-metabolizing phase-I and phase-II enzymes, antioxidant enzymes, glutathione content, lactate dehydrogenase and lipid peroxidation, using two doses of dried extract (50 and 100 mg kg(-1) daily for 14 days), in the liver of mice. The modulatory effect of the extract was also examined on extrahepatic organs (lung, kidney and fore-stomach) for effects on the activity of glutathione S-transferase, DT-diaphorase, superoxide dismutase and catalase. Extract treatment significantly increased the basal levels of acid-soluble sulphydryl (-SH) content, cytochrome P450, NADPH-cytochrome P450 reductase, cytochrome b5, NADH-cytochrome b5 reductase, glutathione S-transferase, DT-diaphorase, superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase in the liver. Aegle acted as a bifunctional inducer since it induced both phase-I and phase-II enzyme systems. Both doses significantly decreased the activity of lactate dehydrogenase and formation of malondialdehyde in liver, suggesting a role in cytoprotection as well as protection against pro-oxidant-induced membrane damage. Butylated hydroxyanisole (positive control) induced almost all the antioxidative parameters measured in this study. The extract was effective in inducing glutathione S-transferase, DT-diaphorase, superoxide dismutase and catalase in lung, glutathione S-transferase, DT-diaphorase and superoxide dismutase in fore-stomach, and DT-diaphorase and superoxide dismutase in lung. These significant changes in the levels of drug-metabolizing enzymes and antioxidative profiles are strongly indicative of the chemopreventive potential of this plant, especially against chemical carcinogenesis.
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PMID:Effect of Aegle marmelos on biotransformation enzyme systems and protection against free-radical-mediated damage in mice. 1100 71

We investigated the role of glutathione (GSH) and antioxidant enzymes in menadione-resistance by using K300 cells (menadione-resistant cells) and parental P19 cells (menadione-sensitive cells). We found that acquisition of resistance was associated with elevations in glutathione content and DT-diaphorase activity. The activity of glutathione S-transferase (GST) was significantly decreased, while the activities of glutathione peroxidase, glutathione reductase, catalase, and superoxide dismutase in K300 cells were maintained at the same levels as compared to the parental P19 cells. Using reactive oxygen species (ROS)-sensitive fluorescence dye 2,7- dichlorodihydrofluorescein diacetate (DCFH/DA), we demonstrated that K300 cells are characterized by reduced cellular ROS as compared to the parental P19 cells during menadione's action. Menadione depleted glutathione to a small extent in the K300 cells, but a rapid depletion was observed in P19 cells. Pretreatment of K300 cells with dicumarol, a DT-diaphorase inhibitor, or buthionine sulfoximine (BSO), an inhibitor of gamma-glutamyl cysteine synthase, sensitized the cells to menadione. BSO treatment was less effective than dicumarol treatment in reversing menadione resistance in K300 cells. These results strongly support the belief that DT-diaphorase plays a central role in protecting cells against menadione-induced oxidative stress by decreasing the ROS formation.
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PMID:The roles of glutathione and antioxidant enzymes in menadione-induced oxidative stress. 1111 72

The effect of two different doses (50 and 100 mg/kg body wt/day for 14 days) of 80% ethanolic extract of the leaves of Adhatoda vesica were examined on drug metabolizing phase I and phase II enzymes, antioxidant enzymes, glutathione content, lactate dehydrogenase and lipid peroxidation in the liver of 8 weeks old Swiss albino mice. The modulatory effect of the extract was also examined on extra-hepatic organs viz. lung, kidney and forestomach for the activities of glutathione S-transferase, DT-diaphorase, superoxide dismutase and catalase. Significant increase in the activities of acid soluble sulfhydryl (-SH) content, cytochrome P450, NADPH-cytochrome P450 reductase, cytochrome b5, NADH-cytochrome b5 reductase, glutathione S-transferase (GST), DT-diaphorase (DTD), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) were observed in the liver at both dose levels of treatments. Adhatoda vesica acted as bifunctional inducer since it induced both phase I and phase II enzyme systems. Both the treated groups showed significant decrease in malondialdehyde (MDA) formation in liver, suggesting its role in protection against prooxidant induced membrane damage. The cytosolic protein was significantly inhibited at both the dose levels of treatment indicating the possibility of its involvement in the inhibition of protein synthesis. BHA has significantly induced the activities of GR and GSH in the present study. The extract was effective in inducing GST and DTD in lung and forestomach, and SOD and CAT in kidney. Thus, besides liver, other organs viz., lung, kidney and forestomach were also stimulated by Adhatoda, to increase the potential of the machinery associated with the detoxification of xenobiotic compounds. But, liver and lung showed a more consistent induction. Since the study of induction of the phase I and phase II enzymes is considered to be a reliable marker for evaluating the chemopreventive efficacy of a particular compound, these findings are suggestive of the possible chemopreventive role played by Adhatoda leaf extract.
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PMID:Modulatory influence of Adhatoda vesica (Justicia adhatoda) leaf extract on the enzymes of xenobiotic metabolism, antioxidant status and lipid peroxidation in mice. 1112 64

The effect of two doses (30 microl and 60 microl/day/mice daily for 14 days) of the fresh leaf pulp extract of Aloe vera was examined on carcinogen-metabolizing phase-I and phase-II enzymes, antioxidant enzymes, glutathione content, lactate dehydrogenase and lipid peroxidation in the liver of mice. The modulatory effect of the pulp extract was also examined on extrahepatic organs (lung, kidney and forestomach) for the activities of glutathione S-transferase, DT-diophorase, superoxide dismutase and catalase. The positive control mice were treated with butylated hydroxyanisole (BHA). Significant increases in the levels of acid soluble sulfhydryl (-SH) content, NADPH-cytochrome P450 reductase, NADH-cytochrome b5 reductase, glutathione S-transferase (GST), DT-diaphorase (DTD), superoxide dismutase (SOD), catalase, glutathione peroxidase (GPX) and glutathione reductase (GR) were observed in the liver. Aloe vera significantly reduced the levels of cytochrome P450 and cytochrome b5. Thus, Aloe vera is clearly an inducer of phase-II enzyme system. Treatment with both doses of Aloe caused a decrease in malondialdehyde (MDA) formation and the activity of lactate dehydrogenase in the liver, suggesting its role in protection against prooxidant-induced membrane and cellular damage. The microsomal and cytosolic protein was significantly enhanced by Aloe vera, indicating the possibility of its involvement in the induction of protein synthesis. BHA, an antioxidant compound, provided the authenticity of our assay protocol and response of animals against modulator. The pulp extract was effective in inducing GST, DTD, SOD and catalase as measured in extrahepatic organs. Thus, besides liver, other organs (lung, kidney and forestomach) were also influenced favorably by Aloe vera in order to detoxify reactive metabolites, including chemical carcinogens and drugs.
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PMID:Chemomodulatory action of Aloe vera on the profiles of enzymes associated with carcinogen metabolism and antioxidant status regulation in mice. 1118 32

The effects of two doses (50 and 100 mg/kg body wt/day for 14 days) of an 80% hydroalcohol extract of Andrographis paniculata and butylated hydroxyanisole (BHA) were examined on drug metabolizing enzymes, antioxidant enzymes, glutathione content, lactate dehydrogenase (LDH) and lipid peroxidation in the liver of Swiss albino mice (6-8 weeks old). The effect of the extract and BHA were also examined on lung, kidney and forestomach for the activities of glutathione S-transferase (GST), DT-diaphorase (DTD), superoxide dismutase (SOD) and catalase. A significant increase in the levels of acid soluble sulphydryl (-SH) content, cytochrome P450, cytochrome P450 reductase, cytochrome b5 reductase, GST, DTD and SOD were observed at both dose levels of extract treatment while catalase, glutathione peroxidase and glutathione reductase (GR) showed significant increases only at the higher dose in the liver. Both Andrographis treated groups showed a significant decrease in activity of LDH and malondialdehyde (MDA) formation. BHA treated mice showed a significant increase in the levels of cytochrome b(5), GST, DTD, -SH content, GR and catalase in liver; while LDH and MDA levels were reduced significantly compared with their control values. In the lung, SOD, catalase and DTD, in the kidney catalase, DTD and GST, and in the forestomach SOD and DTD showed a significant increase at both dose levels of treatment. In BHA treated mice GST, DTD and catalase were significantly induced in the lung and along with these enzymes SOD was also induced in the kidney. In the case of the forestomach of BHA treated mice GST, DTD and SOD were enhanced significantly. These findings indicate the chemopreventive potential of Andrographis paniculata against chemotoxicity including carcinogenicity.
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PMID:Modulatory influence of Andrographis paniculata on mouse hepatic and extrahepatic carcinogen metabolizing enzymes and antioxidant status. 1150 28

The dithiolethione oltipraz is being developed as a chemopreventive agent for many malignancies, including colorectal cancer, on the basis of its in vivo protective activity against chemically induced tumors in a variety of animal models. This protection has been associated with an enhanced capacity to detoxify reactive carcinogens and, more recently, with increased DNA repair. In a previous single-dose study, elevated detoxification gene expression was observed in the days after oltipraz dosing. Now, in this clinical study, we evaluated the effects of oltipraz when given over a 3-month period. Fourteen individuals with increased risk for colorectal cancer were randomly assigned to one of two oral doses (125 or 250 mg/m2) of oltipraz twice weekly for 12 weeks. Two of seven subjects at the 250 mg/m2 dosage required dose reductions, owing to significant fatigue. The 125 mg/m2 dose level was well tolerated by all patients. Blood or colon tissue (or both) for evaluation of glutathione, glutathione S-transferase, DT-diaphorase activity, and DT-diaphorase mRNA expression were obtained prior to treatment and at weeks 6, 12, and 16. No significant modulation of phase II detoxification enzymes was seen at either dose studied during this period. Phase II trials evaluating a tolerable regimen of oltipraz (as demonstrated in this study) and other possible mechanisms that may be responsible for the protective activity of oltipraz should be pursued.
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PMID:Chronic dosing of oltipraz in people at increased risk for colorectal cancer. 1153 Oct 12

Two population-based, case-control studies have documented reduced risk of prostate cancer in men who consume cruciferous vegetables. Cruciferae contain high levels of the isothiocyanate sulforaphane. Sulforaphane is known to bolster the defenses of cells against carcinogens through up-regulation of enzymes of carcinogen defense (phase 2 enzymes). Prostate cancer is characterized by an early and near universal loss of expression of the phase 2 enzyme glutathione S-transferase (GST)-pi. We tested whether sulforaphane may act in prostatic cells by increasing phase 2 enzyme expression. The human prostate cancer cell lines LNCaP, MDA PCa 2a, MDA PCa 2b, PC-3, and TSU-Pr1 were treated with 0.1-15 microM sulforaphane in vitro. LNCaP was also treated with an aqueous extract of broccoli sprouts. Quinone reductase enzymatic activity, a surrogate of global phase 2 enzyme activity, was assayed by the menadione-coupled reduction of tetrazolium dye. Expression of NQO-1, GST-alpha, gamma-glutamylcysteine synthetase-heavy and -light chains, and microsomal GST was assessed by Northern blot analysis. Sulforaphane and broccoli sprout extract potently induce quinone reductase activity in cultured prostate cells, and this induction appears to be mediated by increased transcription of the NQO-1 gene. Sulforaphane also induces expression of gamma-glutamylcysteine synthetase light subunit but not the heavy subunit, and this induction is associated with moderate increases in intracellular glutathione levels. Microsomal and alpha-class glutathione transferases were also induced transcriptionally. Sulforaphane induces phase 2 enzyme expression and activity significantly in human prostatic cells. This induction is accompanied by, but not because of, increased intracellular glutathione synthesis. Our findings may help explain the observed inverse correlation between consumption of cruciferae and prostate cancer risk.
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PMID:Potent induction of phase 2 enzymes in human prostate cells by sulforaphane. 1153 46

The effect of beta-naphthoflavone (beta-NF) on several catalytic activities of cytochrome P450 (CYP) and phase II enzymes putatively controlled by [Ah]-receptor activation in the liver, heart and kidney of gilthead seabream, was investigated. In the liver, beta-NF treatment [intraperitoneal injection (i.p.) 50 mg/kg] resulted in an increase of CYP content, immunoreactive CYP 1A and methoxyresorufin-O-demethylase (MEROD), pentoxyresorufin O-depentylase (PROD) and ethoxyresorufin-O-deethylase (EROD) activities. However, beta-NF had no effect on any of the hepatic phase II enzymes examined (benzaldehyde dehydrogenase, propionaldehyde dehydrogenase, glutathione S-transferase, UDP-glucuronyl-transferase, DT-diaphorase). Single i.p. injection of 10 mg/kg beta-NF showed a maximal induction of CYP 1A-like protein and EROD activity after 3-7 days. CYP 1A and EROD returned to control levels 18-days post-treatment. beta-NF injection also caused a rapid increase of a single band size of mRNA recognized by a CYP 1A1 cDNA fragment from sea bass (Dicentrarchus labrax). Expression of mRNA preceded the increase of EROD activity and declined rapidly by 96 h. Dose-response experiments demonstrated that EROD was significantly enhanced in liver by a single injection of 0.3 mg/kg beta-NF and was the most sensitive measurement for CYP 1A-like induction. beta-NF treatments also increased the expression of CYP 1A-like protein, mRNA and EROD, but not MEROD and PROD activities in heart and kidney.
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PMID:Effects of beta-naphthoflavone on the cytochrome P450 system, and phase II enzymes in gilthead seabream (Sparus aurata). 1154 49

Because of the evidence for the involvement of xenobiotic bioactivation in pulmonary toxicity and carcinogenesis, it is important to improve our understanding of the xenobiotic-metabolizing enzymes in isolated and cultured specific pulmonary cell populations. Some phase I and phase II xenobiotic-metabolizing enzyme activities, reduced glutathione (GSH), and gamma-glutamyl transferase (gamma-GT) were studied in rat type II pneumocytes and alveolar macrophages cultured for up to 48 h and 3 h, respectively. In type II pneumocytes, 7-ethoxyresorufin activity was not detected. 7-Benzyloxyresorufin (BROD) and 7-pentoxyresorufin (PROD) O-dealkylation decreased at 24 h by 84 and 82%, respectively, and continued to decline over the next 24 h with no measurable PROD at 48 h. The activity of NADPH- and NADH-cytochrome c reductase at 48 h decreased by 31 and 67%, respectively. GST activity decreased by 25 and 42% at 24 and 48 h, respectively. A transient increase in DT-diaphorase activity was observed at 24 h (by 55%). GSH content and gamma-GT activity increased significantly with time in culture. In freshly isolated alveolar macrophages, BROD activity was the only cytochrome P450-dependent alkoxyresorufin-O-dealkylase activity measured. BROD activity decreased by 38% in 3-h-attached macrophages. There were no changes in NADPH- and NADH-cytochrome c reductase, GST, and DT-diaphorase. An increase of GSH (by 24%) was observed in attached macrophages. In conclusion, type II pneumocytes and to a lesser extent alveolar macrophages in primary cultures undergo changes in biotransformation-related enzyme activities and intracellular GSH level that may affect xenobiotic toxicity at different times in culture.
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PMID:Xenobiotic-metabolizing enzyme activities in primary cultures of rat type II pneumocytes and alveolar macrophages. 1156 Aug 80


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