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)

The reduced glutathione (GSH)/oxidized glutathione (GSSG) redox state is thought to function in signaling of detoxification gene expression, but also appears to be tightly regulated in cells under normal conditions. Thus it is not clear that the magnitude of change in response to physiologic stimuli is sufficient for a role in redox signaling under nontoxicologic conditions. The purpose of this study was to determine the change in 2GSH/GSSG redox during signaling of differentiation and increased detoxification enzyme activity in HT29 cells. We measured GSH, GSSG, cell volume, and cell pH, and we used the Nernst equation to determine the changes in redox potential Eh of the 2GSH/GSSG pool in response to the differentiating agent, sodium butyrate, and the detoxification enzyme inducer, benzyl isothiocyanate. Sodium butyrate caused a 60-mV oxidation (from -260 to -200 mV), an oxidation sufficient for a 100-fold change in protein dithiols:disulfide ratio. Benzyl isothiocyanate caused a 16-mV oxidation in control cells but a 40-mV oxidation (to -160 mV) in differentiated cells. Changes in GSH and mRNA for glutamate:cysteine ligase did not correlate with Eh; however, correlations were seen between Eh and glutathione S-transferase (GST) and nicotinamide adenine dinucleotide phosphate (NADPH):quinone reductase activities (N:QR). These results show that 2GSH/GSSG redox changes in response to physiologic stimuli such as differentiation and enzyme inducers are of a sufficient magnitude to control the activity of redox-sensitive proteins. This suggests that physiologic modulation of the 2GSH/GSSG redox poise could provide a fundamental parameter for the control of cell phenotype.
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PMID:Glutathione redox potential in response to differentiation and enzyme inducers. 1064 13

Phase II drug-metabolizing enzymes, such as glutathione S-transferase and quinone reductase, play an important role in the detoxification of chemical carcinogens. The induction of these detoxifying enzymes by a variety of agents occurs at the transcriptional level and is regulated by a cis-acting element, called the antioxidant response element (ARE) or electrophile-response element. In this study, we identified a signaling kinase pathway that negatively regulates ARE-mediated gene expression. Treatment of human hepatoma HepG2 and murine hepatoma Hepa1c1c7 cells with tert-butylhydroquinone (tBHQ) stimulated the activity of p38, a member of mitogen-activated protein kinase family. Inhibition of p38 activation by its inhibitor, SB203580, enhanced the induction of quinone reductase activity and the activation of ARE reporter gene by tBHQ. In contrast, SB202474, a negative analog of SB203580, had little effect. Consistent with this result, interfering with the p38 kinase pathway by overexpression of a dominant-negative mutant of p38 or MKK3, an immediate upstream regulator of p38, potentiated the activation of the ARE reporter gene by tBHQ, whereas the wild types of p38 and MKK3 diminished such activation. In addition, inhibition of p38 activity augmented the induction of ARE reporter gene activity by tert-butylhydroxyanisole, sulforaphane, and beta-naphthoflavone. Thus, p38 kinase pathway functions as a negative regulator in the ARE-mediated induction of phase II detoxifying enzymes.
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PMID:p38 mitogen-activated protein kinase negatively regulates the induction of phase II drug-metabolizing enzymes that detoxify carcinogens. 1064 81

The modifying effects of dietary feeding of bovine lactoferrin (bLF) on tongue carcinogenesis initiated with 4-nitroquinoline 1-oxide (4-NQO) were investigated in male F344 rats. The activities of phase II detoxifying enzymes, glutathione S-transferase (GST) and quinone reductase (QR), polyamine content and ornithine decarboxylase (ODC) activity in the tongue were also examined for mechanistic analysis of possible modifying effects of bLF on carcinogenesis. At 7 weeks of age, all animals except those treated with bLF alone and untreated rats were given 20 ppm 4-NQO in drinking water for 8 weeks to induce tongue neoplasms. Starting 7 days before 4-NQO exposure, experimental groups were fed experimental diets containing bLF (0.2% and 2%) for 10 weeks ("initiation feeding"). Starting 1 week after the cessation of exposure to 4-NQO, the other experimental groups given 4-NQO and a basal diet were fed the experimental diets for 22 weeks ("postinitiation feeding"). At week 32, the incidence and multiplicity of tongue neoplasms in the "initiation feeding" groups of 0.2% and 2% bLF and the "post-initiation feeding" group of 0.2% bLF were lower than those of the 4-NQO alone group, but without statistical significance. However, "post-initiation feeding" of 2% bLF caused a significant reduction in the incidence (20% vs. 55%, P=0.02418) and multiplicity (0.25+/-0.54 vs. 0.70+/-0.71, P<0.05) of tongue squamous cell carcinoma (by 64%, P=0.02418). bLF treatment elevated liver and tongue GST activities and liver QR activity. The "post-initiation feeding" with 2% bLF significantly decreased QR activity, proliferating cell nulcear antigen-positive index and ODC activity in the tongue. In addition, feeding with bLF decreased tongue polyamine content. These results suggest that bLF, when given at the 2% dose level during the post-initiation phase, exerts chemopreventive action against tongue tumorigenesis through modification of cell proliferation activity and/or the activities of detoxifying enzymes.
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PMID:Chemopreventive effect of bovine lactoferrin on 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male F344 rats. 1074 41

The modifying effects of dietary feeding of a polyisoprenylated benzophenone, garcinol, isolated from Garcinia indica fruit rind on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats. We also assessed the effects of garcinol on proliferating cell nuclear antigen (PCNA) index in ACF and activities of detoxifying enzymes of glutathione S-transferase (GST) and quinone reductase (QR) in liver. In addition, we examined the effects of garcinol on 12-O-tetradecanoylphorbol-13-acetate-induced O(2)(-) generation in differentiated human promyelocytic HL-60 cells and lipopolysaccharide (LPS)- and interferon (IFN)-gamma-induced nitric oxide (NO) generation in mouse macrophage RAW 264.7 cells. Western blotting analysis of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression was done in LPS- and IFN-gamma-treated mouse macrophage RAW 264.7 cells. Rats were given subcutaneous injections of AOM (15 mg/kg body wt) once a week for 3 weeks to induce ACF. They also received the experimental diet containing 0.01 or 0.05% garcinol for 5 weeks, starting 1 week before the first dosing of AOM. AOM exposure produced 97 +/- 15 ACF/rat at the end of the study (week 5). Dietary administration of garcinol caused significant reduction in the frequency of ACF: 72 +/- 15 (26% reduction, P < 0.01) at a dose of 0.01% and 58 +/- 8 (40% reduction, P < 0.001) at a dose of 0.05%. Garcinol administration significantly lowered PCNA index in ACF. Feeding of garcinol significantly elevated liver GST and QR activities. In addition, garcinol could suppress O(2)(-) and NO generation and expression of iNOS and COX-2 proteins. These findings might suggest possible chemopreventive ability of garcinol, through induction of liver GST and QR, inhibition of O(2)(-) and NO generation and/or suppression of iNOS and COX-2 expression, on colon tumorigenesis.
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PMID:Prevention of colonic aberrant crypt foci by dietary feeding of garcinol in male F344 rats. 1083 8

This study was designed to (1) evaluate retinal lipid peroxidation in early diabetes by the method specific for free malondialdehyde and 4-hydroxyalkenals, (2) identify impaired antioxidative defense mechanisms and (3) assess if enhanced retinal oxidative stress in diabetes is prevented by the potent antioxidant, DL-alpha-lipoic acid. The groups included control and streptozotocin-diabetic rats treated with or without DL-alpha-lipoic acid (100 mg kg(-1) day(-1), i.p., for 6 weeks). All parameters were measured in individual retinae. 4-Hydroxyalkenal concentration was increased in diabetic rats (2.63+/-0.60 vs. 1.44+/-0.30 nmol/mg soluble protein in controls, P<0.01), and this increase was prevented by DL-alpha-lipoic acid (1.20+/-0.88, P<0.01 vs. untreated diabetic group). Malondialdehyde, reduced glutathione (GSH) and oxidized glutathione (GSSG) concentrations were similar among the groups. Superoxide dismutase, glutathione peroxidase (GSHPx), glutathione reductase (GSSGRed) and glutathione transferase (GSHTrans) activities were decreased in diabetic rats vs. controls. Quinone reductase was upregulated in diabetic rats, whereas catalase and cytoplasmic NADH oxidase activities were unchanged. DL-alpha-Lipoic acid prevented changes in superoxide dismutase and quinone reductase activities induced by diabetes without affecting the enzymes of glutathione metabolism. In conclusion, accumulation of 4-hydroxyalkenals is an early marker of oxidative stress in the diabetic retina. Increased lipid peroxidation occurs in the absence of GSH depletion, and is prevented by DL-alpha-lipoic acid.
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PMID:Early changes in lipid peroxidation and antioxidative defense in diabetic rat retina: effect of DL-alpha-lipoic acid. 1085 58

In recent years, considerable efforts have been made to identify new chemopreventive agents which could be useful for man. Myrica nagi, a subtropical shrub, has been shown to possess significant activity against hepatotoxicity and other pharmacological and physiological disorders. We have shown a chemopreventive effect of Myrica nagi on cumene hydroperoxide-induced cutaneous oxidative stress and toxicity in mice. Cumene hydroperoxide treatment at a dose level of 30 mg/animal/0.2 ml acetone enhances susceptibility of cutaneous microsomal membrane for iron-ascorbate-induced lipid peroxidation and induction of xanthine oxidase activity which are accompanied by decrease in the activities of cutaneous antioxidant enzymes such as catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and depletion in the level of cutaneous glutathione. Parallel to these changes a sharp decrease in the activities of phase II metabolizing enzymes such as glutathione S-transferase and quinone reductase has been observed. Application of Myrica nagi at doses of 2.0 mg and 4.0 mg/kg body weight in acetone prior to that of cumene hydroperoxide (30 mg/animal/0.2 ml acetone) treatment resulted in significant inhibition of cumene hydroperoxide-induced cutaneous oxidative stress and toxicity in a dose-dependent manner. Enhanced susceptibility of cutaneous microsomal membrane for lipid peroxidation induced by iron ascorbate and xanthine oxidase activities were significantly reduced (P<0.05). In addition the depleted level of glutathione, the inhibited activities of antioxidants, and phase II metabolizing enzymes were recovered to a significant level (P<0.05). The protective effect of Myrica nagi was dose-dependent. In summary our data suggest that Myrica nagi is an effective chemopreventive agent in skin and capable of ameliorating cumene hydroperoxide-induced cutaneous oxidative stress and toxicity.
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PMID:Myrica nagi attenuates cumene hydroperoxide-induced cutaneous oxidative stress and toxicity in Swiss albino mice. 1086 2

The modifying effects of dietary administration of ferulic acid (FA) on azoxymethane (AOM)-induced colon carcinogenesis were examined in three experiments with male 344 rats. In the first experiment, the modifying effect of FA on AOM (15 mg/kg body weight, once a week, for 3 weeks)-induced formation of aberrant crypt foci (ACF) was examined in five groups. Numbers of ACF/colon of groups 2 (AOM+250 ppm FA) and 3 (AOM+500 ppm FA) at the termination (5 weeks after the start) were smaller than of group 1 (AOM alone). Those of ACF/cm(2) of group 3 were also smaller than of group 1 (P<0.05). In the second experiment, a long-term assay for the effects of FA was conducted with seven groups. At the termination (35 weeks), groups 2 and 3 which were given FA during the initiation phase at doses of 250 and 500 ppm, respectively, had lower incidences of colonic carcinomas (23 and 27%, respectively) than group 1 which was given AOM alone (59%; P<0.05). In the third experiment, to determine whether FA could modify the activities of phase II detoxifying enzymes, glutathione S-transferase (GST) and quinone reductase (QR) in liver and colon, 60 rats were gavaged with FA at four doses (0, 25, 50, 100 mg/kg body weight). Dosing of 100 mg/kg significantly elevated GST activity in liver (P<0.03), and QR activities in liver and colonic mucosa (P<0.01 and P<0.02, respectively), suggesting that detoxifying enzymes are related to the blocking effect of FA on AOM-induced colon carcinogenesis.
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PMID:Modifying effects of ferulic acid on azoxymethane-induced colon carcinogenesis in F344 rats. 1089 37

The ability of the naturally-occurring naphthoquinone derivatives, juglone and plumbagin, to increase tissue activities of the Phase II detoxification enzymes quinone reductase (QR) and glutathione transferase (GT) has been investigated in rats. Groups of female Sprague-Dawley rats were dosed by oral intubation on 5 consecutive days with either juglone or plumbagin at 12.5, 25, 50, 75, 100 or 125 mumoles/kg/day. The animals were then killed and the activities of QR and GT determined in tissue homogenates. The naphthoquinone derivatives had no significant effect on enzyme activities in the liver, spleen, heart, lung or urinary bladder. Increases in the activities of one or both enzymes were recorded, however, in the caecum, kidney, forestomach, duodenum, colon, glandular stomach and jejunum. The possibility that induction of Phase II enzymes could contribute to the previously-reported ability of juglone and plumbagin to protect animals against chemically-induced intestinal neoplasia is discussed.
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PMID:Induction of quinone reductase and glutathione transferase in rat tissues by juglone and plumbagin. 1090 56

The global increase in transcription of cytoprotective genes induced in response to oxidative challenge has been termed the antioxidant response. Ferritin serves as the major iron-binding protein in nonhematopoietic tissues, limiting the catalytic availability of iron for participation in oxygen radical generation. Here we demonstrate that ferritin is a participant in the antioxidant response through a genetically defined electrophile response element (EpRE). The EpRE of ferritin H identified in this report exhibits sequence similarity to EpRE motifs found in antioxidant response genes such as those encoding NAD(P)H:quinone reductase, glutathione S-transferase, and heme oxygenase. However, the EpRE of ferritin H is unusual in structure, comprising two bidirectional motifs arranged in opposing directions on complementary DNA strands. In addition to EpRE-mediated transcriptional activation, we demonstrate that ferritin is subject to time-dependent translational control through regulation of iron-regulatory proteins (IRP). Although IRP-1 is initially activated to its RNA binding (ferritin-repressing) state by oxidants, it rapidly returns to its basal state. This permits the translation of newly synthesized ferritin transcripts and ultimately leads to increased levels of ferritin protein synthesis following oxidant exposure. Taken together, these results clarify the complex transcriptional and translational regulatory mechanisms that contribute to ferritin regulation in response to prooxidant stress and establish a role for ferritin in the antioxidant response.
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PMID:Coordinate transcriptional and translational regulation of ferritin in response to oxidative stress. 1091 65

Obacunone and limonin are bitter limonoids in citrus. Their modifying effects on the development of aberrant crypt foci (ACF), the activity of detoxification enzymes, glutathione S-transferase (GST) and quinone reductase (QR), and cell proliferation activity were investigated in male F344 rats treated with azoxymethane (AOM). Obacunone and limonin were administered in the diet, during the initiation (for 4 weeks) or postinitiation phase (for 4 weeks) of AOM-induced tumorigenesis. Feeding of obacunone and limonin (0.02% or 0.05%) caused significant reduction (55-65% by "initiation" feeding and 28-42% by "postinitiation" feeding) in the yield of ACF. The ability to reduce the proliferating cell nuclear antigen-labeling index in crypts and correlated well with the prevention of ACF. In a subsequent long-term experiment (38 weeks), in which rats were initiated with AOM and fed 0.05% obacunone or 0.05% limonin during the initiation or post-initiation phase, both compounds in diet caused significant reduction (65%-92% inhibition) in the incidence of colonic adenocarcinoma. Thus, citrus bitter limonoids obacunone and limonin possess chemopreventive effects on chemically induced rat colon carcinogenesis.
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PMID:Citrus limonoids obacunone and limonin inhibit azoxymethane-induced colon carcinogenesis in rats. 1123 84


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