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)

The liver is the main organ of drug metabolism, but the expression and induction by xenobiotics of drug-metabolizing enzymes is also often observed in extrahepatic tissues. Recently, we reported that lipophilic cytochrome P450 inducers, beta-naphthoflavone (BNF), phenobarbital, and dexamethasone, induced CYP1, CYP2B, and CYP3A enzymes, respectively, in rat epididymal white adipose tissue (WAT) at both mRNA and protein levels. To further confirm the xenobiotic-induced expression of drug-metabolizing enzymes in adipose tissue, we studied the induction of CYP1A1 and other detoxifying enzymes by aryl hydrocarbon receptor (AhR) agonists and antioxidants. BNF increased CYP1A1 mRNA levels in several visceral WATs (epididymal, perirenal, and mesenteric) to a greater degree than in subcutaneous WAT in rats. Using C57BL/6 and DBA/2 mice with different responsiveness to aryl hydrocarbons and detecting cytoplasmic levels of AhR proteins, we have demonstrated that AhR mediates this CYP1A1 induction by BNF in WAT. Moreover, the NF-E2-related factor 2 (Nrf2)/antioxidant responsive element pathway is also functional in WAT, since BNF, which is known to activate both AhR and Nrf2, and antioxidants including tert-butylhydroquinone, 1-chloro-2,4-dinitrobenzene, and menadione induced the expression of Nrf2-target genes (NAD-(P)H:quinone oxidoreductase, glutathione S-transferase A subunits, and heme oxygenase-1) in rats and mice. These results suggest that both AhR and Nrf2 pathways are active in WAT and that lipophilic compounds accumulated in WAT can activate these transcription factors to increase detoxification capability in the tissue.
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PMID:Induction of detoxifying enzymes in rodent white adipose tissue by aryl hydrocarbon receptor agonists and antioxidants. 1658 46

The activities of glutathione reductase (EC 1.6.4.2), glutathione peroxidase (EC 1.11.1.9), and glutathione S-transferase (EC 2.5.1.18) were found to increase during slow drying or during rehydration following rapid drying of the drought-tolerant moss Tortula ruralis. Little change was observed in the activity of malate deydrogenase (NAD(+) oxidoreductase, EC 1.1.1.37) during dehydration or subsequent rehydration. When the tissue was treated with cycloheximide, actinomycin D, or cordycepin, the increase in the activities of glutathione reductase and glutathione S-transferase was largely prevented while effect on glutathione peroxidase was much smaller. Concomitantly, oxidized glutathione (GSSG) as percentage of total glutathione increased. GSSG level was correlated positively with the levels of lipid peroxidation and solute leakage and negatively with the rate of protein synthesis. The results show that GSSG level is a good indicator of oxidation stress and provide support to the suggestion that GSSG mediates, at least in part, the drought stress-induced inhibition of protein synthesis.
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PMID:Drought Stress, Enzymes of Glutathione Metabolism, Oxidation Injury, and Protein Synthesis in Tortula ruralis. 1666 32

Airborne particulate pollutants, such as diesel exhaust particles, are thought to exacerbate lung and cardiovascular diseases through induction of oxidative stress. Sulforaphane, derived from cruciferous vegetables, is the most potent known inducer of phase II enzymes involved in the detoxification of xenobiotics. We postulated that sulforaphane may be able to ameliorate the adverse effects of pollutants by upregulating expression of endogenous antioxidant enzymes. Stimulation of bronchial epithelial cells with the chemical constituents of diesel particles result in the production of proinflammatory cytokines. We first demonstrated a role for phase II enzymes in regulating diesel effects by transfecting the airway epithelial cell line (BEAS-2B) with the sentinel phase II enzyme NAD(P)H: quinine oxidoreductase 1 (NQO1). IL-8 production in response to diesel extract was significantly reduced in these compared with untransfected cells. We then examined whether sulforaphane would stimulate phase II induction and whether this would thereby ablate the effect of diesel extracts on cytokine production. We verified that sulforaphane significantly augmented expression of the phase II enzyme genes GSTM1 and NQO1 and confirmed that sulforaphane treatment increased glutathione S-transferase activity in epithelial cells without inducing cell death or apoptosis. Sulforaphane pretreatment inhibited IL-8 production by BEAS-2B cells upon stimulation with diesel extract. Similarly, whereas diesel extract stimulated production of IL-8, granulocyte-macrophage colony-stimulating factor, and IL-1beta from primary human bronchial epithelial cells, sulforaphane pretreatment inhibited diesel-induced production of all of these cytokines. Our studies show that sulforaphane can mitigate the effect of diesel in respiratory epithelial cells and demonstrate the chemopreventative potential of phase II enzyme enhancement.
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PMID:Sulforaphane-stimulated phase II enzyme induction inhibits cytokine production by airway epithelial cells stimulated with diesel extract. 1690 40

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental carcinogens and metabolized by a variety of xenobiotic-metabolizing enzymes such as cytochrome P450 (P450 or CYP), epoxide hydrolase, glutathione transferase, UDP-glucuronosyltransferase, sulfotransferase, NAD(P)H quinone oxidoreductase 1, and aldo-keto reductase. These enzymes mainly participate in the conversion of PAHs to more polar and water-soluble metabolites, and the resultant metabolites are readily excreted from the body. However, during the course of metabolism, a variety of unstable and reactive intermediates of PAHs are formed, and these metabolites attack DNA, causing cell toxicity and transformation. P450s and epoxide hydrolase convert PAHs to proximate carcinogenic metabolites, PAH-diols, and these products are further metabolized by P450s to ultimate carcinogenic metabolites, PAH diol-epoxides, or by aldo-keto reductase to reactive PAH o-quinones. PAHs are also activated by P450 and peroxidases to reactive radical cations that bind covalently to DNA. The oxygenated and reactive metabolites of PAHs are usually converted to more polar and detoxified products by phase II enzymes. Inter-individual differences exist in levels of expression and catalytic activities of a variety of enzymes that activate and/or detoxify PAHs in various organs of humans and these phenomena are thought to be critical in understanding the basis of individual differences in response to PAHs. Factors affecting such variations include induction and inhibition of enzymes by diverse chemicals and, more importantly, genetic polymorphisms of enzymes in humans.
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PMID:Xenobiotic-metabolizing enzymes involved in activation and detoxification of carcinogenic polycyclic aromatic hydrocarbons. 1694 53

The levels of the enzymes, glutathione S-transferase, catalase, NAD(P)H-cytochrome c reductases, and DT-diaphorase were determined and compared in the tissues of three invertebrates commonly used in monitoring environmental quality: a freshwater mussel, Dreissena polymorpha, the earthworm Allolobophora chlorotica and the fourth instar of Chironomus riparius. It was found that the activities of GST, catalase, and NAD(P)-cytochrome c reductases were comparable in A. chlorotica and C. riparius, whereas comparatively a higher GST and a lower catalase activity was determined in the mussel tissues. DT-diaphorase was not detectable in A. chlorotica and the C. riparius larvae tissues, whereas this enzyme is present in the gills and the rest of soft mussel tissues (soft mussel tissues minus gills). It is suggested that the relatively low catalase activity observed in the tissues of the latter organism might be compensated by the presence of the antixidant role of DT-diaphorase. In addition, the inducibility of DT-diaphorase in D. polymorpha, by butylated hydroxyanisole (BHA) and lead (Pb) was investigated. Despite the bioaccumulation of both BHA (5.2+/-0.14 microgg(-1) wet weight) and Pb (233.7+/-0.95 mgkg(-1) dry weight) in the soft mussel tissues, the mussel DT-diaphorase was not induced. Although the activity of NADPH-cytochrome c (P-450) reductase was also not affected by these reagents, its activity was 2-fold higher in the gills than the rest of soft mussel tissues.
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PMID:Comparison of key enzymes in the zebra mussel, Dreissena polymorpha, the earthworm Allolobophora chlorotica and Chironomus riparius larvae. 1705 54

Inflammatory bowel diseases, chronic inflammatory disorders, have been strongly linked with an increased risk of the development of colorectal cancer. Understanding the etiology of these diseases is pivotal for the improvement of currently available strategies to fight against inflammatory bowel disease, and more importantly, to prevent colorectal cancer. Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been known to be a transcriptional factor which plays a crucial role in cytoprotection against inflammation, as well as oxidative and electrophilic stresses. The aim of this study is to investigate the role of Nrf2 in the regulation of dextran sulfate sodium (DSS)-induced experimental colitis in mice. Nrf2-deficient mice were found to be more susceptible to DSS-induced colitis as shown by the increased severity of colitis following 1 week of oral administration of 1% DSS. The increased severity of colitis in Nrf2(-/-) mice was found to be associated with decreased expression of antioxidant/phase II detoxifying enzymes including heme-oxygenase-1, NAD(P)H-quinone reductase-1, UDP-glucurosyltransferase 1A1, and glutathione S-transferase Mu-1. In addition, proinflammatory mediators/cytokines such as COX-2, inducible nitric oxide, interleukin 1beta, interleukin 6, and tumor necrosis factor alpha were significantly increased in the colonic tissues of Nrf2(-/-) mice compared with their wild-type (Nrf2+/+) counterparts. In summary, we show for the first time that mice lacking Nrf2 are more susceptible to DSS-induced colitis. Our data suggests that Nrf2 could play an important role in protecting intestinal integrity, through regulation of proinflammatory cytokines and induction of phase II detoxifying enzymes.
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PMID:Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. 1717 49

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

Stress plays a potential role in the onset and exacerbation of depression. Chronic restraint stress in rats, and psychosocial stress in humans, is implicated in the pathophysiology of mood and anxiety disorders. Oxidative damage is an established outcome of restraint stress, which has been suggested to induce many damaging processes contributing to the pathology of stress-induced depression. However, the modulatory role of clinically effective antidepressants, such as fluoxetine, in attenuating oxidative stress has not been well characterized. Therefore, the current study was designed to investigate the antioxidant effects of chronic treatment with fluoxetine in animals submitted to restraint stress. The antioxidant potential of the antidepressant fluoxetine was compared with that of turmeric, used as a standard since it integrates both antioxidant and antidepressant properties. Chronic fluoxetine administration to stressed animals for 21 days prevented restraint stress-induced oxidative damage with an efficacy similar to that of turmeric, as evidenced by significant enhancement of key endogenous antioxidant defense components, comprising the free-radical scavenging enzymes, superoxide:superoxide oxidoreductase (EC 1.15.1.1), hydrogen-peroxide:hydrogen-peroxide oxidoreductase (EC 1.11.1.6), glutathione S-transferase (EC 2.5.1.18) and glutathione:NADP(+)oxidoreductase (EC 1.8.1.7), as well as non-enzymatic antioxidants, GSH, glucose and uric acid, which were severely depleted by restraint stress in animals receiving no treatment. Oxidative stress markers, (S)-lactate:NAD(+) oxidoreductase activity (EC 1.1.1.27), malondialdehyde levels (lipid peroxidation product) and protein carbonyl content were also significantly decreased following fluoxetine treatment. Both these drugs when given alone to non-stressed animals did not alter basal levels of antioxidant defense components and oxidative stress markers significantly. Our findings suggest that the therapeutic efficacy of fluoxetine may be mediated, at least partially, via reversal of oxidative damage as demonstrated by protective enhancement of antioxidant status following a stress-induced decline. In addition, this study demonstrates important implications for pharmacological interventions targeting cellular antioxidants as a promising strategy for protecting against oxidative insults in stress-induced depression.
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PMID:Antioxidant potential of fluoxetine in comparison to Curcuma longa in restraint-stressed rats. 1761 Aug 75

Anthocyanins, belonging to the flavonoid family of phytochemicals, have received attention as agents that may have potential in preventing chronic diseases such as cardiovascular diseases and certain cancers. In the present study, an anthocyanin-rich extract from Concord grapes [referred to as Concord grape extract (CGE)] and the anthocyanin delphinidin were evaluated for their capacity to inhibit DNA adduct formation due to the environmental carcinogen benzo[a]pyrene (BP) in MCF-10F cells, a noncancerous, immortalized human breast epithelial cell line. CGE at 10 and 20 microg/mL and delphinidin at 0.6 microM concentrations significantly inhibited BP-DNA adduct formation. This was associated with a significant increase in activities of the phase II detoxification enzymes glutathione S-transferase and NAD(P)H:quinone reductase 1. In addition, these grape components also suppressed reactive oxygen species (ROS) formation, but did not induce antioxidant response element-dependent transcription. Taken together, these data suggest that CGE and a component grape anthocyanin have breast cancer chemopreventive potential due in part to their capacity to block carcinogen-DNA adduct formation, modulate activities of carcinogen-metabolizing enzymes, and suppress ROS in these noncancerous human breast cells.
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PMID:Anthocyanin-rich grape extract blocks breast cell DNA damage. 1765 Oct 59

The challenge of consuming plant compounds that are recognized to have toxic physiological effects is an unavoidable consequence of an herbivorous diet and requires mechanisms to metabolize and eliminate them after consumption. We took a pharmacological approach to understanding how an oak (Quercus agrifolia) specialist (Neotoma macrotis) and generalist (N. lepida) herbivores process the same dietary toxins. Oak contains polyphenolic compounds considered toxic to most other mammals. N. macrotis includes up to 85% of oak in their diet. N. lepida includes oak as a portion of the diet but is considered a generalist in areas where sympatric with N. macrotis. Xenobiotic metabolizing enzyme activities of N. macrotis and N. lepida were investigated after animals were fed a 70% oak diet and a toxin-free control diet. Biotransformation activities of five major enzymes [cytochrome P450s (CYP), NAD(P)H/quinone oxidoreductase (QOR), UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), and glutathione S-transferase (GST)] and three specific CYP isozymes (CYP1A, CYP2B, and CYP3A) were investigated. The results indicate that, with the exception of CYP2B induction, N. macrotis and N. lepida enzyme activities are not changed by an oak diet. The major differences in enzyme activities were constitutive. The specialist, N. macrotis, had higher constitutive activity of QOR, UGT, and GST. The generalist, N. lepida, had higher constitutive activity levels of CYP1A and SULT.
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PMID:Xenobiotic metabolism of plant secondary compounds in oak (Quercus agrifolia) by specialist and generalist woodrat herbivores, genus Neotoma. 1792 91


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