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)

Numerous mechanisms have been proposed to explain the anti-carcinogenic effects of Se, among them altered carcinogen metabolism. We investigated the effect of Se supplementation on activities of glutathione peroxidase (GPX), glutathione reductase (GR) and glutathione S-transferase (GST) in different blood compartments, and expression of selected phase 1 and phase 2 genes in leucocytes (GPX1, gamma-glutamylcysteine ligase catalytic subunit (GCLC), AP-1 transcription factor Fos-related antigen 1 (Fra1), NAD(P)H:quinone oxidoreductase (NQO1), and aryl hydrocarbon receptor repressor (AhRR)). Healthy elderly Danes (n 105; age 71.3 (SD 4.26) years; 36% reporting use of multivitamin/mineral supplements) participated and were supplemented daily for 5 years with placebo, 100 microg, 200 microg or 300 microg Se as Se-enriched yeast (SelenoPrecise). Blood samples were collected after 5 years of intervention. When all four groups were compared we found no effect of Se supplementation on plasma GPX or GR, on erythrocyte GPX, GR or GST, or on thrombocyte GR or GST. We found increased thrombocyte GPX activity at the two highest dosage levels in women only, but not in men. No effects on GPX1, NQO1 or AhRR gene expression were found. When all Se-supplemented groups were pooled we found significant down regulation of the expression of some phase 2 genes (GCLC, Fra1). A significant increase in AhRR gene expression with smoking was found but was independent of Se supplementation. Down regulation of phase 2 genes could increase the risk of cancer. However, further studies are needed to establish whether the observed effect in leucocytes reflects a similar expression pattern in target tissues.
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PMID:Effect of long-term selenium yeast intervention on activity and gene expression of antioxidant and xenobiotic metabolising enzymes in healthy elderly volunteers from the Danish Prevention of Cancer by Intervention by Selenium (PRECISE) pilot study. 1806 29

We reported earlier that exposure of rats to 3-methylcholanthrene (MC) causes sustained induction of hepatic cytochrome P450 (CYP)1A expression for up to 45 days by mechanisms other than persistence of the parent MC (Moorthy, J. 2000. Pharmacology. Exp. Ther. 294, 313-322). The CYP1A genes are members of the Ah gene battery that also encode CYP1B1 and phase II enzymes such as glutathione S-transferase (GST-alpha), UDP glucuronyl transferase (UGT)1A, NAD(P)H (nicotinamide adenine dinucleotide phosphate, reduced):quinone oxidoreductase I (NQO1), aldehyde dehydrogenase (ALDH), etc. Therefore, in this investigation, we tested the hypothesis that MC elicits persistent induction of CYP1B1 and phase II genes, which are in part regulated by the Ah receptor (AHR). Female Sprague-Dawley rats were treated with MC (100 mumol/kg), ip, once daily for 4 days, and expression of CYP1B1 and several phase II (e.g., GST-alpha, NQO1) genes and their corresponding proteins were determined in lung and liver. The major finding was that MC persistently induced (3- to 10-fold) the expression of several phase II enzymes, including GST-alpha, NQO1, UGT1A1, ALDH, and epoxide hydrolase in both tissues for up to 28 days. However, MC did not elicit sustained induction of CYP1B1. Our results thus support the hypothesis that MC elicits coordinated and sustained induction of phase II genes presumably via persistent activation of the AHR, a phenomenon that may have implications for chemical-induced carcinogenesis and chemopreventive strategies in humans.
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PMID:Persistent induction of hepatic and pulmonary phase II enzymes by 3-methylcholanthrene in rats. 1820 89

In view of the crucial involvement of oxidative and electrophilic stress in various kidney disorders, this study was undertaken to test the hypothesis that pharmacologically-mediated coordinated upregulation of endogenous renal antioxidants and phase 2 enzymes is an effective strategy for renal protection. Notably, studies on the pharmacological inducibility of a series of antioxidants and phase 2 enzymes in renal tubular cells are lacking. Here we reported that incubation of normal rat kidney (NRK-52E) proximal tubular cells with low micromolar concentrations (10-50 microM) of the cruciferous nutraceutical, 1,2-dithiole-3-thione (D3T), led to a significant concentration-dependent induction of a wide spectrum of antioxidants and phase 2 enzymes, including catalase (CAT), reduced form of glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1 (NQO1), and heme oxygenase (HO). We further observed that D3T treatment also increased the protein and mRNA expression for CAT, gamma-glutamylcysteine ligase, GR, GST-A, GST-M, NQO1, and HO-1. Incubation of the renal tubular cells with H(2)O(2), SIN-1-derived peroxynitrite, or 4-hydroxy-2-nonenal led to concentration-dependent decreases in cell viability. Pretreatment of the renal tubular cells with 10-50 microM D3T afforded remarkable protection against the nephrocytotoxicity elicited by the above oxidative and electrophilic species. The D3T-mediated cytoprotection showed a concentration-dependent relationship. Taken together, this study for the first time comprehensively characterized the inducibility by a unique nutraceutical of a wide spectrum of antioxidative and phase 2 defenses in renal tubular cells at the levels of enzyme activity as well as protein and mRNA expression, and demonstrated that such a coordinated upregulation of cellular defenses led to remarkable protection of renal tubular cell from oxidative and electrophilic stress. Because of the crucial role of oxidative and electrophilic stress in inflammatory injury, D3T-mediated coordinated induction of endogenous antioxidative and phase 2 defenses may also serve as an important anti-inflammatory mechanism in kidneys.
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PMID:Coordinated upregulation of a series of endogenous antioxidants and phase 2 enzymes as a novel strategy for protecting renal tubular cells from oxidative and electrophilic stress. 1840 43

In the present paper, we examined the incidence of polymorphic genes involved with the detoxification of exogenous chemicals, including carcinogens, namely GSTT1 (glutathione transferase theta1), GSTM1 (glutathione transferase micro1) and NQO1 (NAD(P)H:quinone oxidoreductase 1) in 60 Filipino paediatric patients with ALL (acute lymphoblastic leukaemia). We found a significantly high incidence of the GSTM1 null genotype in ALL children (71.7%) compared with 51.7% in the control group of children (P<0.05). The GSTT1 null genotype was observed in 35.0% and 33.3% of the ALL cases and the control subjects respectively, with no significant difference. Screening for NQO1 (609C>T) mutant alleles showed a high incidence of the NQO1 C/C genotype (NQO1 homozygous wild-type allele genotype) in 60.0% of ALL cases and was significantly higher than in the control group (23.3%) (P<0.01). These GSTM1 null and NQO1 wild-type genotypes are independently associated with the risk of ALL in Filipino patients. When these two genotypes, GSTM1 null and NQO1 C/C, were combined, the hazard rate for childhood leukaemia was significantly increased (P<0.001). We also noticed that the incidences of GSTM1 null mutations and the NQO1 C/C genotype were significantly higher among Filipinos. These findings suggest a possible role of the GSTM1 null and NQO1 C/C genotypes in the susceptibility of paediatric ALL cases in the Philippines.
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PMID:Prevalence of GSTT1, GSTM1 and NQO1 (609C>T) in Filipino children with ALL (acute lymphoblastic leukaemia). 1844 11

Estrogen exposure through early menarche, late menopause, and hormone replacement therapy increases the risk factor for hormone-dependent cancers. Although the molecular mechanisms are not completely established, DNA damage by quinone electrophilic reactive intermediates, derived from estrogen oxidative metabolism, is strongly implicated. A current hypothesis has 4-hydroxyestrone-o-quinone (4-OQE) acting as the proximal estrogen carcinogen, forming depurinating DNA adducts via Michael addition. One aspect of this hypothesis posits a key role for NAD(P)H-dependent quinone oxidoreductase (NQO1) in the reduction of 4-OQE and protection against estrogen carcinogenesis, despite two reports that 4-OQE is not a substrate for NQO1. 4-OQE is rapidly and efficiently trapped by GSH, allowing measurement of NADPH-dependent reduction of 4-OQE in the presence and absence of NQO1. 4-OQE was observed to be a substrate for NQO1, but the acceleration of NADPH-dependent reduction by NQO1 over the nonenzymic reaction is less than 10-fold and at more relevant nanomolar concentrations of substrate is less than 2-fold. An alternative detoxifying enzyme, glutathione-S-transferase, was observed to be a target for 4-OQE, rapidly undergoing covalent modification. These results indicate that a key role for NQO1 and GST in direct detoxification of 4-hydroxy-estrogen quinones is problematic.
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PMID:Problematic detoxification of estrogen quinones by NAD(P)H-dependent quinone oxidoreductase and glutathione-S-transferase. 1858 20

The multifunctional, anti-Alzheimer drug, ladostigil (TV3326) [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] combines the neuroprotective effects of the anti-Parkinson drug, rasagiline, a selective monoamine oxidase (MAO)-B inhibitor, with the cholinesterase (ChE) inhibitory activity of rivastigmine in a single molecule. Ladostigil has been shown to possess potent antiapoptotic and neuroprotective activities in various oxidative insults in vitro and in vivo, such as prevention of the fall in mitochondrial membrane potential and regulation of Bcl-2 family proteins. In the present study, we demonstrate that ladostigil (1 microM) increased cell viability, associated with the increase of catalase activity and decrease of intracellular reactive oxygen species (ROS) production in human SH-SY5Y neuroblastoma cells exposed to (hydrogen peroxide) H(2)O(2). Furthermore, ladostigil significantly elevated mRNA levels of the antioxidants enzymes, catalase, NAD(P)H quinone oxidoreductase 1 (NQO1) and peroxiredoxin 1 (Prx 1) in H(2)O(2)-treated SH-SY5Y cells. Chronic treatment with ladostigil (1 mg/kg gavage per day for 30 days) markedly up-regulated mRNA expression levels of various antioxidant enzymes in aged rat hippocampus (e.g. glutathione peroxidase precursor (GSHPX-P), glutathione S-transferase (GST) and glucose-6-phosphate dehydrogenase (G6PD)). These findings indicate that in addition to its multiple neuroprotective characteristics, ladostigil also possesses antioxidant properties, which might be beneficial for the treatment of oxidative stress (OS) in aging and age-associated neurodegenerative diseases.
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PMID:The neuroprotective effect of ladostigil against hydrogen peroxide-mediated cytotoxicity. 1859 87

Sulforaphane, a cruciferous isothiocyanate compound, upregulates cytoprotective genes in liver, but its effects on antioxidants and phase 2 defenses in vascular cells are unknown. Here we report that incubation of rat aortic smooth muscle A10 cells with sulforaphane (0.25-5 microM) resulted in concentration-dependent induction of a spectrum of important cellular antioxidants and phase 2 enzymes, including superoxide dismutase (SOD), catalase, the reduced form of glutathione (GSH), glutathione peroxidase, glutathione reductase (GR), glutathione S-transferase (GST), and NAD(P)H:quinone oxidoreductase 1 (NQO1). Sulforaphane also increased levels/activities of SOD, catalase, GSH and GST in isolated mitochondria of aortic smooth muscle cells. Time-dependent sulforaphane-induced increases in the mRNA levels for MnSOD, catalase, the catalytic subunit of gamma-glutamylcysteine ligase, GR, GST-A1, GST-P1, and NQO1 were observed. Pretreatment with sulforaphane (0.5, 1, and 5 microM) protected aortic smooth muscle cells from oxidative and electrophilic cytotoxicity induced by xanthine oxidase (XO)/xanthine, H2O2, SIN-1-derived peroxynitrite, 4-hydroxy-2-nonenal, and acrolein. Furthermore, sulforaphane pretreatment prevented intracellular accumulation of reactive oxygen species (ROS) after exposure of the cells to XO/xanthine, H2O2, or SIN-1. Taken together, this study demonstrates that in the aortic smooth muscle cells sulforaphane at physiologically relevant concentrations potently induces a series of total cellular as well as mitochondrial antioxidants and phase 2 enzymes, which is accompanied by dramatically increased resistance of these vascular cells to oxidative and electrophilic stress.
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PMID:Potent induction of total cellular and mitochondrial antioxidants and phase 2 enzymes by cruciferous sulforaphane in rat aortic smooth muscle cells: cytoprotection against oxidative and electrophilic stress. 1860 71

Polycyclic aromatic hydrocarbons (PAHs) including benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) are environmental pollutants, which undergo metabolic activation to exert their carcinogenic effects. Our earlier studies showed that naturally occurring plant phenols, protocatechuic, chlorogenic, tannic acids and resveratrol, besides inhibiting B[a]P and DMBA binding to DNA, modulate the activity of the enzymes involved in PAHs activation. The aim of the present study was further examination of the effect of these compounds on the expression and activities of CYP1A1/1A2, CYP1B1, CYP2B, and phase 2 enzymes in female BALB/C mouse epidermis treated with an initiating dose of B[a]P or DMBA. Application of a single 400 nmol dose of B[a]P alone significantly (by 119-127%) increased the activities of ethoxy- (EROD) and methoxy- (MROD) resorufin dealkylases and to lesser extent penthoxyresorufin depentylase (PROD) (by 32%). Western blot analysis with CYP1A1/1A2, CYP1B1 and CYP2B-specific antibodies showed the increase of CYP1A1/1A2 and CYP2B levels in B[a]P-treated animals. Phase 2 enzymes, gluthatione S-transferase and NAD(P)H:quinone oxidoreductase-1 (NQO1) were also significantly increased. In contrast to B[a]P, application of the initiating dose of DMBA (10 nmol) on mouse skin did not change the activities or protein levels of cytochrome P450, however increased the activities of NQO1 and GST. Pretreatment of mice with phenolic compounds one hour before B[a]P application significantly decreased the activities of all alkoxyresorufin dealkylases in comparison with the group of mice treated only with B[a]P. The sole exception was tannic acid which did not affect the PROD activity. This polyphenol, however, decreased the protein level of CYP1A1/1A2 and CYP1B1 isozymes enhanced by B[a]P. All phenolics, particularly resveratrol, significantly (by 129-174%) increased the activity of NQO1 in comparison with B[a]P-treated animals. On the other hand, pretreatment with phenolic compounds significantly diminished NQO1 activity in comparison with DMBA-treated group. These results indicate that the reduction of B[a]P-DNA adducts observed in our earlier studies may result from the decreased B[a]P activation by investigated plant phenols. In case of DMBA-DNA adducts, the scavenging or masking the binding sites to be occupied by DMBA reactive metabolites is more probable. Moreover, the lack of cytochrome P450 induction by the initiating dose of DMBA suggests that the constitutive expression of P450, particularly CYP1B1 is sufficient for DMBA activation and subsequent DNA adducts formation.
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PMID:The effect of initiating doses of benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene on the expression of PAH activating enzymes and its modulation by plant phenols. 1869

Human metabolism of benzene involves pathways coded for by polymorphic genes. To determine whether the genotype at these loci might influence susceptibility to the adverse effects of benzene exposure, 208 Bulgarian petrochemical workers and controls, whose exposure to benzene was determined by active personal sampling, were studied. The frequency of DNA single-strand breaks (DNA-SSB) was determined by alkaline elution, and genotype analysis was performed for five metabolic loci. Individuals carrying the NAD(P)H:quinone oxidoreductase 1 (NQO1) variant had significantly twofold increased DNA-SSB levels compared to wild-type individuals. The same result was observed for subjects with microsomal epoxide hydrolase (EPHX) genotypes that predict the fast catalytic phenotype. Deletion of the glutathione S-transferase T1 (GSTT1) gene also showed a consistent quantitative 35-40% rise in DNA-SSB levels. Neither glutathione S-transferase M1 (GSTM1) nor myeloperoxidase (MPO) genetic variants exerted any effect on DNA-SSB levels. Combinations of two genetic polymorphisms showed the same effects on DNA-SSB as expected from the data on single genotypes. The three locus genotype predicted to produce the highest level of toxicity, based on metabolic pathways, produced a significant 5.5-fold higher level of DNA-SSB than did the genotype predicted to yield the least genotoxicity.
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PMID:Genetic susceptibility to benzene toxicity in humans. 1883 23

The overarching goals were: (i) to develop an in vitro coculture model, including two relevant lung target cells: human alveolar macrophage (AM) isolated from bronchoalveolar lavage fluid, and immortalized cells originated from the normal lung tissue of a human embryo (L132 cell line), as a future strategy for near-realistic exposures to air pollution particulate matter (PM), and (ii) to study the gene expression of volatile organic compound (VOC) and/or polycyclic aromatic hydrocarbons (PAH)-metabolizing enzymes in this in vitro coculture model. Human AM and/or L132 cells in mono- and coculture were exposed for 24, 48 and 72h to Dunkerque City's PM2.5 at its lethal concentrations at 10% and 50% (i.e. AM: LC10=14.93 microgPM/mL and LC50=74.63 microgPM/mL; L132: LC10=18.84 microgPM/mL and LC50=75.36 microgPM/mL), and the gene expression (i.e. Cytochrome P450 1A1, CYP1A1; CYP2E1; CYP2F1; microsomal Epoxide Hydrolase; NADPH Quinone Oxydo-Reductase-1, NQO1; and Glutathione S-Transferase pi-1 and mu-3, GST-pi1 and GST-mu3) was studied. In human AM in mono- and coculture, and in L132 cells in monoculture, VOC and/or PAH-coated onto PM induced the gene expression of CYP1A1, CYP2E1, NQO1, GST-pi1, and/or GST-mu3. However, there were quiet different outcomes based on the use of L132 cells in mono- vs. coculture: the pattern of VOC and/or PAH-metabolizing enzymes induced by PM in L132 cells in monoculture remained almost unaffected when in coculture with AM. Taken together, these results reinforced the key role of PM-exposed target human AM in the defenses of the human lung from external injuries, notably through their higher capacity to retain PM, and indicated that carbonaceous cores of PM, as physical vector of the penetration and retention of coated-VOC and/or PAH into cells, enabled them to exert a longer toxicity. The use of such a near realistic exposure system could also be a very useful and powerful tool to identify the mechanisms by which air pollution PM induced adverse health effects.
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PMID:Air pollution particulate matter (PM2.5)-induced gene expression of volatile organic compound and/or polycyclic aromatic hydrocarbon-metabolizing enzymes in an in vitro coculture lung model. 1895 61


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