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 drug disulfiram (DSF, Antabuse) has been used in the therapy of alcohol abuse. It is a potent inhibitor of aldehyde dehydrogenase. Its reduced form, diethyldithiocarbamate (DDTC), and further metabolites show similar activities. DSF and DDTC have also been widely used to inhibit mixed-function oxidases. In this study, the reversible inhibition and time-dependent inactivation of the major rat and human glutathione S-transferase (GST) isoenzymes by DSF and DDTC was investigated. Reversible inhibition, using 1-chloro-2,4-dinitrobenzene as substrate for the GST alpha-, mu-, and pi-class, expressed as I50 (in microM), ranged from 5-18 (human A1-1), 43-57 (rat 4-4) and 66-83 (rat 1-1), for both DSF and DDTC. The I50 for rat GST theta, using 1,2-epoxy-3-(p-nitrophenoxy)-propane as substrate, was 350 microM for DDTC. The other GSTs were significantly less sensitive to inhibition. The major part of reversible inhibition by DSF was shown to be due to DDTC, formed rapidly upon reduction of DSF by the glutathione (GSH) present in the assay to measure GST activity. The oxidized GSH formed upon reduction of DSF might also have made a minor contribution to reversible inhibition. The rat and human pi-class was, by far, the most sensitive class for time-dependent inactivation by DSF, but no such inactivation was observed for any of the GSTs by DDTC. Moderate susceptibility to inactivation by DSF of all the other GSTs was observed, except for human A2-2, which does not possess a cysteine residue. Consistent with the assumption that a thiol residue is involved in this inactivation, a significant part of the activity could be restored by treatment of the inactivated GST with GSH or dithiotreitol.
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PMID:In vitro inhibition of rat and human glutathione S-transferase isoenzymes by disulfiram and diethyldithiocarbamate. 869 43

Benzene is a known carcinogen and hematopoietic toxin in humans and experimental animals. The effect of acute, high-dose exposure to benzene on hepatic bioactivation and detoxication enzymes has been defined, while little is known about the effect of repeated, low-dose benzene exposure on these enzymes. Our objective was to determine whether repeated, oral benzene exposure alters enzymes involved in benzene metabolism. Specifically, we were concerned with cytochrome P-450-2E1, a bioactivation enzyme, and glutathione transferase and aldehyde dehydrogenase, two detoxifying enzymes. Female CD-1 mice were treated by gavage for 3 wk with benzene doses of 5 mg/kg (0.064 mmol/kg) or 50 mg/kg (0.646 mmol/kg) in corn oil. These doses of benzene produced 0.048 and 0.236 mumol muconic acid/d, respectively. We found that repeated exposure to 50 mg benzene/kg/d decreased P-450-2E1 activity by 34% and induced glutathione transferase activity by 30% without affecting aldehyde dehydrogenase activity. These changes in enzyme activities may serve a protective role against repeated exposure to benzene.
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PMID:Repeated oral benzene exposure alters enzymes involved in benzene metabolism. 875 34

The regulation of hepatic P450s has been the focus of numerous studies because of the importance of these proteins in endocrinology, oncology, and toxicology, as well as drug development. Considerable evidence exists demonstrating that many hepatic P450s are regulated by developmental, sex, or hormonal factors in addition to receptors that interact with foreign chemicals. The focus of work in our laboratory has been on the effects of steroid hormones, especially glucocorticoids, on expression of genes regulated by the Ah receptor. We have shown that most rat hepatic genes of the Ah receptor gene battery are regulated by glucocorticoids. We have used glucocorticoid-deficient animal models to demonstrate that these steroids do modulate the expression (basal and inducible) of these genes in vivo. Using cultured rat hepatocytes, we have demonstrated that polycyclic aromatic hydrocarbon (PAH) induction of cytochrome P4501A1, glutathione S-transferase Ya1, and UDP-glucuronosyltransferase 1*6 are apparently potentiated two- to fourfold upon inclusion of glucocorticoids in the media to activate the glucocorticoid receptor and further, that the receptor antagonist RU 38486 reverses these phenomenon. NAD(P)H:quinone oxidoreductase and aldehyde dehydrogenase 3 gene expression were repressed 70-80% by glucocorticoids in cultured hepatocytes through a glucocorticoid receptor-mediated process as well. The effect of glucocorticoid concentration on PAH induction of glutathione S-transferase Ya1 subunit for glucocorticoids was biphasic, but at physiological concentrations gene expression was repressed to approximately 20-40% of control. At supraphysiological concentrations, glucocorticoids alone induced expression two- to threefold and potentiated the PAH-inducible expression of the Ya1 subunit gene. Subsequent work in our laboratory has focused on defining the molecular basis of this hormonal regulation, specifically elucidating responsive elements responsible for the action of the glucocorticoid receptor and the mechanisms by which some of these genes are positively regulated and others are negatively regulated.
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PMID:Hormonal regulation of hepatic enzymes involved in foreign compound metabolism. 890 7

Cytosolic class-3 aldehyde dehydrogenase (ALDH-3) may help to protect organisms from certain environmental aldehydes by catalysing their detoxification. Consistent with this notion are the reports that relatively high levels of this enzyme are present in tissues, e.g. stomach mucosa and lung, that are so-called ports of entry for such agents. Further, it is found in human saliva. The present investigation revealed that small amounts of this enzyme are also present in human salivary glands; mean values for ALDH-3 activities (NADP-dependent enzyme-catalysed oxidation of benzaldehyde) in cytosolic fractions prepared from submandibular and parotid glands were 52 (range: 29-92) and 44 (range: 13-73) mIU/g tissue, respectively. Essentially identical or slightly lower levels of this enzyme activity were found in pleomorphic adenomas, an undifferentiated carcinoma, and an adenocystic carcinomas, of the parotid gland. On the other hand, Warthin tumours, and mucoepidermoid carcinomas of the parotid gland exhibited relatively elevated levels of ALDH-3 activity; mean values were 1200 (range: 780-1880) and 810 (range: 580-1200) mIU/g tissue, respectively. The ALDH-3 found in normal salivary glands was, as judged by physical, immunological and kinetic criteria, identical to human stomach mucosa ALDH-3 whereas the ALDH-3 present in Warthin tumours, and mucoepidermoid carcinomas, of the parotid gland appeared to be a subtle variant thereof. Qualitatively paralleling the relatively elevated ALDH-3 levels in mucoepidermoid carcinomas and Warthin tumours were relatively elevated levels of glutathione S-transferase (alpha and pi) and DT-diaphorase. As was the case with ALDH-3 levels, glutathione S-transferase (alpha and pi) and DT-diaphorase levels were not elevated in pleomorphic adenomas. Glutathione S-transferase mu was not detected in the two normal parotid gland samples, or in the single pleomorphic adenoma sample, tested. It was found in the single mucoepidermoid carcinoma sample, and in one of the two Warthin tumour samples tested. Cellular levels of ALDH-3, glutathione S-transferases and/or DT-diaphorase could be useful criteria when the decision to be made is whether a salivary gland tumour is a mucoepidermoid carcinoma. ALDH-3 and glutathione S-transferases are known to catalyse the detoxification of two agents that are used to treat salivary gland tumours, viz. cyclophosphamide and cisplatin, respectively. Thus, elevated levels of these enzymes in the mucoepidermoid carcinomas must account for, or at least contribute to, the relative ineffectiveness of these agents when used to treat this tumour.
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PMID:Over-expression of glutathione S-transferases, DT-diaphorase and an apparently tumour-specific cytosolic class-3 aldehyde dehydrogenase by Warthin tumours and mucoepidermoid carcinomas of the human parotid gland. 893 51

Previously, we proposed that reactive aldehydic products generated from lipid peroxidation might be the deleterious cause of mitochondrial dysfunction during aging. Our present study focuses on the roles that aging and dietary restriction (DR) play in the elimination of 4-hydroxynonenal (HNE) in rat liver by exploring three enzymatic systems: aldehyde dehydrogenase (ALDH), glutathione S-transferase (GST), and alcohol dehydrogenase (ADH). Results show that the main pathways of HNE elimination in mitochondria are through ALDH-catalyzed oxidation, and the GST-catalyzed conjugation of HNE. Findings also show that age reduces both ALDH and GST activities; mitochondrial HNE oxidation by ALDH declines at 18 and 24 months of age, and the glutathione conjugation of HNE reduces at 24 months of age. However, these enzymatic processes were found to be well-preserved in DR animals throughout their life span, supporting the evidence of less HNE accumulation in the membranes of restricted rats. These findings are consistent with our earlier proposal that indicates an age-associated decrease in mitochondrial detoxification as a major underlying process for malondialdehyde and lipofuscin accumulation in older animals. They also indicate that the prevention of the age-associated decrease in aldehyde detoxification by DR may be an important mechanism underlying enhanced aldehyde elimination, thus minimizing the functional deterioration observed in mitochondria of old animals.
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PMID:Detoxification of reactive aldehydes in mitochondria: effects of age and dietary restriction. 895 35

The aryl hydrocarbon receptor (AHR) is a transcriptional activator of genes encoding a group of drug-metabolizing enzymes, including cytochrome P450 1A1 (CYP1A1), glutathione S-transferase, tumor-associated aldehyde dehydrogenase and quinone reductase. Both the constitutive and inducible expression of these genes in the liver is zonated, i.e., dominant in hepatocytes of the centrilobular region, a poorly understood position-dependent phenomenon. By comparing cell lysates obtained from opposite acinar regions we observed that immunoreactive AHR protein was almost exclusively confined to centrilobular cells. The AHR mRNA, as analyzed from cell lysates by reverse transcriptase polymerase chain reaction, exhibited a similar, although somewhat less pronounced zonation. By contrast, only slight zonation of the AHR nuclear translocator mRNA was observed. Treatment of rats with omeprazole, an atypical nonligand activator of the AHR, caused a zone-specific induction of CYP1A1 in the centrilobular region similar to that seen after pretreatment with the AHR ligand 3-methylcholanthrene. Our results suggest that the zone-restricted expression of AHR protein will allow the constitutive and inducible expression of AHR-regulated genes in the centrilobular region, but will limit their expression in the periportal region.
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PMID:Selective centrilobular expression of the aryl hydrocarbon receptor in rat liver. 899 35

In the present study, we analysed the expression of monooxygenase activities and mRNAs associated with cytochrome P-450 (CYP), including CYP1A1/2, CYP2B1/2, CYP2C6, CYP2E1, CYP3A1/2, glutathione transferase alpha (GST alpha), aldehyde dehydrogenase and epoxide hydrolase in co-cultures of primary rat hepatocytes and rat liver epithelial cells. We observed that pentoxyresorufin O-deethylation activity was well maintained and ethoxyresorufin O-deethylation activity gradually decreased during co-culture time. In addition, we showed that phenobarbital and 3-methylcholanthrene treatments resulted in a significant increase of these activities. Two general patterns of accumulation of liver-specific mRNAs were observed. CYP1A1/2, CYP2B1/2, CYP3A1/2, GST alpha, aldehyde dehydrogenase and epoxide hydrolase mRNAs were maintained at a stable level, whereas CYP2C6 and CYP2E1 mRNAs showed a continuous decline. In addition, we observed a strong increase of CYP1A1/2 (13.6-fold) and GST alpha (3.9-fold) mRNA expression in 3-methylcholanthrene-treated co-cultures and induction of CYP2B1/2 (19-fold), CYP2C6 (10-fold), CYP3A1/2 (11.2-fold), GST alpha (9-fold), aldehyde dehydrogenase (6-fold) and epoxide hydrolase (5-fold) mRNA expression in phenobarbital-treated co-cultures. Furthermore, we demonstrated that liver-specific gene expression was restricted to hepatocytes, with the notable exception of epoxide hydrolase and CYP2E1 which were expressed in both cell types during the co-culture, as shown by the selective recovery of both hepatocytes and rat liver epithelial cells. Finally, to investigate whether co-cultures could be used to study the molecular mechanisms regulating CYP transcription, we performed transfection of hepatocytes, before the establishment of the co-culture, with large CYP2B1 (3.9 kb) or CYP2B2 (4.5 kb) promoter chloramphenicol acetyltransferase constructs or with a construct containing a 163-bp DNA sequence element reported to confer phenobarbital responsiveness. A 2-3-fold increase over the basal level of chloramphenicol acetyltransferase activity was observed in phenobarbital-treated co-cultures transfected with the phenobarbital-responsive element construct, although phenobarbital had no effect on large CYP2B1 or CYP2B2 promoter fragments. Our results demonstrate that the co-culture system provides a good tool for studying drug metabolism, and shows promise as a new tool for analysing transcriptional regulation under the influence of xenobiotics within primary hepatocytes.
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PMID:Regulation of the major detoxication functions by phenobarbital and 3-methylcholanthrene in co-cultures of rat hepatocytes and liver epithelial cells. 906 51

The dioxin-inducible mouse [Ah] battery contains at least six genes that "cross-talk" with one another and are believed to play important roles in reproduction and development, and in environmental toxicity, cancer, and oxidative stress. In addition to two P450 genes, Cyp1a1 and Cyp1a2, this laboratory has shown that the four Phase II [Ah] genes include: NAD(P)H:menadione oxidoreductase (Nmo1); a cytosolic "class 3" aldehyde dehydrogenase (Ahd4); a UDP glucuronosyltransferase having 4-methylumbelliferone as substrate (Ugt1a6); and a glutathione transferase having 2,4-dinitro-1-chlorobenzene as substrate (Gsta1, Ya). The Ah receptor-mediated coordinate induction is controlled positively in all six [Ah] battery genes. Oxidative stress up-regulates the four Phase II [Ah] genes. This laboratory is generating conventional, plus inducible, knockout mouse lines having homozygous disruptions in the above-mentioned genes; this novel methodology is described herein. If the conventional knockout is healthy and viable, the mouse line would be useful for studies involving environmental agents. If the conventional knockout is lethal during development, this model would be important for developmental biology, but the inducible (also called conditional) knockout can still be used--at selected ages and even in selected tissue or cell types--for studies designed to understand the mechanisms involved in reproduction and development, and in environmental toxicity, cancer, and oxidative stress.
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PMID:How knockout mouse lines will be used to study the role of drug-metabolizing enzymes and their receptors during reproduction and development, and in environmental toxicity, cancer, and oxidative stress. 906 27

The tumor-associated aldehyde dehydrogenase 3 (ALDH3) and the glutathione transferase (GST)Ya form are coded by members of the Ah (aryl hydrocarbon) battery group of genes activated in the liver by polycyclic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The physiological role of the Ah receptor (AHR), its gene-activating mechanism and its endogenous ligands are still poorly clarified. We had previously observed that 3-methylcholanthrene (3MC) and beta-naphthoflavone (betaNF) induced the AHR-associated CYP1A1/1A2 pair in different liver regions, an effect not explained by the acinar distribution of the AHR protein. Here, we investigated AHR-associated regional induction by comparing the expression patterns of ALDH3 and GSTYa. Analysis of samples from periportal and perivenous cell lysates from 3MC-treated animals revealed that ALDH3 mRNA, protein and benzaldehyde-NADP associated activity were all confined to the perivenous region. In contrast, such regio-specific induction was not seen after beta-NF induction. Immunohistochemically, a peculiar mono- or oligocellular induction pattern of ALDH3 was seen, consistently surrounding terminal hepatic veins after 3MC but mainly in the midzonal region after betaNF. A ligand-specific difference in regional induction of GSTYa1 mRNA was also observed: The constitutive perivenous dominance was preserved after 3MC while induction by betaNF was mainly periportal. A 3MC-betaNF difference was also seen by immunohistochemistry and at the GSTYa protein level, in contrast to that of the AHR-unassociated GSTYb protein. However, experiments with hepatocytes isolated from the periportal or perivenous region to replicate these inducer-specific induction responses in vitro were unsuccessful. These data demonstrate that the different acinar induction patterns by 3MC and betaNF previously observed for CYP1A1 and CYP1A2 are seen also for two other Ah battery genes, GSTYa1 and ALDH3, but in a modified, gene-specific form. We hypothesize that unknown protein(s) operating in vivo and modifying the Ah-mediated response at the common XRE element located upstream of these genes is affected zonespecifically by 3MC and betaNF.
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PMID:Aryl hydrocarbon receptor-associated genes in rat liver: regional coinduction of aldehyde dehydrogenase 3 and glutathione transferase Ya. 951 75

The cellular metabolism of 4-hydroxy-2-nonenal (4-HNE), a cytotoxic and genotoxic product of oxidative stress-induced lipid peroxidation, was investigated in rat H35 hepatoma cells. Previous studies from our laboratory (1) have characterized the degree to which oxidative, reductive, and conjugative metabolic pathways function simultaneously during hepatocellular metabolism of 4-HNE to rapidly eliminate the compound from suspensions of freshly isolated rat hepatocytes. In the current studies, we have extended the investigation of 4-HNE metabolism to examine the pharmacokinetic parameters of 4-HNE elimination and export in a hepatoma cell line and determined that the ensuing oxidative and conjugative metabolites of 4-HNE are rapidly and efficiently transported out the cell. Low concentrations of 4-HNE (25 microM) were used in an attempt to simulate physiologically relevant conditions. The H35 hepatoma cell line studied was first evaluated for enzymes known to play important roles in the metabolism of 4-HNE and were found to possess activities for glutathione S-transferase, aldehyde dehydrogenase (ALDH), and alcohol dehydrogenase of 24.00 +/- 1.12, 3. 45 +/- 0.17, and 6.44 +/- 0.29 nmol min-1 mg-1 protein, respectively. Hepatoma cells were incubated with 25 microM 4-HNE and metabolites in intra- and extracellular fractions were quantitated by reversed-phase HPLC over the time course of treatment. Reduced glutathione (GSH) and the GSH metabolites of 4-HNE were quantitated by reversed-phase HPLC as the dinitrobenzene derivatives. Uptake of 4-HNE from the extracellular medium occurred with an estimated rate of 0.398 +/- 0.181 min-1 10(6) hepatoma cells-1. The oxidative metabolite of 4-HNE, 4-hydroxy-2-nonenoic acid (HNA), produced by ALDH, appeared rapidly in the intracellular fraction achieving concentrations of 0.28 HNA nmol 10(6) hepatoma cells-1 and was efficiently eliminated with a first-order rate constant of 0.988 min-1. The GST-mediated conjugative metabolite, 3-glutathionyl-4-hydroxy-2-nonanal (4-HNE-SG), rapidly reached maximal intracellular concentrations of 1.88 +/- 0.44 nmol 10(6) hepatoma cells-1 and was eliminated at a rate of 0.101 +/- 0.033 min-1. Extracellular rates of formation, representing export, for HNA and 4-HNE-SG were 0.247 +/- 0.045 and 0.044 +/- 0.009 min-1 10(6) hepatoma cells-1, resulting in maximal extracellular concentrations for HNA and 4-HNE-SG of 0.70 +/- 0.10 and 3.03 +/- 0. 84 nmol 10(6) hepatoma cells-1. Approximately 75% of the administered concentration of 4-HNE was converted to measurable metabolites, with the 4-HNE-GSH conjugate accounting for 61% of total administered 4-HNE and HNA accounting for 14%. Collectively, these results demonstrate that oxidative and conjugative pathways are primarily responsible for elimination of 4-HNE at low concentrations in the hepatoma cell line evaluated and that the 4-HNE metabolites resulting from these pathways are rapidly and efficiently exported out of the cell.
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PMID:Formation and export of the glutathione conjugate of 4-hydroxy-2, 3-E-nonenal (4-HNE) in hepatoma cells. 988 35


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