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)

After oral administration of rifampicin and 25-desacetylrifampicin, which is a major metabolite of rifampicin in man but not in rat, to male Wister rats for 7 days, hepatic microsomal cytochrome P450, cytochrome b5, and activities of aniline hydroxylase, aminopyrine demethylase, bilirubin-conjugating enzymes and supernatant glutathione S-transferase were measured. Rifampicin induced bilirubin UDP-glucuronyltransferase, bilirubin UDP-glucosyltransferase, bilirubin UDP-xylosyltransferase and glutathione S-transferase activities, but did not induce mixed function oxidase activities. No inductive effect of desacetylrifampicin on any enzymes was observed. Serum bilirubin increased till the third day, and decreased after 7 days of rifampicin treatment. Plasma clearances of indocyanine green and sulfobromophthalein showed a marked delay after 1 day and 7 days of rifampicin treatment. Induction of bilirubin-conjugating enzymes and glutathione S-transferase by rifampicin in rats was different from that in humans, in which selective induction of mixed function oxidase is reported to occur. This species difference does not seem to be derived from the species difference of rifampicin metabolism, because no effect of desacetylrifampicin was observed. These results suggested that in rats rifampicin directly inhibits the hepatic excretion of bilirubin, whereas it enhances bilirubin conjugation due to enzyme induction.
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PMID:Induction of rat liver bilirubin-conjugating enzymes and glutathione S-transferase by rifampicin. 316 72

To exclude the possibility that changes in hepatotoxicity and biotransformation were induced by diabetogen administration, the influence of long-lasting experimental insulin-dependent diabetes on the activities of benzphetamine demethylase, styrene oxide hydrolase, and UDP-glucuronosyl-transferases toward 1-naphthol, diethylstilbestrol, estrone and testosterone, and glutathione S-transferases toward 1-chloro-2,4-dinitrobenzene, ethacrynic acid, and sulfobromophthalein was studied. Adult male Sprague-Dawley rats injected with 45 mg streptozotocin/kg rapidly developed the classical symptoms of diabetes which persisted throughout the 90-day test period. Ketonemia was detectable at 6 but not at either 35 or 90 days after streptozotocin administration. After acute challenge with bromobenzene or carbon tetrachloride (CCl4), aspartate and alanine aminotransferase activities in rats diabetic for 35 and 90 days were markedly higher than those in normal rats, suggesting that diabetes potentiated the hepatotoxicity of these chemicals. Administration of 25 microliters CCl4/kg, ip, to diabetic rats decreased enzyme activities toward benzphetamine, sulfobromophthalein, 1-chloro-2,4-dinitrobenzene, and 1-naphthol. In normal rats, a dose of 400 microliters CCl4/kg, ip, was required to cause similar changes in enzyme activities. Bromobenzene (500 microliters/kg, ip) elicited opposing responses in diabetic and normal rats in N-demethylase activity, in UDP-glucuronosyltransferase activity toward 1-naphthol, estrone, and testosterone, and in glutathione S-transferase activity toward 1-chloro-2,4-dinitrobenzene. Total cytochrome P450 concentrations were reduced by both induction of diabetes and hepatotoxicant challenge. Thus, chronic uncontrolled diabetes alters the response of hepatic xenobiotic biotransformation enzymes in a non-uniform, substrate-dependent manner, independent of initial diabetogen effects. The role of cytochrome P450j in potentiating CCl4 toxicity is discussed.
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PMID:The effect of long-term streptozotocin-induced diabetes on the hepatotoxicity of bromobenzene and carbon tetrachloride and hepatic biotransformation in rats. 335 67

Effects of three different doses of endosulfan respectively designated as low, medium and high on cytochrome P450(Cyt.P450), glutathione S-transferase(GST) activity and glutathione content (GSH) of hepatic and extra hepatic tissues of rat were determined after 24 hours of treatment. Endosulfan caused induction of cyt. P450 in liver, lung and brain at all the three doses tested while in kidney, spleen and heart either induction or reduction took place and was unrelated with dosages of endosulfan. Similarly, GST activity significantly changed in extra hepatic tissues while liver GST activity did not record any significant alteration under the experimental conditions. The GSH content also showed changes (increase/decrease) unrelated to endosulfan dosages in different organs. Thus, the effects varied with organ and dosages. As these metabolic parameters are involved in biotransformation of many endogenous molecules as well, the study may throw some light on physiological disturbances due to changes in metabolizing system on one side and organ specificity in toxic action of endosulfan on the other.
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PMID:Some metabolic changes induced by endosulfan in hepatic and extra hepatic tissues of rat. 368 Aug 62

The synergistic hepatotoxicity of dietary disulfiram (DSF) with 1,2-dichloroethane (DCE) subchronically administered by inhalation at three concentration levels (150, 300, and 450 ppm) was studied. The criteria for hepatotoxicity were treatment-related increases in serum activities of sorbitol dehydrogenase, 5'-nucleotidase, and alkaline phosphatase, and in liver-to-body weight ratios. DSF alone did not elicit these responses while DCE at the highest concentration level increased liver-to-body weight ratios and the activity of 5'-nucleotidase. Exposure to DSF alone decreased cytochrome P450 levels, but in combination with DCE, the decrement of cytochrome P450 was additive in a DCE concentration-dependent manner. However, depression of cytochrome P450 by DCE alone was not concentration dependent. Although DSF and DSF/DCE combination increased the activity of glutathione S-transferases (GSTs), both DSF and DCE singly and in combination increased the tissue levels of reduced glutathione (GSH). Evidence is presented showing that the potentiation of the hepatotoxicity of DCE observed in the presence of DSF may be due to an inhibition of microsomal mixed-function oxidase-mediated metabolism of DCE and to a compensatory increase in DCE metabolism to reactive metabolites generated by GST-mediated conjugation of DCE with GSH.
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PMID:Interaction between 1,2-dichloroethane and tetraethylthiuram disulfide (disulfiram). II. Hepatotoxic manifestations with possible mechanism of action. 378 26

The ability of S-9 fractions isolated from the livers of 4-, 12-, and 26-month-old male inbred F344 rats to activate and metabolize the hepatocarcinogen aflatoxin B1 [(AFB1) CAS: 1162-65-8] was studied. The following observations were made: The activation of AFB1 to compounds that are mutagenic in the Ames Salmonella-microsome test and to compounds that covalently bind DNA in vitro was similar for liver S-9 from 4- and 12-month-old rats. A 30-50% decrease in the activation of AFB1 occurred in rats between 12 and 26 months of age. The in vitro metabolism of AFB1 to chloroform-soluble and water-soluble metabolites was similar for 4- and 12-month-old rats and decreased significantly in rats after 12 months of age. The proportion of most of the chloroform-soluble metabolites of AFB1 formed by liver S-9 from 4-, 12-, and 26-month-old rats was similar. However, the proportion of aflatoxicol (CAS: 29611-03-8) produced by liver S-9 increased approximately twofold in rats between 12 and 26 months of age. The cytochrome P450 content and the NADPH cytochrome c reductase activity of liver microsomes decreased 40-45% in rats between 12 and 26 months of age. However, the activities of UDPglucuronyltransferases and most forms of glutathione S-transferase did not change significantly with increasing age in liver microsomes and cytosol, respectively.
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PMID:Metabolism, covalent binding, and mutagenicity of aflatoxin B1 by liver extracts from rats of various ages. 391 13

The influence of a prolonged treatment with disulfiram (DSF) and D(-)penicillamine (PA) on biological and biochemical effects induced by nitrosodiethylamine (NDEA) was studied in rats. The combination of NDEA and DSF led to a massive and early development of esophageal tumors, which were fatal to the animals. No liver tumors were observed in this group, whereas PA in combination with NDEA led to an increased development of liver tumors compared with NDEA alone. In the last two groups, only incidental tumors of the esophagus were observed. Nasal cavity tumors also appeared earlier in the animals treated with DSF and NDEA than in animals treated with NDEA alone or with NDEA plus PA. At a biochemical level, DSF led to a significant inhibition of hepatic anilinehydroxylase and nitroso-dimethylaminedemethylase in contrast to PA, which had no influence on these enzymes. The reduced activities of these drug-metabolizing enzymes did not appear to be related to gross cytochrome P450 content. Highly significant increases in glutathione content and glutathione-S-transferase activity (GSH/GST) were induced by DSF but not by PA. Because N-nitrosodiethylamine requires enzymatic activation to form the ultimate carcinogen, it is suggested that the observed inhibition of nitrosamine-transforming enzymes in the liver during DSF treatment leads to an increased amount of intact nitrosamines in other organs, e.g., in the esophagus, where it could be transformed to the ultimate carcinogen. DSF treatment alone or in combination with NDEA leads to an accumulation of trace elements in the liver, whereas PA eliminated copper and cobalt. The possible influence of these elements on tumor development is discussed in part II of this study.
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PMID:Influence of a prolonged treatment with disulfiram and D(-)penicillamine on nitrosodiethylamine-induced biological and biochemical effects in rats. I. Investigations on the drug metabolizing system. 397 88

Noninbred Long-Evans rats fed the reduced form of glutathione (GSH) 2 hours before injection with 7,12-dimethylbenz[a]anthracene [(DMBA) CAS: 57-97-6)] showed a significant suppression of DMBA-induced chromosome aberrations (CA) in bone marrow cells. However, rats given injections of ethyl maleate [(EM) CAS: 141-05-9; (z)-2-butenedioic acid diethyl ester] 0.5 or 2 hours before being killed showed a remarkable fall in the hepatic GSH level. Furthermore, the administration of EM and bromosulfophthalein [CAS: 71-67-0; 3,3'-(4,5,6,7-tetrabromo-3-oxo-1(3H)-isobenzofuranylidene) bis(6-hydroxy)benzenesulfonic acid disodium salt] shortly before the DMBA injection inhibited the suppressive effects of Sudan III on DMBA-induced CA. A clear positive correlation was found between the capacity of Sudan III and related azo dyes to protect against DMBA-induced CA in bone marrow cells and glutathione transferase (GST) activity toward 1-chloro-2,4-dinitrobenzene in the liver cytosol induced by these azo dyes. DMBA activation with hepatic S-9 obtained from rats treated by polychlorinated biphenyls (PCB), phenobarbital, and Sudan III in the Ames system was high in this order as was also the case for the cytochrome P450 content. The addition of GSH to the Ames system containing S-9 from PCB-treated rats resulted in a substantial loss in the mutagenicity of DMBA. The present results suggest that GST and GSH play important roles in DMBA inactivation in rats previously administered Sudan III.
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PMID:Induction of hepatic glutathione transferase and suppression of 7,12-dimethylbenz[a]anthracene-induced chromosome aberrations in rat bone marrow cells by Sudan III and related azo dyes. 620 95

In order to determine the target portion of acetaminophen-induced hepatotoxicity, 750 mg per kg of body weight of acetaminophen was administered to male Wistar strain rats with or without the pretreatment of thiol compounds. In the liver, glutathione content decreased throughout the observation periods, and glutathione S-transferase initially, and later adenosine triphosphatase decreased, followed as elevations of aminotransferases and ornithione carbamoyltransferase in serum. The pretreatment of thiol compounds could not restore hepatic enzyme activities, but partially hepatic glutathione content and serum enzyme elevations. Although distinct time lag existed in biochemical alterations in the liver, hepatic glutathione content was significantly correlated solely with hepatic glutathione S-transferase. The mechanism of acetaminophen hepatotoxicity was discussed from the aspect of biochemical events in cytosol and membrane structure in hepatocytes. The mechanism of acetaminophen induced hepatotoxicity has been extensively investigated, and the hepatotoxicity seems to be related to the toxic metabolites generated by biotransformation process (Gillette et al., 1974, Mitchell et al., 1976). Since the toxic metabolites are conjugated with glutathione (GSH), it is generally accepted that when the hepatocellular GSH content has critically depleted, the metabolites seem to react with hepatocyte macromolecules and/or to produce lipid peroxidation, resulting in biochemical and structural changes leading to cell death (Black, 1980). A hepatotoxic dose of labelled acetaminophen was found throughout the liver and the highest concentration was found in centrilobular area, where considerable disruption and vacuolation of the plasma membrane and of the endoplasmic reticulum also occurred (Jollow et al., 1973, Chiu and Bhakthan, 1978). However remarkably little impairment of several enzyme systems in microsome, such as cytochrome P450 content, arylhydrocarbon hydroxylase and glucuronyl transferase has been reported (Thorgeirsson et al., 1976, Chiu and Bhakthan, 1978: Willson and Hart, 1977, Yamada et al., 1981). To elucidate the exact mechanism of acetaminophen hepatotoxicity, we observed time related biochemical alterations of hepatic GSH content, some marker enzymes in hepatocyte subfractions and serum enzymes. The present results indicated that acetaminophen reduced hepatic GSH content, followed as depletions of glutathione S-transferases (GSTs) and finally adenosine triphosphatase (ATPase), associated with elevations of serum enzymes.
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PMID:The target portion of acetaminophen induced hepatotoxicity in rats: modification by thiol compounds. 666 1

Various natural and synthetic compounds are known to protect against cancer by elevating phase II detoxification enzymes. Generally classified as monofunctional, these inducers are believed to trigger cellular signal(s) that activate gene transcription through an antioxidant or electrophile response element (ARE/EpRE) in responsive genes. In contrast, the phase I enzymes of drug metabolism (cytochrome P450s) are not believed to be induced by monofunctional inducers and P450 genes have not been found to contain functional ARE/EpREs. In this study, rats were treated with the monofunctional inducers tert-butylated hydroxyanisole, ethoxyquin, and oltipraz to study the inducibility of individual glutathione S-transferase isozymes, NADP(H):quinone oxidoreductase, gamma-glutamylcysteine synthetase, UDP-glucuronosyl transferase, and cytochrome P450 enzymes. Hepatic mRNAs were analyzed on Northern blots using gene-specific oligonucleotide probes for GST Ya1, Ya2, Yc1, Yc2, Yb1, Yb2, and Yf, for UGT 1*06, and for P450 1A1, 1A2, 2B1, 2C11, 3A2, and 4A1. NADP(H):quinone oxidoreductase and gamma-glutamylcysteine synthetase mRNAs were detected using cDNA probes. All the phase II detoxification enzymes analyzed, except GST Yf, were induced by the three monofunctional inducers, suggesting that these genes may be regulated by a mechanism involving an ARE/EpRE element in their promoter region. Interestingly, it was found that ethoxyquin was a particularly good inducer for both members of the P450 2B family, 2B1 and 2B2, and both ethoxyquin and oltipraz were also capable of modestly inducing P450 1A2 and 3A2. Oltipraz was found to slightly induce P450 2B2, but not 2B1, at the dose and time analyzed. Induction of mRNA generally correlated well with induction of protein levels determined by Western blot and/or enzyme activity measurements for selected enzymes. The results of this study suggest that many phase II enzymes may contain ARE/EpRE elements in addition to those confirmed to be regulated by a mechanism involving ARE/EpRE elements. In addition, it was found that several P450 enzymes were induced by monofunctional inducers, suggesting a possibility that some phase I enzymes may also be regulated by a mechanism involving ARE/EpRE elements.
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PMID:Induction of phase I and phase II drug-metabolizing enzyme mRNA, protein, and activity by BHA, ethoxyquin, and oltipraz. 748 39

Patients with idiopathic Addison's disease are characterized by cytoplasmic adrenal autoantibodies, detectable by indirect immunofluorescence of cryocut sections of human adrenal cortex. Recently, autoantibodies that bind a 55-kilodalton protein in the microsomal fraction of adrenal gland extracts identified to be the cytochrome P450 enzyme 21-hydroxylase have been found in Addisonian patient sera. We confirm the finding and report here the autoantigenic epitopes involved in the autoantibody reactivity using recombinant DNA technology. Six cDNA fragments spanning different regions of the 21-hydroxylase gene were expressed as fusion proteins with glutathione S-transferase in Escherichia coli. Immunoblot analyses were used to evaluate the reactivity of the recombinant proteins with patients' sera to determine the autoepitopes involved. We found that a conserved region (amino acids 164-356) reacted with 25 of 30 adrenal autoantibody-positive sera tested. One serum sample reacted only with the amino portion of the 21-hydroxylase (amino acids 1-162). In addition, 4 other enzymes important to steroid hormone biosynthesis, 11 beta-hydroxylase, 17 alpha-hydroxylase, side-chain cleavage enzyme P450, and 3 beta-hydroxysteroid dehydrogenase, were expressed in E. coli, but none of them gave positive autoantibody reactions by Western blot assays, even using sera from 5 patients with type I autoimmune polyglandular syndrome. The availability of recombinant antigens has permitted structural analysis of the autoepitopes involved in the autoimmune response to 21-hydroxylase in Addison's disease. Our findings should lead to the development of a simple and specific tool for immunodiagnosis of the disease.
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PMID:Autoantibody epitope mapping of the 21-hydroxylase antigen in autoimmune Addison's disease. 751 15


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