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)

A method for specific determination of glutathione (GSH) is described. This method utilizes the enzymatic conjugation of GSH to 1-chloro-2,4-dinitrobenzene through reaction catalyzed by glutathione S-transferase. The recovery of GSH as determined by this method is comparable to that in currently used methods. The method is specific for GSH determination. Other sulfhydryl (-SH) compounds including the protein -SH or beta-mercaptoethanol, which are often included in tissue homogenates, do not interfere with GSH determination. Acid extraction of the tissue is not required in this method and comparatively smaller amounts of tissue samples (as little as 20 microliters of a 10% w/v tissue homogenate) are needed for the analyses. The method when applied for GSH determination in ocular tissues yielded results in agreement with the reported values in literature. Evidence for the sensitivity, accuracy, and convenience of the method is provided by analysing the sample containing GSH in the range of 1-200 nmol by this method.
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PMID:A specific, sensitive, and rapid method for the determination of glutathione and its application in ocular tissues. 142 77

Developmental profiles of the activity of the antioxidant enzymes superoxide dismutase (SOD), catalase, glutathione peroxidase (GSH-Px), glutathione transferase (GSH-Tr), and hexose monophosphate shunt (HMS) were measured in the rat testis and liver. The level of SOD in the testis was high at the age of 6 to 10 days, after which it dropped to approximately one third of that level by 20 days of age, and remained there up to 8 months of age. In the liver, SOD activity steadily increased from the neonatal to adult stage of life, reaching the same level as detected in the testis. The testicular activity of catalase was only 2% to 7% of that found in liver at all ages. It increased in both organs up to 6 weeks of age, whereafter the hepatic activity gradually decreased and no further changes were seen in the testis. The GSH-Px activity was low in the testis and declined slightly with age, whereas activity in the liver increased four-fold between birth and adulthood. The activity of GSH-Tr was similar in both organs studied: it increased after birth, showing a maximum in the liver at 1.5 months (ten-fold increase) and in the testis at 5 months of age (four-fold increase). The HMS activity was two to three times higher in the liver than in the testis, and decreased slightly with age in both organs. Thus, the basal levels and developmental profiles of antioxidant enzymes in the testis differ greatly from those in the liver.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antioxidant enzyme activity in the maturing rat testis. 142 21

This study was undertaken to elucidate the mechanism(s) of cross-resistance (4.9-fold) to mitomycin C (MMC) in a multi-drug-resistant cell line, P388/R-84. Intracellular accumulation of MMC by sensitive (P388/S) and P388/R-84 cells was comparable. Despite a 32% reduction in NADPH cytochrome P-450 reductase activity (responsible for MMC activation) in P388/R-84 cells, the rate of MMC bio-reduction by sensitive and resistant cells was similar. These results suggested that MMC resistance in P388/R-84 cell line must depend on factors other than impaired drug accumulation or bio-activation. Recent studies suggest that glutathione transferase (GST) dependent drug detoxification also contributes to cellular resistance of a variety of alkylating agents. Even though overexpression of GST has been noted in some MMC resistant tumor cells, it is not known if its level affects sensitivity to MMC. We have, therefore, determined the effect of ethacrynic acid (an inhibitor of GST activity) treatment on MMC cytotoxicity in P388/R-84 cells, which have about 2-fold higher GST activity than P388/S cells. The IC50 value for the inhibition of GST activity in vitro by ethacrynic acid (EA) was 16.5 microM (5 micrograms/ml). A depletion in intracellular GSH was also observed by treating P388/R-84 cells with EA alone or in combination with MMC. A non-toxic concentration of EA (1 microgram/ml; 3.3 microM) increased MMC cytotoxicity by 36% in P388/R-84 cells. MMC cytotoxicity was increased 2-fold by EA treatment in glutathione (GSH)-depleted P388/R-84 cells. These results suggest that GST mediated drug inactivation may represent another important mechanism of MMC resistance.
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PMID:Modulation of mitomycin C resistance by glutathione transferase inhibitor ethacrynic acid. 144 27

The glutathione S-transferase (GST)-dependent conjugation of reduced glutathione (GSH) with leukotriene A4 (LTA4)-methyl ester in rodent and human skin was investigated. Incubation of [3H]LTA4-methyl ester (1 nmole, approximately 200,000 dpm) with cytosol prepared from rat, mouse and human skin or with affinity purified GST from rat skin cytosol in the presence of GSH resulted in the formation of LTC4-methyl ester. Maximum enzyme activity was observed in rat skin followed by mouse and human skin. With heat-denatured cytosol or in the absence of GSH, the product formation was negligible. GST purified from rat skin cytosol by GSH-agarose affinity chromatography exhibited a several-fold increase in the specific activity of enzyme with 1-chloro-2,4-dinitrobenzene (55-fold), ethacrynic acid (67-fold) and LTA4-methyl ester (12-fold) as substrates. Western blot analysis of the affinity purified GST indicated a predominant expression of the Pi class of GST isozyme followed by Mu and Alpha classes of isozymes. The formation of LTC4-methyl ester was established by its radioactivity profile on high pressure liquid chromatography and absorption spectroscopy. These results suggest that, in addition to xenobiotic metabolism, cutaneous GSTs may also be capable of metabolizing physiological substrates such as LTA4.
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PMID:Glutathione S-transferase-dependent conjugation of leukotriene A4-methyl ester to leukotriene C4-methyl ester in mammalian skin. 144 22

Species and sex differences of aflatoxin B1 (AFB1)-induced glutathione S-transferase placental form (GST-P) positive single hepatocytes have been investigated 48 h after an intraperitoneal injection of AFB1 to young male and female Fischer rats (2 mg AFB1/kg body wt) and male Syrian golden hamsters (6 mg AFB1/kg body wt). The presence of GST-P positive hepatocytes was examined by the immunohistochemical method. Male rats formed three times as many AFB1-induced GST-P positive hepatocytes as females. Pretreatment of both male and female rats with an inhibitor of GSH synthesis, buthionine sulfoximine (BSO) (4 mmol/kg body wt), 2 h and 4 h before AFB1 injection increased AFB1-induced GST-P positive hepatocytes by about 120% above the controls. Male hamsters formed several-fold less AFB1-induced GST-P positive hepatocytes than male rats. Pretreatment with BSO did not increase AFB1-induced GST-P positive hepatocytes in hamsters even though it produced an increase in hepatic necrosis. It appears that GSH and GSH S-transferases play an important role in modulating hepatic AFB1-DNA binding and AFB1-induced GST-P positive hepatocytes in rats and hamsters.
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PMID:Species and sex differences of aflatoxin B1-induced glutathione S-transferase placental form in single hepatocytes. 145 Nov 6

The role of glutathione (GSH) in the effectiveness of and resistance to 7 platinum compounds [5 Pt(II) and 2 Pt(IV) drugs] was evaluated in a 8.6-fold cisplatin (CDDP)-resistant human small cell lung cancer cell line (GLC4/CDDP), the parent GLC4 line, a 3.7-fold CDDP-resistant human embryonal carcinoma cell line (Tera-CP), and the parent Tera line (NTera2/D1). Resistance factors for both CDDP-resistant cell lines were determined after continuous incubation (4 days) with CDDP. Continuous incubation with the other studied platinum drugs revealed complete cross-resistance for carboplatin (CBDCA) and zeniplatin but less for enloplatin (ENLO) and iproplatin in both models. Tetraplatin and lobaplatin showed, respectively, partial and complete cross-resistance in GLC4/CDDP but no cross-resistance in Tera-CP. GSH level, but not glutathione S-transferase activity, of the 4 cell lines correlated with platinum drug concentrations inhibiting cell survival by 50% after continuous incubation (r = 0.86, P < 0.05). GSH depletion by DL-buthionine-S,R-sulfoximine (BSO) increased sensitivity, as measured after a 4-h exposure to the drugs, of GLC4/CDDP for CDDP 2.0-fold, for CBDCA 1.7-fold, for zeniplatin 1.7-fold, and almost to the level of the sensitive GLC4 for ENLO, whereas no effect was observed for lobaplatin and the Pt(IV) compounds iproplatin and tetraplatin. BSO-modulating effect was higher in the sensitive GLC4 line for most compounds; therefore reduction of resistance could be achieved only for CDDP and ENLO. In contrast to GLC4, no modulation occurred in Tera. In Tera-CP BSO increased sensitivity for CDDP 1.5-fold, for CBDCA 1.9-fold, and for zeniplatin 1.2-fold; no effect was observed for ENLO, lobaplatin, and the Pt(IV) compounds. Reduction of CDDP resistance by BSO was known to occur with identical cellular platinum levels and higher Pt-DNA binding in GLC4/CDDP. However, pretreatment with BSO followed by 4 h ENLO incubation increased cellular platinum levels in both GLC4 and GLC4/CDDP while Pt-DNA binding remained unchanged. In conclusion, GSH reflected sensitivity to platinum-containing drugs. However, since the involvement of GSH differed between the models and the various platinum drugs, the effect of modulation with BSO was unpredictable.
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PMID:Relationship of cellular glutathione to the cytotoxicity and resistance of seven platinum compounds. 145 77

Neonatal exposure of rats to xenobiotics has been shown to produce long-term alterations in hepatic enzyme activities and in levels of DNA adducts following carcinogen exposure. We exposed newborn male rats to diethylstilbestrol (DES), pregnenolone-16 alpha-carbonitrile, 7,12-dimethylbenz[a]anthracene or phenobarbital on days 1, 3 and 5 of age. At five months of age, males were injected with 1 mg/kg of [3H]aflatoxin B1 (AFB1), killed after 2 h and examined for AF-DNA adduction in the liver. Males neonatally exposed to DES showed a 35% decrease in DNA adduction levels. Analysis of the adducted DNA bases failed to show any changes in relative proportions of individual adducts in the DES samples compared to controls. Hepatic glutathione concentrations were unchanged. However, Western blot analysis of alpha-class glutathione S-transferases (alpha GST), enzymes known to inactivate the toxic AFB1-8,9-epoxide, showed a 2-fold increase in subunit levels in the DES-treated males, suggesting that the detoxifying activity of the cytosol may have been increased. To confirm this, in vitro tests were undertaken using butylated hydroxyanisole (BHA) induced mouse microsomes to activate [3H]AFB1 in the presence of treated cytosol and GSH. Analysis of metabolites by HPLC showed that DES-treated males formed 245% of the AFB-SG conjugate relative to vehicle controls. These results indicate that neonatal DES treatment resulted in long-term changes in basal alpha GST levels and suggest that these changes were responsible for lower levels of DNA adduction following adult exposure to AFB1.
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PMID:Changes in adult metabolism of aflatoxin B1 in rats neonatally exposed to diethylstilbestrol. Alterations in alpha-class glutathione S-transferases. 147 47

1. Phenol compounds (ellagic acid, quercetin and purpurogallin), glutathione analogues (S-hexylglutathione and S-octylglutathione) and a diuretic drug (ethacrynic acid) were compared for their inhibitory effects on glutathione S-transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GSH-Px) in the canine erythrocytes. 2. All these compounds inhibited GST activity; quercetin was found to be the most potent inhibitor. 3. Ellagic acid, purpurogallin, quercetin and ethacrynic acid inhibited GR activity; S-hexylglutathione and S-octylglutathione had no effect on GR and GSH-Px activities. 4. Quercetin and purpurogallin inhibited GST non-competitively toward glutathione, whereas ellagic acid showed a competitive inhibition. Ellagic acid and purpurogallin inhibited GR non-competitively toward oxidized glutathione.
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PMID:Effects of phenol compounds, glutathione analogues and a diuretic drug on glutathione S-transferase, glutathione reductase and glutathione peroxidase from canine erythrocytes. 147 66

The present paper describes a theoretical study on the mechanism underlying the reaction of cellular glutathione (GSH) with polyunsaturated fatty acid ozonides. The reaction can be catalyzed by glutathione S-transferases and leads to detoxication of the ozonides. Semi-empirical molecular orbital computer calculations suggest that the reaction of glutathione with ozonides involves a nucleophilic attack at one of the carbon atoms of the ozonide ring, instead of at one of the peroxidic oxygen atoms of the ozonide ring. This implies a mechanism different from that of the glutathione S-transferase-mediated reaction with hydroperoxides, previously proposed for the glutathione-dependent detoxication of fatty acid ozonides.
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PMID:Molecular orbital study on the glutathione-dependent detoxication of ozonides. 147 70

The effects of nickel (Ni) on hepatic monooxygenase activities (aniline 4-hydroxylase, AH; ethylmorphine N-demethylase, EMND; aminopyrine N-demethylase, AMND), cytochrome P-450, cytochrome b5, microsomal haem and reduced glutathione (GSH) levels, and glutathione S-transferase (GST) activities toward several substrates (1, chloro-2-4-dinitrobenzene, CDNB; 1,2 dichloro-4-nitrobenzene, DCNB; ethacrynic acid, EAA) in mice, rats and guinea-pigs were studied. Ni (59.50 mg NiCl2.6H2O/kg, subcutaneously) was administered to the animals 16 hr prior to sacrifice. Ni significantly inhibited AH, EMND, AMND activities, and decreased cytochrome P-450, cytochrome b5 (except in the livers of rats), and microsomal haem levels in the livers of all the animal species examined. However, the depressions were more profound in livers of mice than in those of the other two species. The hepatic GSH level was significantly inhibited in mice whereas no alteration was observed in rats. In guinea-pigs, the hepatic GSH level was significantly increased by Ni. The hepatic GST activity toward the substrate CDNB was significantly depressed in mice, unaltered in rats and significantly increased in guinea-pigs by Ni. The hepatic GST activity toward DCNB was significantly inhibited in mice whereas no significant alteration was observed in rats. In guinea-pigs, Ni caused significant increase in hepatic GST activity for DCNB. However, hepatic GST activity toward EAA was significantly inhibited in mice whereas significantly increased in rats and guinea-pigs. These results seem to indicate that i) there exists quantitative, but not qualitative, differences among the hepatic monooxygenases of rodents in response to Ni, mice being more sensitive than rats and guinea-pigs, ii) the influence of Ni on hepatic GSH level varies depending on the animal species and iii) the hepatic GSTs of rodents are differentially regulated by Ni.
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PMID:Responses of hepatic xenobiotic metabolizing enzymes of mouse, rat and guinea-pig to nickel. 148 May 52


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