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)

HepG2 cells were cultured in the presence of different concentrations of cyclosporin A (CsA) or Nva2-cyclosporin (Nva2-Cs) for up to 20 days. At a low concentration (2 micrograms/ml) of CsA or Nva2-Cs, the [3H]thymidine incorporation into DNA and the rate of incorporation of [3H]leucine into total protein decreased by 20-25%. Concentrations of 10 micrograms/ml resulted in a 70% reduction of the [3H]thymidine incorporation in comparison with controls. Low concentrations of CsA resulted in mitochondria in the condensed state together with autophagosomes, large vacuoles, and elevated numbers of coated vesicles, as shown by electron microscopy. Low concentrations of Nva2-Cs resulted in swollen mitochondria, increased autophagocytosis, and increased numbers of intermediate filaments and microtubules. Higher doses of these substances (5 micrograms/ml) caused disarrangement of mitochondrial cristae, vesiculation of the endoplasmic reticulum, an elevated number of free polysomes, and accelerated autophagocytosis. Labeling of phospholipids and triglycerides with [3H]glycerol and of cholesterol and dolichol with [3H]acetate was decreased after exposure of HepG2 cells to CsA, or, in particular, Nva2-Cs. Phospholipids secreted from the cells into the medium exhibited an increased level of labeling, but the specific radioactivity of the neutral lipids in the medium was significantly decreased. Treatment of HepG2 cells with either CsA or Nva2-Cs doubled the mitochondrial cytochrome oxidase and carnitine acetyl-transferase, as well as microsomal NADPH-cytochrome c reductase activities. Such treatment also increased the cyanide-insensitive beta-oxidation of fatty acids in peroxisomes, as well as cytoplasmic DT-diaphorase and glutathione transferase activities. Prolonged treatment of the cells with CsA did not result in any cumulative effect. HepG2 cells appear to be suitable for studying the effects of cyclosporins on cellular structure and metabolism and in this system the two drugs studied here exhibited similar effects.
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PMID:Modulation of metabolism in HepG2 cells upon treatment with cyclosporin A and Nva2-cyclosporin. 164 68

The activities of tissue glutathione (reduced and oxidized) and glutathione-dependent enzymes such as glutathione S-transferase (GSH S-transferase), glutathione reductase (GSSG reductase) and glutathione peroxidase (GSH-Px) were determined for control and uremic rats. Acute renal failure (ARF) was produced by glycerol-water injection. Cytosolic and microsomal GSH S-transferase activity in the kidney was decreased by 38% and 15%, respectively. Hepatic microsomal GSH S-transferase was also decreased by 40% in uremic rats. GSH-Px activity was decreased by 51% in the cytosolic fraction and 33% in the microsomal fraction in the kidney, but was not affected in the liver and whole blood. GSSG reductase activity was also decreased by 48% in the cytosolic fraction in the kidney of uremic rats. In whole blood, however, GSSG reductase activity was increased by 12-fold (0.66 +/- 0.12 mumol NADPH oxidized/min/ml blood in the control; 8.03 +/- 3.29 mumol NADPH oxidized/min/ml blood in uremia). Although the total glutathione concentrations were not significantly affected, the GSSG/GSH ratio, which is an indication of oxidative stress, was significantly increased in the liver and whole blood of uremic rats. In addition to the decreases in hepatic and renal GSH S-transferase activities, which is important in drug disposition, ARF caused decreases in GSSG reductase and GSH-Px activity, which are essential for the protection against lipid peroxidation.
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PMID:Effects of glycerol-induced acute renal failure on tissue glutathione and glutathione-dependent enzymes in the rat. 187 Mar 54

The in vitro spasmolytic activity of glycerol trinitrate was measured on the KCl-contraction of aorta strips from the rabbit. In the presence of sulphobromophthalein, a known inhibitor of glutathione S-transferase, the dose-activity curve for the nitrate was displaced to the right. Much smaller displacements were obtained with the control spasmolytic substances--papaverine and S-nitroso-N-acetylpenicillamine. It was confirmed that sulphobromophthalein inhibits glutathione S-transferase activity in aorta homogenates. Aorta extracts did not detectably catalyze the reaction between glutathione and sulphobromophthalein and the glutathione level was not decreased by treating the intact aorta with sulphobromophthalein. It is concluded that sulphobromophthalein acts as a specific antagonist of the spasmolytic activity of glycerol trinitrate, probably as a result of its inhibition of glutathione S-transferase. It thus seems probable that glutathione and glutathione S-transferase are involved in the pharmacological activation of the organic nitrates.
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PMID:Antagonism of glycerol trinitrate activity by an inhibitor of glutathione S-transferase. 250 Jan 24

1. The pharmacokinetics, biliary excretion and binding of dibromosulphophthalein (DBSP) to plasma proteins and hepatic cytosol proteins have been studied in male rats with glycerol-induced acute renal failure (ARF). 2. The rate constants for hepatic uptake, efflux from liver to plasma and excretion into bile were all significantly decreased in rats with ARF. Furthermore, the plasma clearance of DBSP was also reduced. 3. The initial (0-10 min) and maximum biliary excretion rates of DBSP were both diminished in animals with ARF. The maximum excretion rate occurred between 5-10 min in control rats and 10-15 min in rats with ARF. However, there was no statistically significant change in the percentage dose recovered from bile after 30 min. 4. The plasma-protein binding of DBSP was decreased in rats with ARF and this change was due to a significant reduction in the association constant for the primary binding sites. 5. The binding of DBSP to ligandin (Y protein) was reduced by about 38% in rats with ARF but no change was noted in binding to Z protein. Reduced binding to ligandin was accompanied by decreased total liver glutathione S-transferase (GST) activity and a 36% reduction in the GST activity of ligandin. 6. The results support the contention that altered hepatic handling of cholephilic dyes in rats with ARF may be due to reduced binding to ligandin.
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PMID:Dibromosulphophthalein: its pharmacokinetics and binding to hepatic cytosol proteins in rats with acute renal failure. 322 67

The reaction of 1,2-dibromoethane and glutathione with DNA in the presence of glutathione S-transferase results in the formation of a single major DNA adduct, which can be released by thermal hydrolysis at neutral pH and separated by octadecylsilyl and propylamino high-performance liquid chromatography. The same DNA adduct is the only major one formed in livers of rats treated with 1,2-dibromo[1,2-14C]ethane. The DNA adduct was identified as S-[2-(N7-guanyl)ethyl]glutathione: (1) The chromatographic behavior was altered by treatment with gamma-glutamyl transpeptidase or Streptomyces griseus protease. (2) The molecular ions observed in positive and negative mode fast atom bombardment mass spectrometry were those expected for the structure when either glycerol or a mixture of dithiothreitol and dithioerythritol was used as the bombardment matrix. (3) The two-dimensional 1H NMR correlated spectroscopy spectrum of the DNA adduct was compared to the spectra of glutathione, oxidized glutathione, and N7-methylguanine and found to be consistent with the assigned structure. No evidence for in vitro or in vivo opening of the guanyl imidazole ring was observed under these conditions. The structure of the adduct supports a pathway involving enzyme-catalyzed conjugation of 1,2-dibromoethane with glutathione, non-enzymatic dehydrohalogenation of the resulting half-mustard to form a cyclic episulfonium ion, and attack of the N7 nitrogen of DNA guanine on the episulfonium ion to generate this major DNA adduct, which may be related to the carcinogenicity of this chemical.
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PMID:S-[2-(N7-guanyl)ethyl]glutathione, the major DNA adduct formed from 1,2-dibromoethane. 370 41

Glutathione-depleted hepatocytes, by incubation with diethylmaleate (DEM) or phorone (2,6-dimethyl-2,5-heptadiene-4-one), i.e., substrates of the GSH S-transferases (EC 2.5.1.18), showed rates of gluconeogenesis from various precursors significantly lower than controls; however the rate of glucose synthesis from fructose was similar to that of controls. Isolated hepatocytes from rats pretreated with those substrates 1 h before isolation to deplete hepatic glutathione (GSH) also showed a decrease of the rate of gluconeogenesis from lactate plus pyruvate. Incubation of hepatocytes with L-buthionine sulfoximine, a specific inhibitor of gamma-glutamyl-cysteine synthetase (EC 6.3.2.2), resulted in a decreased rate of gluconeogenesis from lactate plus pyruvate only when GSH values were lower than 1 mumol/g cells. Freeze-clamped livers from GSH-depleted rats showed a higher concentration of malate and glycerol 3-phosphate, indicating that GSH depletion probably affects phosphoenolpyruvate carboxykinase and glycerol-3-phosphate dehydrogenase activities. Several indicators of cell viability, such as lactate dehydrogenase leakage, malondialdehyde accumulation, ATP concentration, or urea synthesis from different precursors, were not affected by GSH depletion under the experimental conditions used here. Besides, the GSH/GSSG ratio remained unchanged in all cases.
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PMID:Effects of glutathione depletion on gluconeogenesis in isolated hepatocytes. 402 24

The biotransformation of allyl alcohol and acrolein by rat lung and liver preparations was investigated by measuring acrolein, acrylic acid, glycidol, and glycidaldehyde. Acrolein was detected by high-pressure liquid chromatography from incubation mixtures containing allyl alcohol, NAD+, and liver 9000g supernatant fraction or cytosol. Acrolein was not formed when lung fractions were treated similarly. Addition of pyrazole in the incubation mixture inhibited the reaction. The metabolism of acrolein to acrylic acid by liver 9000g supernatant fraction, cytosol, and microsomes has been demonstrated; acrylic acid formation was greater with NAD+ than with NADP+ in all three fractions. Acrylic acid was also formed from allyl alcohol. Disulfiram inhibited the NAD+- and NADP+-dependent reactions. Acrylic acid was not formed when lung preparations were used. Lung and liver microsomal epoxidation products of allyl alcohol and acrolein have been identified. Conversion of glycidol to glycerol and glycidaldehyde to glyceraldehyde by liver epoxide hydrase has been demonstrated. Epoxides, glycidol, and glycidaldehyde were also found to be substrates for lung and liver cytosolic glutathione S-transferase.
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PMID:The biotransformation of allyl alcohol and acrolein in rat liver and lung preparations. 610 26

An acid glutathione S-transferase from human liver has been partially purified and characterized. The relative molecular mass of the enzyme is 46,000, and a double reciprocal plot of velocity against glutathione concentration is biphasic and shows in addition substrate inhibition. The enzyme differs from the basic human liver transferases alpha, beta, gamma, delta, and epsilon in the characteristics studied, but it bears a resemblance to transferase rho from human erythrocytes. When liver cytosol was analysed by isoelectric focusing using a short pH gradient and a density gradient formed of either glycerol or saccharose, the peak of glutathione S-transferase activity appeared at pH 4.63 +/- 0.02, in contrast to blood cell lysate which was found to contain a major peak at pH 4.63 and at least two additional peaks at pH 4.44 and 4.51, respectively.
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PMID:Acid glutathione S-transferase from human liver: preliminary report. 725 86

Poliovirus protein 3B (also known as VPg) is covalently linked to the 5' ends of both genomic and antigenomic viral RNA. Genetic and biochemical studies have implicated protein 3AB, the membrane-bound precursor to VPg, in the initiation of genomic RNA synthesis. We have purified 3AB to near homogeneity following thrombin cleavage of purified glutathione S-transferase-3AB. When added to transcription reaction mixtures catalyzed by poliovirus RNA polymerase (3Dpol), 3AB stimulated RNA synthesis up to 75-fold with oligo(U)-primed virion RNA, globin mRNA, and unprimed synthetic, full-length minus-strand viral RNA as the templates. Synthetic VPg also stimulated RNA synthesis but was only 1 to 2% as effective as 3AB on a molar basis. The increased level of transcription was not the result of enhancing the elongation rate of the polymerase. No evidence was found for uridylylation of 3AB or for covalent linkage to RNA transcription products. 3AB sedimented as a multimer in glycerol gradients. In the presence of the polymerase, the sedimentation rate of both proteins increased, suggesting the formation of a complex. Detergent prevented both multimerization and complex formation. The polymerase also bound to immobilized glutathione S-transferase-3AB; this procedure was used to purify the polymerase to near homogeneity. These results suggest a mechanism for bringing together 3AB, 3Dpol (or its precursor 3CD), and viral RNA in host cell membranous vesicles in which all viral RNA synthesis occurs.
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PMID:Poliovirus protein 3AB forms a complex with and stimulates the activity of the viral RNA polymerase, 3Dpol. 747 38

The haemolysin exporter HlyB and its homologues are central to the unconventional signal-peptide-independent secretion of toxins, proteases and nodulation proteins by bacteria. HlyB is a member of the ATP-binding cassette (ABC) or traffic ATPase superfamily, and resembles closely in structure and function mammalian exporters such as the multidrug-resistance P-glycoprotein, combining both integral membrane and cytosolic domains. Overproduction of the HlyB cytoplasmic domain as a C-terminal peptide fused to glutathione S-transferase allowed the direct affinity purification and concentration of 30-50 mg ml-1 of soluble protein (GST-Bctp) in an apparently dimeric form possessing both transferase and ATPase activity. GST-Bctp bound to ADP-agarose and was eluted specifically by ATP and ADP, affinity behaviour which was confirmed in both the full-length HlyB and the unfused HlyB cytoplasmic domain synthesized in vitro. The stoichiometry of binding to MgATP and MgADP was close to equimolar and both ligands induced substantial conformational change in the protein. Mg(2+)-dependent ATPase activity of GST-Bctp (Vmax 1 mumol min-1 mg-1, Km 0.2 mM) was comparable with the activity of the bacterial importer MalK and human P-glycoprotein reconstituted into proteoliposomes, and over an order of magnitude higher than in vitro measurements of disaggregated MalK purified from inclusion bodies. Activity was unaffected by inhibitors of F- and V-type ATPases, non-hydrolysable ATP analogues, or translocation substrate, but was severely inhibited by inhibitors of E1E2 (P-type) ATPases, and the acidic phospholipid phosphatidyl glycerol.
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PMID:ATPase activity and ATP/ADP-induced conformational change in the soluble domain of the bacterial protein translocator HlyB. 836 61


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