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: KEGG:D00031 (Glutathione)
5,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Translocation of intracellular glutathione to the medium was studied in lymphoid cells (grown in tissue culture) that have very high, very low, or intermediate levels of membrane-bound gamma-glutamyl transpeptidase, in the absence and presence of various inhibitors of this enzyme. The data show that glutathione is translocated to the medium by all of the cell lines studied, but that glutathione does not accumulate in the medium unless the cellular transpeptidase activity is either very low or substantially inhibited. Translocation of glutathione does not seem to be directly related to the activity of gamma-glutamyl transpeptidase. The present and previous [Griffith, O.W. & Meister, A. (1979) Proc. Natl. Acad. Sci. USA 76, 268--272] findings suggest that translocation of intracellular glutathione is a general property of many mammalian cells. Glutathione exported from cells that have membrane-bound transpeptidase may be recovered by the cell in the form of transpeptidation or degradation products. Translocation of glutathione may also reflect operation of a rather general mechanism that protects and maintains the integrity of cell membranes.
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PMID:Translocation of glutathione from lymphoid cells that have markedly different gamma-glutamyl transpeptidase activities. 3 14

Glutathione is translocated out of cells; cells that have membrane-bound gamma-glutamyl transpeptidase can utilize translocated glutathione, whereas glutathione exported from cells that do not have appreciable transpeptidase enters the blood plasma. Glutathione is removed from the plasma by the kidney and other organs that have transpeptidase. Studies in which mice and rats were treated with buthionine sulfoximine, a selective and potent inhibitor of gamma-glutamylcysteine synthetase and therefore of glutathione synthesis, show that glutathione turns over at a significant rate in many tissues, especially kidney, liver, and pancreas; the rate of turnover in mouse skeletal muscle is about 60% of that in the kidney. Experiments on rats surgically deprived of one or both kidneys and treated with the gamma-glutamyl transpeptidase inhibitor D-gamma-glutamyl-(o-carboxy)phenylhydrazide establish that extrarenal gamma-glutamyl transpeptidase activity accounts for the utilization of about one-third of the total blood plasma glutathione. Normal animals treated with the transpeptidase inhibitor excrete large amounts of glutathione in their urine. They also excrete gamma-glutamylcysteine, suggesting that cleavage of glutathione at the cysteinylglycine bond may be of metabolic significance. The present and earlier findings lead to a tentative scheme (presented here) for the metabolism and translocation of glutathione, gamma-glutamyl amino acids, and related compounds.
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PMID:Glutathione: interorgan translocation, turnover, and metabolism. 4 2

An appreciable fraction of the sulphur present in the mammal occurs in the form of glutathione, whose concentration in various tissues ranges from about 0.8 to about 8 mM; the extracellular concentration of glutatione (largely present as the disulphide) is in the micromolecular range. The synthesis of glutathione and its utilization take place by the reactions of the gamma-glutamyl cycle, which include those catalysed by gamma-glutamylcysteine and glutathione synthetases, gamma-glutamyl transpeptidase, cysteinylglycinase, gamma-glutamyl cyclotransferease, and 5-oxoprolinase. gamma-Glutamyl transpeptidase catalyses transpeptidation (with amino acids and dipeptides) and hydrolysis reactions with both blutathione and its disulphide. The transpeptidase is membrane-boudn, apparently to the outer surface of the cell, and is found in certain epithelial cells in anatomical sites that are involved in transport and secretory activities (e.g., renal tubule, jejunal villi, choroid plexus, ciliary body). Evidence that the reactions of the gamma-glutamyl cycle take place in vivo has come from studies with labelled metabolites and selective enzyme inhibitors, and on inborn errors of metabolism associated with specific enzyme deficiencies. Inhibition in vivo of gamma-glutamyl cyclotransferase and 5-oxoprolinase leads, respectively, to decreased and increased renal levels of 5-oxoproline. Administration of a specific inhibitor of gamma-glutamylcysteine synthetase, such as buthionine sulphoximine, leads to a rapid decline in the glutamylcysteine synthetase, such as buthionine sulphoximine, leads to a rapid decline in the glutathione level of the kidney and other tissues, reflecting the appreciable rate of glutathione utilization. When gamma-glutamyl transpeptidase is inhibited in vivo by injection of L- or D-gamma-glutamyl-(o-carboxy)phenylhydrazide, there is extensive glutathionuria and the blood plasma level of glutathione increases. Studies in which inhibitors of glutathione synthesis and transpeptidation were given to mice showed that transport of intracellular glutathione to membrane-bound transpeptidase is a discrete step in the gamma-glutamyl cycle, and that the level of plasma glutatione reflects (a) synthesis of glutathione and its export by liver, muscle, and other tissues and (b) utilization of glutatione by kidney and other tissues. Studies on several lymphoid cell lines show that these cells also actively translocate glutathione out of the cell. A summary scheme is given for the metabolism of glutathione in which glutathione is translocated to the cell membrane where it may be utilized as such or oxidized to glutathione disulphide. Oxidation is inhibited, and transpeptidation is promoted by the presence of amino acids that are substrates of the transpeptidase. Glutathione exported from cells that have membrane-bound transpeptidase may be recovered by the cell transport of gamma-glutamyl amino acids and free amino acids...
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PMID:New aspects of glutathione metabolism and translocation in mammals. 4 11

Glutathione (L-gamma-glutamyl-L-cysteinylglycine) is an important constituent of the antioxidant and detoxifying mechanisms of cells. The plasma membrane bound enzyme, gamma-glutamyl transpeptidase (GGT), catalyzes the first step in the degradation of extracellular glutathione, the components of which are then used for de novo glutathione synthesis. We tested the hypothesis that an increase in GGT activity would enhance the utilization of extracellular glutathione by cells challenged with a glutathione-depleting agent. A eukaryotic system stably overexpressing GGT (nearly 200-fold) was developed by transfection of NIH-3T3 fibroblasts with a human placental GGT cDNA. These cells and controls were incubated for 30 min with 1 mM diethyl maleate, which caused approximately 80% intracellular glutathione depletion. Glutathione was added to the medium and cells were allowed to resynthesize intracellular glutathione. The transfected cells used extracellular glutathione much more efficiently than controls in terms of both the concentration dependence and the rate of glutathione resynthesis. Serine-borate, a competitive inhibitor of GGT, blocked the restoration of intracellular glutathione. The results support the hypothesis that the increase in GGT activity that occurs in some toxicologic or pathologic conditions could provide protection against glutathione depletion.
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PMID:Transfection with gamma-glutamyl transpeptidase enhances recovery from glutathione depletion using extracellular glutathione. 135 Jan 17

The effects of reduced glutathione (GSH) administration (1.2 g/day and 2.4 g/day intravenously) on erythrocyte glutathione levels, serum gamma-glutamyl transpeptidase activity (GGTP) and urinary glucaric acid elimination were studied in a population of 24 chronic alcoholics voluntarily admitted to a 30 day detoxification protocol in comparison to a 12 patient control group treated only with chlordiazepoxide (initial dose 75-100 mg/day). Glutathione treatment increases dose-dependently and in a significant way erythrocyte glutathione levels and hastens the recovery of serum GGTP and urinary glucaric acid elimination. The relationship between glutathione, GGTP and glucaric acid is discussed, suggesting the possible role of GSH against the oxidative damage of alcohol.
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PMID:[Contribution of glutathione to detoxification in alcoholism. Biochemical-clinical studies]. 135 98

Glutathione is important in the regulation of the redox state, and a decline in its tissue level has often been considered to be indicative of increased oxidative stress in diabetes. In this study of diabetic rats, the level of hepatic glutathione was normal unless food intake was restricted. Thus, the previous report of a reduction in hepatic glutathione in diabetes is likely to be the result of food deprivation rather than diabetes alone. In contrast to changes characteristic of oxidative stress, the efflux of glutathione in bile from diabetic animals was significantly decreased, whereas hepatic mixed disulfides were unchanged, and the hepatic gamma-glutamyltransferase activity was considerably increased. These changes were not reproduced by food deprivation. The decrease in biliary excretion of glutathione in diabetes may reflect an attempt to conserve glutathione by activation of the hepatic gamma-glutamyl cycle. We conclude that the disturbances of glutathione metabolism in diabetes are not typical of those seen in oxidative stress or food restriction.
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PMID:Changes in hepatic glutathione metabolism in diabetes. 167 44

Primary cultures of renal rabbit proximal tubule cells were initiated from a pure suspension of proximal tubule fragments. Proximal tubule cells were grown in a hormone-supplemented, serum-free medium containing low concentrations of antibiotics. Confluent monolayers exhibited multicellular dome formation, indicating the presence of transepithelial solute and water transport. Ultrastructural examination revealed a monolayer of polarized epithelial cells with tight junctions and sparse membraneous microvilli facing the culture medium. Time course biochemical characterization was performed using a palette of 12 enzymes, representative of important metabolic functions or pathways. Brush-border-associated enzymes (gamma-glutamyl transpeptidase and alanine aminopeptidase) were moderately reduced throughout the culture whereas alkaline phosphatase was markedly decreased at confluency. Mitochondrial and lysosomal marker enzymes were well preserved over the culture period. Glutathione-S-transferase activity remained stable during the 16-day culture period investigated. Glycolysis enzyme activities (lactate dehydrogenase and hexokinase) were enhanced, as a function of culture age. Na(+)-K(+)-ATPase activity rise was concomitant with the increase of glycolysis marker enzymes. In contrast, the gluconeogenesis marker enzyme, glucose-6-phosphatase, fell dramatically to reach a low level equivalent to 4% of the activity measured in isolated proximal tubules. Primary cultures exhibited several differentiated functions of the proximal tubule cell: (a) PTH alone was able to induce a significant stimulation of adenylate cyclase activity, unlike isoproterenol, thyrocalcitonin, and arginine vasopressin, and (b) sodium-dependent alpha-methylglucoside (AMG) transport was detected. This AMG uptake was selectively inhibited by phlorizin (5 X 10(-3) M), which is a competitive inhibitor of glucose uptake at the apical membrane. Complete characterization made it possible to investigate hitherto unexplored aspects of in vitro cultured proximal tubule cells. This primary culture model could provide a useful and reliable tool to investigate in vitro renal proximal tubule function, under normal conditions or after a drug-induced toxicity.
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PMID:Biochemical, functional, and morphological characterization of a primary culture of rabbit proximal tubule cells. 167

Higher body and carcass (body - liver) weights in sodium phenobarbital (PB) treated mice correlate with formation of multiple hepatocellular adenomas in yellow Avy/A and agouti A/a (C3H x VY) F1 hybrid male mice. To assess differences in PB induction of hepatic drug metabolizing enzymes, yellow Avy/A (C3H x VY) F1 hybrid male mice were fed 0.05% sodium PB in NIH-31 diet for 7 months. Livers from the heaviest and lightest mice in the untreated and PB groups were assayed. Total cytochrome P450 content, cytochrome P450IA-selective 7-ethoxyresorufin-O-deethylase and P450IIIA-selective testosterone-6 beta-hydroxylase activities were preferentially induced in the light mice. In contrast, P450IIB-selective 7-pentoxyresorufin-O-dealkylase activity was increased only 3-fold by PB in the light mice but 6-fold in the heavy mice. Testosterone UDP-glucuronyltransferase and gamma-glutamyltranspeptidase activities were induced in the light mice but not in the heavy mice. Glutathione-S-transferase N1:1-dependent activity was induced preferentially in the heavy mice. Significant differences also occurred in constitutive expression of P450IIIA-selective testosterone-6 beta-hydroxylase, P450IA-selective 7-ethoxyresorufin-O-deethylase and testosterone UDP-glucuronyltransferase activities between the untreated weight groups. Thus, expression of constitutive and PB-inducible forms of hepatic drug metabolizing enzymes differs between heavy and light Avy/A (C3H x VY) F1 hybrid subpopulations. This suggests that differential susceptibility to PB promotion of hepatocellular adenomas among genetically identical mice is accompanied by differences in the regulation of gene expression.
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PMID:Susceptibility to phenobarbital promotion of hepatotumorigenesis: correlation with differential expression and induction of hepatic drug metabolizing enzymes in heavy and light male (C3H x VY) F1 hybrid mice. 167 34

Glutathione-deficient mutants (gshA) of the yeast Saccharomyces cerevisiae, impaired in the first step of glutathione (GSH) biosynthesis were studied with respect to the regulation of enzymes involved in GSH catabolism and cysteine biosynthesis. Striking differences were observed in the content of the sulphur amino acids when gshA mutants were compared to wild-type strains growing on the same minimal medium. Furthermore, all mutants examined showed a derepression of gamma-glutamyltranspeptidase (gamm-GT), the enzyme initiating GSH degradation. However, gamma-cystathionase and cysteine synthase were unaffected by the GSH deficiency as long as the nutrient sulphate source was not exhausted. The results suggest that the mutants are probably not impaired in the sulphate assimilation pathway, but that the gamma-glutamyl cycle could play a leading role in the regulation of the sulphur fluxes. Studies of enzyme regulation showed that the derepression of gamma-GT observed in the gshA strains was most probably due to an alteration of the thiol status. The effectors governing the biosynthesis of cysteine synthase and gamma-cystathionase seemed different from those playing a role in gamma-GT regulation and it was only under conditions of total sulphate deprivation that all these enzymes were derepressed. As a consequence the endogenous pool of GSH was used in the synthesis of cysteine. GSH might, therefore, fulfil the role of a storage compound.
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PMID:Glutathione as an endogenous sulphur source in the yeast Saccharomyces cerevisiae. 167 26

Efflux of glutathione (GSH) and GSH-conjugates from cultured rat liver epithelial cell lines; the non-tumorigenic ARL-15C1 and the gamma-glutamyl transpeptidase containing, tumorigenic ARL-16T2, has been assessed under basal condition and during chronic treatment with 75 and 150 microM ethacrynic acid (EA). The intracellular level of GSH increased in proportion to EA concentration during chronic exposure. The rates of GSH and GSH-EA conjugate efflux increased with intracellular GSH in both ARL cell lines. Glutathione-S-transferase activity measured with EA as substrate increased over the experimental time course after treatment with 150, but not 75 microM EA. When intracellular GSH content was increased by treatment with the cysteine pro-drug, 2-L-oxothiazolidine 4-carboxylic acid, the rate of GSH efflux was increased, but not the rate of GS-EA conjugate export. Inhibition of gamma-glutamyl transpeptidase by acivicin (AT-125) increased the GSH and GS-EA conjugate efflux rate in ARL-16T2 cells by factors of approximately 2 and 15, respectively. Acivicin treatment of ARL-16T2 cells chronically treated with EA elevated GSH efflux rate by 10-fold and GS-EA efflux by 40-fold versus control samples. These studies show that GSH and GSH conjugate efflux are accomplished as independently regulated processes. Efflux of GSH is enhanced by increased intracellular GSH, but increase in the conjugate transport rate requires the presence of the GSH conjugate. The response of the efflux process to treatment with a chronic GSH depleting agent was identical in two cell lines in which the metabolic fate of glutathione is known to differ fundamentally.
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PMID:Glutathione and glutathione conjugate efflux from cultured liver cells. 167 26


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