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:6.3.2.3 (glutathione synthetase)
678 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of enzyme systems are important in the protection of cells from chemical-induced oxidative damage. Little is known of the relative importance of these enzymes during postnatal development and its is possible that changes in their activity during this period may alter the susceptibility to toxic agents. This study investigated the activities of glutathione peroxidase, glutathione reductase, catalase, superoxide dismutase, gamma-glutamyl-cysteine synthetase and glutathione synthetase in the liver, lung and kidney of postnatal and adult mice. The first 3 postnatal weeks are characterized by marked changes in the activities of enzymes that protect against oxidative stress (glutathione peroxidase/reductase, catalase and superoxide dismutase). Overall, the activity of these enzymes suggests that the mouse has a higher level of protection against peroxides at various stages during this period but lower capacity to detoxify superoxide anions. The activities of the glutathione-synthetic enzymes (gamma-glutamylcysteine synthetase and glutathione synthetase) were significantly lower in the kidney of the postnatal mice, but the liver and lung had levels similar to those in the adult. Glutathione turnover in the liver of 2-week-old mice was not different from that in adults. The results indicate a complex pattern of development in the activities of detoxification enzyme systems during postnatal development.
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PMID:Postnatal development of enzyme activities associated with protection against oxidative stress in the mouse. 196 50

A loss of glutathione from the kidney can cause increased sensitivity to oxygen free radical-induced injury. In this study we investigated the effects of kidney preservation on glutathione and how various glutathione precursors affect glutathione concentration in the dog kidney. During 5-day continuous machine perfusion of the kidney at 5 degrees C, a loss of glutathione from the cortex tissue was seen (24% +/- 1% glutathione remained after 5 days). Perfusion with reduced glutathione (GSH, 3 mmol/L) suppressed this loss (77% +/- 11% of glutathione remained after 5 days). Oxidized glutathione (GSSG) did not prevent the loss of glutathione. The addition of the three amino acids that make up glutathione (glycine, glutamic acid, and cysteine, 3 mmol/L each) also suppressed the loss of glutathione (82% +/- 13% remained at 5 days). The glutathione precursor, thioproline, a cysteine delivery compound, in combination with glycine and glutamic acid (3 mmol/L each), stimulated the synthesis of glutathione in the kidney during hypothermic perfusion (137% +/- 23% of control values at 5 days). The increase in tissue glutathione stimulated by GSH or other precursors was sensitive to the glutathione synthetase inhibitor, buthionine sulfoximine. This indicated the existence of active glutathione metabolism even at 5 degrees C in perfused kidneys. This study showed that in kidney preservation a loss of glutathione occurred that could be suppressed by the addition of various precursors for glutathione synthesis. The loss of glutathione from preserved kidneys may be one cause of posttransplant renal injury that could be prevented by use of the appropriate glutathione precursors.
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PMID:Changes in glutathione concentration in hypothermically perfused dog kidneys. 199 54

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase catalyses the rate-limiting step in cholesterol synthesis. Glutathione (GSH) has been postulated to be an important activator of HMG-CoA reductase in vivo. HMG-CoA reductase activity was assayed in cultured fibroblasts from healthy children. Solubilized enzyme preparations were prepared by ultracentrifugation after freezing and thawing of fibroblasts. Such treatment increased the relative enzyme activity markedly. Enzymological assay conditions were established. Addition of GSH stimulated the reaction, whereas there was inhibition after addition of glutathione disulphide (GSSG). The inhibitory effect of GSSG could be reversed by the addition of excess GSH. Fibroblast preparations, deficient in GSH, were obtained from children with glutathione synthetase deficiency or from normal subjects after the growth of fibroblasts in the presence of buthionine sulphoximine. Solubilized enzyme preparations from GSH-deficient fibroblasts had HMG-CoA reductase activities lower than or comparable with those of control preparations. The results indicate only some reduction in the capacity for cholesterol synthesis in subjects with glutathione deficiency. The existence of additional activation mechanisms in vivo, alternative to GSH, for thiol-dependent modulation of HMG-CoA reductase activity seems likely.
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PMID:Cholesterol synthesis in patients with glutathione deficiency. 212 8

Sertoli cells play a major role in the regulation of spermatogenic cell energy metabolism and differentiation. This study demonstrates that Sertoli cells are essential for the maintenance of spermatogenic cell glutathione (GSH), an important intracellular reductant and detoxicant. Primary spermatocytes and round spermatids isolated from Xenopus laevis contained 1.5 +/- 0.1 mM GSH, but sperm lacked detectable GSH. During a 5-day culture period, isolated spermatocytes and spermatids lost 80% of the initial GSH (t 1/2 = 55 h). The levels of GSH were unaffected by L-buthionine-SR-sulfoximine (BSO), a selective inhibitor of GSH synthesis. Cultures of testicular lobules and spermatocysts (composed of germ cells and Sertoli cells) depleted of interstitial tissue lost only 30% of their initial GSH in 4.5 days; the GSH levels decreased during treatment with BSO. Spermatogenic cells in cultured testes maintained their GSH levels for 7 days by a BSO-sensitive mechanism. These results demonstrate that the intracellular GSH levels of spermatogenic cells are dependent upon germ cell-somatic cell interactions. Spermatogenic cells were shown to possess gamma-glutamyl transpeptidase, glutathione synthetase, 5-oxoprolinase, and gamma-glutamylcysteine synthetase activities. [35S] Cysteine incorporation and distribution as analyzed by high performance liquid chromatography (HPLC) showed that isolated spermatogenic cells are capable of GSH synthesis. The rate of GSH synthesis, however, was insufficient to compensate for GSH turnover. These results demonstrate that production of spermatogenic cell GSH is dependent upon Sertoli cells. To our knowledge, this is the first evidence that interactions between different cell types may be of significance in GSH metabolism.
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PMID:Spermatogenic cell-somatic cell interactions are required for maintenance of spermatogenic cell glutathione. 272 29

The oxidized form of glutathione transport was studied in human erythrocytes in pyrimidine 5'-nucleotidase (P5N) deficiency, a disorder in which the amounts of CTP and UTP in the erythrocytes are elevated. The inhibition of ATP-requiring oxidized glutathione (GSSG) transport by CTP and UTP is believed to play a role in elevating the levels of the reduced form of glutathione (GSH) in the erythrocytes of patients with P5N deficiency. The current investigation was undertaken to determine if GSSG transport actually decreases in the erythrocytes of such patients. Erythrocytes from a 17-year-old patient and a 13-year-old patient with P5N deficiency hemolytic anemia and from ten normal subjects were used as materials for the experiment. Erythrocytes, which had been previously incubated with [3H]glycine, were incubated at 37 degrees C, and the rate of [3H]GSSG transported by the cells was estimated. The velocity of GSSG transport out of the erythrocytes was quite low in the patients, 3.17-3.65 nmol GSSG/ml erythrocytes/hr at 37 degrees C in one case, and 3.30 nmol GSSG/ml erythrocytes/hr in the other case, vs that in the normal controls (6.00 +/- 0.80 nmol GSSG/ml erythrocytes/hr; mean +/- SD). The activity of gamma-glutamylcysteine synthetase and glutathione synthetase did not decrease in the patients. Decreased transport activity of GSSG in addition to a normal synthesis rate for GSH may explain the increased concentration of erythrocyte GSH in P5N deficiency.
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PMID:Erythrocyte-oxidized glutathione transport in pyrimidine 5'-nucleotidase deficiency. 288 6

The zonal distribution of GSH metabolism was investigated by comparing hepatocytes obtained from the periportal (zone 1) or perivenous (zone 3) region by digitonin/collagenase perfusion. Freshly isolated periportal and perivenous cells had similar viability (dye exclusion, lactate dehydrogenase leakage and ATP content) and GSH content (2.4 and 2.7 mumol/g respectively). During incubation, periportal cells slowly accumulated GSH (0.35 mumol/h per g), whereas in perivenous cells a decrease occurred (-0.14 mumol/h per g). Also, in the presence of either L-methionine or L-cysteine (0.5 mM) periportal hepatocytes accumulated GSH much faster (3.5 mumol/h per g) than did perivenous cells (1.9 mumol/h per g). These periportal-perivenous differences were also found in cells from fasted rats. Efflux of GSH was faster from perivenous cells than from periportal cells, but this difference only explained 10-20% of the periportal-perivenous difference in accumulation. Furthermore, periportal cells accumulated GSH to a plateau 26-40% higher than in perivenous cells. There was no significant difference in gamma-glutamylcysteine synthetase or glutathione synthetase activity between the periportal and perivenous cell preparations. The periportal-perivenous difference in GSH accumulation was unaffected by inhibition of gamma-glutamyl transpeptidase or by 5 mM-glutamate or -glutamine, but was slightly diminished by 2 mM-L-methionine. This suggests differences between periportal and perivenous cells in their metabolism and/or transport of (sulphur) amino acids. Our results suggest that a lower GSH replenishment capacity of the hepatocytes from the perivenous region may contribute to the greater vulnerability of this region to xenobiotic damage.
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PMID:Glutathione replenishment capacity is lower in isolated perivenous than in periportal hepatocytes. 290 50

A single acute dose of carbon disulfide (CS2, 5 mmol/kg ip) caused hepatic damage in rats pretreated with phenobarbital. Rats pretreated with phenobarbital and cobaltous chloride (CoCl2, 250 mumol/kg sc) were protected against CS2 induced hepatotoxicity. When single acute doses of CS2 and CoCl2 were given at the same time, however, rats developed a much more severe hepatic lesion than that seen following CS2 alone. Similar cotreatment of CoCl2 with bromobenzene, carbon tetrachloride or thioacetamide did not enhance the hepatotoxicity of these well-studied hepatotoxins. Additionally, other divalent metal salts (CuSO4 and ZnCl2) did not enhance CS2 hepatotoxicity. Hence, the interaction between CS2 and CoCl2 (that results in enhanced CS2 induced hepatic damage) appears to be relatively specific for these two agents. CS2 caused an approximate 50% decrease in hepatic cytochrome P-450 when given alone, but an approximate 85% decrease when given with CoCl2. This observation supports the hypothesis that the breakdown products of cytochrome P-450 heme are responsible for CS2 induced hepatotoxicity. In addition, single doses of CS2 or CoCl2 caused increases of 30 to 60% in hepatic glutathione (GSH), but additive responses were not obtained when the two agents were given at the same time. GSH synthetase and gamma-glutamyl transpeptidase activity were inconsistently changed by these treatments, and did not provide a consistent explanation for the increases in GSH. The enhanced hepatotoxicity of CS2 + CoCl2 is not due to changes in hepatic glutathione metabolism.
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PMID:Paradoxical effect of cobaltous chloride on carbon disulfide induced hepatotoxicity in rats. 317 44

Ethylene dichloride (EDC) is metabolized by two competing pathways both of which consume glutathione (GSH). EDC undergoes oxidation to form chloroacetaldehyde (CAA) which is detoxified by GSH and also reacts directly with GSH to form 2-(s-chloroethyl)-GSH. A physiological pharmacokinetic model developed for EDC was extended to describe tissue GSH turnover and its depletion after EDC exposures. This GSH model was necessary to keep track of GSH concentrations with time, as EDC metabolism is affected by GSH status. Reactions of GSH with EDC and GSH with CAA were defined as second-order. Steady-state GSH formation was modeled as zero-order and GSH loss as first-order. GSH rebound effects after its depletion were controlled by a GSH synthetase reaction, which allowed time- and GSH concentration-dependent feedback for increased GSH resynthesis. The model was developed for liver GSH in the rat and was extrapolated to include the lung. Allometric scaling was used to extrapolate the model to other animal species. Experimental observations in the rat and mouse were consistent with model predictions.
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PMID:Physiological model for tissue glutathione depletion and increased resynthesis after ethylene dichloride exposure. 336 6

In order to examine the role of cellular glutathione (GSH) in the in vitro aging of human diploid fibroblasts, we studied the effects of manipulated cellular GSH levels on their in vitro life span. An increase in cellular GSH level was produced by the addition of N-acetylcysteine (NAC), a carrier of cysteine across cell membranes, into the culture medium, while a decrease in GSH level was produced by the addition of L-buthionine-(R,S)-sulfoximine (BSO), a specific inhibitor of GSH synthetase. When the cells were serially subcultivated in a medium containing NAC or BSO, their life spans were markedly extended or shortened, respectively, in comparison to the life span of cells grown in a control medium. These results suggest that the cellular GSH level is a determinant of the in vitro life span of human diploid cells.
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PMID:Relationships between the cellular glutathione level and in vitro life span of human diploid fibroblasts. 340 54

The activity and the kinetic properties of glutathione synthetase and the concentrations of non-protein bound thiols of the gamma-glutamyl cycle were measured in 11 human fibroblast cell strains. Six of these strains were derived from patients suffering from 5-oxoprolinuria, a recessive genetic disease characterized by a deficiency in glutathione synthetase; the other cell strains were derived from healthy heterozygous or homozygous relatives of the patients. The glutathione synthetase activities of homozygous deficient strains were 1/3 of control values while those of heterozygous strains were 2/3 of control values. The total thiol concentration was lower in only 3 of the 6 deficient homozygotes and that of glutathione (GSH) was lower in only 4 of the 6 deficient homozygotes. This lower GSH level was at least partly offset by an accumulation of gamma-glutamylcysteine, a precursor of GSH, which is almost completely absent from control cells. The total quantities of thiols and GSH in plateau phase cells were about 50% and 30% respectively of the levels in growth phase cells. Approximately 80% of the GSH was in the reduced form in both quiescent and growing cells.
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PMID:Low molecular weight thiol content in glutathione synthetase-deficient human fibroblasts. 343 51


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