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

---

Query: EC:2.5.1.47 (cysteine synthase)
625 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of glutathione (GSH) depletion by isoniazid (INH) was studied in M. smegmatis. INH increased the activity of gamma-glutamyl transferase (GGT) whether added before medium inoculation or to actively growing cells. The activity of GGT in cells grown from the beginning in INH-containing medium increased significantly on growth days 2-6. Three-day old M. smegmatis cells treated with INH exhibited a 30-65% increase in the activity of GGT. The activities of gamma-glutamyl-cysteine synthase (GGCS) and GSH synthase (GS) were lowered by 50 and 56% respectively on the second day of growth when M. smegmatis was grown in a medium supplemented with 1.5 mg INH per L. In 3-day old M. smegmatis, INH significantly inhibited the activities of GSH biosynthetic enzymes. The results demonstrate that the increased activity of GGT and decreased activities of GSH biosynthetic enzymes are responsible for GSH depletion by INH in M. smegmatis.
...
PMID:Effect of isoniazid on glutathione biosynthesis and degradation in Mycobacterium smegmatis. 855 25

We investigated the effect of intracellular glutathione (GSH) levels on apoptosis in KB cells induced by cisplatin (CDDP). The mode of cell death, apoptosis or necrosis, was evaluated by biochemical and morphological criteria. The treatment of KB cells with D,L-buthionine-(S,R)-sulfoximine (BSO, a gamma-glutamyl cysteine synthetase inhibitor) decreased GSH level to 1/7th of that of control cells, and augmented cell death induced by CDDP via a necrotic rather than apoptotic process (the ratio of necrosis to apoptosis; n/a>14). In contrast, treatment with 2-oxothiazolidine-4-carboxylic acid (OTZ, a precursor of cysteine) increased GSH levels 1.7 fold compared with that of untreated cells, inhibited cell death induced by CDDP and switched the mode of cell death from necrosis to apoptosis (n/a<0.8, similar to untreated cells). These results suggest that the GSH level affects the cytotoxicity of CDDP and plays an important role in switching the mode of cell death induced by CDDP.
...
PMID:Involvement of intracellular glutathione in induction of apoptosis by cisplatin in a human pharyngeal carcinoma cell line. 868 13

Elevation of glutathione (GSH) is commonly observed in cellular resistance to a number of anticancer agents. Most frequently reported change in GSH metabolism that is associated with the elevated GSH levels is increased mRNA expression and activity of gamma-glutamyl cysteine synthetase (gamma GCS), the first enzyme of the GSH biosynthetic pathway. We have isolated sublines of the A2780 ovarian carcinoma cell line (C10 and C25) that are 8- and 12-fold resistant to oxaliplatin by repeatedly exposing the cells to increasing concentrations of the platinum agent. The GSH levels in C10 and C25 cell sublines are 3.1- and 3.8-fold higher than the parent A2780 cell line. The mRNA levels and activities for gamma GCS and that for gamma-glutamyl transpeptidase (gamma GT), the GSH salvage pathway enzyme, were measured in these cells. The mRNA for gamma GT and gamma GCS were measured by RT-PCR, with quantitation of the PCR product by HPLC; mRNA levels are expressed as ratios to beta-actin mRNA, used as an endogenous standard. GSH and gamma GCS activity were measured by HPLC assays and gamma GT activity by a colorimetric assay. The increase in GSH in C10 and C25 was associated with an elevation in gamma GT mRNA (2.5- and 8-fold) and gamma GT activity (2.7- and 2.8-fold). No changes were observed in gamma GCS mRNA levels or activity. The data indicate that alterations in GSH metabolism leading to elevations in cellular GSH in A2780 ovarian carcinoma cells selected for low levels of resistance to oxaliplatin are mediated by gamma GT, the "salvage' pathway, rather than an increase in GSH biosynthesis.
...
PMID:Altered glutathione metabolism in oxaliplatin resistant ovarian carcinoma cells. 868 32

The steady state expression of glutathione S-transferases (GSTs) at both the protein and mRNA level is reported for the 60 tumor cell lines that are used for the National Cancer Institute Drug Screening Program. Individual GST isozymes were separated, identified, and quantified (with reverse-phase calibration curves) through a novel high performance liquid chromatographic procedure. GSTP1 was the predominant isozyme and was found at quantifiable levels in all but two of the cell lines. This isozyme ranged from 0.03% to 2.7% of the total cytosolic protein. For the mu family, 90% of the lines had GSTM2, 68% had GSTM3, but only 28% were positive for the M1 phenotype. The M1 proportion is lower than would be expected from the standard M1 null phenotype for human populations. Isozymes of the alpha family were detected only at very low levels in 35% of the lines. Significant quantitative correlations among enzyme activity, total enzyme protein, and mRNA were shown for GSTP1. However, such relationships were not apparent for the mu or alpha families. Levels of glutathione (GSH), and the transcript levels of other enzymes involved in GSH homeostasis were determined. gamma-Glutamyl cysteine synthetase (gamma-GCS) was present in all cell lines, but did not correlate with levels of intracellular GSH. Glyoxalase-I and gamma-glutamyl transpeptidase, both involved in GSH salvage, were found in 100% and 70% of the cell lines, respectively. Using a pattern-matching computer program, COMPARE, we compared and correlated the arrays of mRNA and protein levels with the pattern of chemosensitivity or chemoresistance of the 60 cell lines with 175 agents constituting a standard agent database. This database is composed of compounds to which a putative mechanism of action has been assigned. Although Pearson correlation coefficients relating the target and drug patterns were generally modest, when the patterns for the enzyme protein and mRNA levels for GST pi were correlated to drug sensitivity patterns, the list of 30 agents most closely matching (for which P < 0.05) was enriched with alkylating agents. gamma-GCS also showed an enrichment of alkylating agents in the COMPARE correlations, indicating that high levels of gamma-GCS may be an important determinant of resistance. In contrast, none of the other enzymes or GSH had patterns of expression that resulted in an obvious correlation to the sensitivity or resistance of alkylating agents.
...
PMID:Glutathione-associated enzymes in the human cell lines of the National Cancer Institute Drug Screening Program. 870 Jan 7

It has previously been found that chronic O2 deficiency decreases activity of the enzymes of the glutathione (GSH) redox system in the liver. To study the effects of O2 deficiency on intestinal detoxication capacity, pair-fed (16 g food/day) Sprague-Dawley rats were exposed to air (20.9% O2; n = 4) or 10% O2 (n = 4) for 10 days. Animals were killed, and intestinal mucosal homogenate (20% wt/vol) was obtained and assayed for activities of glucose-6-phosphate dehydrogenase (G6PD), GSH peroxidase (GSHPx), GSH disulfide reductase (GSSGRd), and gamma-glutamyl cysteine synthetase (gamma-GCS). Hypoxia decreases activities of GSHPx, GSSGRd, and gamma-GCS by approximately 50%, which suggests compromised detoxication. A proximal-to-distal reduction in enzymatic capacity indicates impairment of detoxication may be more pronounced in the distal intestine. G6PD, a key enzyme in NADPH production, remains unchanged. Urinary malondialdehyde was also monitored. Hypoxic rats exhibited a threefold increase in thiobarbituric acid-reactive substance, consistent with a generalized oxidative stress in these animals. Taken together, the results indicate that chronic hypoxia promotes tissue oxidative stress and impairs the ability of the enterocyte to metabolize ingested oxidants.
...
PMID:Chronic hypoxia and glutathione-dependent detoxication in rat small intestine. 892 4

Nigral cell death in Parkinson's disease (PD) may involve oxidative stress and mitochondrial dysfunction initiated by a decrease in reduced glutathione (GSH) levels in substantia nigra. L-buthionine-(S,R)-sulphoximine (BSO; 4.8 and 9.6 mg/kg/day), an irreversible inhibitor of gamma-glutamyl cysteine synthetase, was chronically infused into the left lateral ventricle of rats over a period of 28 days and markedly reduced GSH concentrations in substantia nigra (approx. 59% and 65% in 4.8 and 9.6 mg/kg/d BSO respectively) and the striatum (approx. 63% and 80% in 4.8 and 9.6 mg/kg/d BSO respectively). However, the number of tyrosine hydroxylase (TH)-positive cells in substantia nigra was not altered by BSO-treatment compared to control animals. Similarly, there was no difference in specific [3H]-mazindol binding in the striatum and nucleus accumbens of BSO-treated rats compared to control rats. In conclusion, depletion of GSH following chronic administration of BSO in the rat brain does not cause damage to the nigrostriatal pathway and suggests that loss of GSH alone is not responsible for nigrostriatal damage in PD. Rather, GSH depletion may enhance the susceptibility of substantia nigra to destruction by endogenous or exogenous toxins.
...
PMID:Glutathione depletion in rat brain does not cause nigrostriatal pathway degeneration. 908 94

We have previously observed that transforming growth factor beta 1 (TGF beta 1) produces a pro-oxidant effect and decreases cellular glutathione (GSH) levels of cultured bovine pulmonary artery endothelial cells (BPAEC) (White A. C., S. K. Das, and B. L. Fanburg. Am. J. Respir. Cell Mol. Biol. 6:364-368, 1992). In the present studies we demonstrate that 2 ng/ml TGF beta 1 reduces the uptake of two GSH precursor amino acids (cystine and glutamate) by 50% (cystine; control 359.35 +/- 100, TGF beta 1 187.7 +/- 26 pmol/10 min/10(6) cells, p < 0.05; glutamate; control 215.15 +/- 18, TGF beta 1 110.2 +/- 16 pmol/10 min/10(6) cells, p < 0.001). The inhibitory effect of TGF beta 1 on the uptake of GSH precursor amino acids persisted in the presence of buthionine sulfoximine (inhibits gamma-glutamyl cysteine synthetase, the rate limiting step in GSH synthesis) or acivicin (inhibits gamma-glutamyl transpeptidase). The uptake of leucine, an amino acid that does not serve as a precursor for GSH, was unaffected by TGF beta 1. In additional experiments TGF beta 1 decreased the levels of cellular and medium GSH-indicating that TGF beta 1 did not increase efflux of GSH from BPAEC. We propose from these observations that TGF beta 1 decreases cellular glutathione, at least in part, through down regulation of precursor amino acid transport and, thereby, its rate of synthesis.
...
PMID:Transforming growth factor B1 decreases uptake of glutathione precursor amino acids in bovine pulmonary artery endothelial cells. 914 17

Time-dependent alterations in glutathione (GSH) concentration and the activities of several key enzymes of GSH metabolism were studied in a rat model of experimental Fanconi syndrome induced by i.p. injection of sodium maleate (400 mg/kg BW). The changes in the parameters tested were monitored 0, 2, 4, and 12 h after sodium maleate administration. A significant decrease in renal GSH level was observed 2 and 4 h after sodium maleate treatment (27% and 38% of control values, respectively). The renal GSH depletion did not appear to be due to the decreased production rate or to an increased degradation of the tripeptide. This suggestion is based on the findings that the activities of the GSH synthesis (gamma-glutamyl cysteine synthetase and glutathione reductase) and those of the catabolic pathways (gamma-glutamyl transpeptidase) were unaltered at the same time points. The unchanged activity of gamma-glutamyl transpeptidase also suggests preserved luminal membrane integrity in experimental Fanconi syndrome. The decreased activity of glutathione peroxidase, which utilizes GSH as a cosubstrate in the course of inactivation of free radicals, in the first hours after treatment could facilitate lipid peroxidation reactions in this model of acute renal failure. The observed changes in all parameters tested were transient, with recovery to baseline levels in a period of 12 h after sodium maleate administration. At the same time a pronounced functional impairment still existed. The beneficial effect of fast recovery of renal GSH level on the functional and morphological restitution in experimental Fanconi syndrome is suggested.
...
PMID:Time course of renal glutathione levels in experimental Fanconi syndrome: an enzyme-based approach. 915 54

Overproduction of reactive oxygen intermediates (ROI) may have an important role in the pathophysiology of lipopolysaccharide-mediated liver-injury. This study examined the role of cytosolic and mitochondrial glutathione in protecting hepatocytes from oxidative stress during exposure to lipopolysaccharide. In addition, the possible participation of changes of inner mitochondrial membrane permeability in lipopolysaccharide-induced hepatotoxicity was investigated. The changes of hepatic glutathione content following lipopolysaccharide challenge (2 mg/kg) were measured in mice by reverse-phase high-performance liquid chromatography. Glutathione depletion and a glutathione-rich state were produced by intraperitoneal administration of a specific inhibitor of gamma-glutamyl cysteine synthetase, buthionine sulfoximine (3 mmol/kg), and by administration of glutathione monoethyl ester (10 mmol/kg), respectively. Intracellular ROI generation and the mitochondrial membrane potential were quantified by flow cytometry. Changes of inner mitochondrial membrane permeability in hepatocytes were assessed by radioactive sucrose entrapment. There was increased production of ROI along with depletion of cellular and mitochondrial glutathione in the liver after lipopolysaccharide administration. There was also a change of inner mitochondrial membrane permeability in hepatocytes, with the loss of coupled functions. Buthionine sulfoximine decreased the hepatic antioxidant capacity, worsened mitochondrial function, and reduced the survival rate of the mice. In contrast, glutathione monoethyl ester improved all of these parameters. Glutathione may have an important role in cellular defenses against lipopolysaccharide-induced liver damage in mice, and excessive oxidative stress may precipitate the mitochondrial membrane permeability transition in hepatocytes and lead to cell death.
...
PMID:Lipopolysaccharide-mediated hepatic glutathione depletion and progressive mitochondrial damage in mice: protective effect of glutathione monoethyl ester. 922 27

Cadmium (Cd) is a highly toxic metal and a known carcinogen. Although the carcinogenic mechanism of action is unknown, Cd will induce transcriptional activation of c-myc and c-jun. We have previously found that the extent of Cd-induced oncogene expression is limited by the presence of cellular metallothionein (MT) in rat L6 myoblasts. Glutathione (GSH) is thought to play an important role in protection against Cd before the onset of MT synthesis. Thus, this study examined the effects of GSH depletion on Cd-induced MT synthesis, cytotoxicity, and proto-oncogene expression in rat L6 myoblasts after pretreatment with L-buthionine sulfoximine (BSO), a potent inhibitor of gamma-glutamyl-cysteine synthetase, which effectively depletes GSH. Exposure of L6 cells to BSO (5 or 25 microM) resulted in a dose-dependent decrease in cellular GSH levels. GSH depletion had no effect on Cd- or zinc-induced MT synthesis. Although the depletion of GSH was not itself cytotoxic in L6 cells, BSO pretreatment, particularly at the higher dose (25 microM), resulted in a dose-dependent increase in the sensitivity to Cd cytotoxicity, as assessed by a tetrazolium-based dye (MTT) assay. Low levels of Cd (1 microM) slightly increased the expression of both c-myc and c-jun as assessed by increases in gene-specific mRNA levels, in accordance with previous studies. GSH depletion (5 muM BSO) likewise caused an increase in expression of c-myc and c-jun. However, combined GSH depletion and Cd exposure decreased levels of c-myc and c-jun transcription well below control levels. These results suggest that increased cytotoxicity resulting from exposure to Cd after BSO depletion of cellular GSH abrogates the oncogene activation observed after either treatment alone. Thus proto-oncogene expression induced by Cd appears to be dependent on the absence of over Cd-induced cytotoxicity.
...
PMID:Effects of glutathione depletion on cadmium-induced metallothionein synthesis, cytotoxicity, and proto-oncogene expression in cultured rat myoblasts. 924 31


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---