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

1-Cyano-2-hydroxy-3-butene (CHB), an aliphatic nitrile found in cruciferous vegetables, causes a two- and sevenfold elevation in reduced glutathione (GSH) in rat liver and pancreas, respectively, after oral administration of 200 mg/kg. While this dose is also associated with pancreatotoxicity, a single 100 mg/kg dose or multiple lesser doses show the same effect, although somewhat reduced in magnitude, with no concomitant toxicity. In an attempt to identify the mechanism of this increase, we investigated the effect of CHB on GSH synthesis by examining the effect of buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, on CHB-induced GSH elevation. Male Fischer 344 rats received 3 mmol BSO/kg ip 24 and 34 hr following CHB or corn oil. The CHB-mediated elevation in hepatic and pancreatic GSH was eradicated by BSO, suggesting that increased synthesis was responsible. The rate-limiting step in synthesis is gamma-glutamyl cysteine synthetase (GCS); the limiting substrate is cysteine. Therefore, CHB effects on GCS activity and hepatic and pancreatic cysteine equivalents were investigated. When rats were treated by gavage with CHB (100 mg/kg), hepatic GCS mRNA concentrations were increased 24 hr after treatment and hepatic cysteine equivalents were significantly elevated 4 hr following CHB. No significant elevation in hepatic GCS activity was observed, however, even 24 hr following CHB. Pancreatic cysteine equivalents were elevated at both 4 and 8 hr after CHB treatment. However, there was no detectable GCS mRNA or activity in pancreas, in either control or treated animals. Furthermore, CHB had no direct effect on the activity of GCS purified from kidney, regardless of whether GSH was present or absent. These results suggest that the mechanism of CHB-mediated induction of GSH may involve early increases in GSH precursors as well as a later increase in GCS mRNA. The mechanism of GSH elevation identified in these studies may hold therapeutic or prophylactic implications.
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PMID:Differential effect of cyanohydroxybutene on glutathione synthesis in liver and pancreas of male rats. 790 18

A cis-diamminedichloroplatinum (II) (CDDP)-resistant cell line (NOS2CR) demonstrated 7.4-fold greater resistance to CDDP compared with the parental cell line (NOS2) established from a patient with serous cystadenocarcinoma of the ovary. We investigated the role of enzyme systems associated with glutathione (GSH) in these cell lines. The GSH content was almost identical in both cell lines. Preincubation with 50 microM DL-buthionine-S, R-sulfoximine (BSO), an inhibitor of gamma-glutamyl cysteine synthetase, for 24 hr reduced the IC50 in both NOS2 and NOS2CR cells. Glutathione-S-transferase pi (GST-pi) activity and mRNA level in NOS2CR cells were higher than in NOS2 cells. However, gamma-glutamyltranspeptidase (GGT) activity in NOS2CR cells was 2.4-fold less than in NOS2 cells. The GST activity and mRNA level in both cell lines were constant when the cells were exposed to CDDP. Exposure to CDDP for 48 hr increased the GGT mRNA level 4.4 and 1.8 times in NOS2 and NOS2CR cells, respectively, compared with no exposure. By exposure to CDDP for 48 hr, the GGT activities in NOS2 and NOS2CR cells were increased 1.6-and 2.5-fold, respectively, compared with no exposure. The above data provide the first evidence that GGT activity and GGT mRNA are induced by CDDP in human carcinoma cell lines.
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PMID:Glutathione related enzymes in cis-diamminedichloroplatinum (II)-sensitive and-resistant human ovarian carcinoma cells. 790 18

We have measured glutathione content in small tissue samples derived from biopsies of primary and metastatic human colon tumors and from colon cancer cell lines in tissue culture and xenografts in athymic mice. Measurements were performed using an enzymatic cycling assay designed to quantitate extremely low levels of glutathione (GSH) (down to 10(-14) mol) from perchlorate extracts of tissue samples weighing less than 1 mg wet weight. Glutathione was stable in these acid extracts for at least 6 months when stored at -80 degrees C. A survey of normal tissues in mice, rats, and some human tissues showed considerable variation in GSH content of different tissues but generally similar levels were identifiable for the same tissues from different species. The highest GSH level was 56.9 nmol/mg protein in rat liver and the lowest was 1.8 nmol/mg protein in rat skeletal muscle. High GSH levels were also determined in mouse and human liver, while low GSH levels were detected in mouse muscle. Human colon cancer cell lines showed slightly higher GSH levels than did colon cancer tumor samples obtained from biopsies. These studies revealed a marked inter-individual difference in tumor GSH content, as well as a difference in GSH content between tumor deposits at different metastatic sites in the same individual. These results indicate the importance of direct tumor measurements of GSH content in clinical trials designed to modulate tumor glutathione content to try to increase sensitivity to chemotherapy or radiation therapy. Buthionine sulfoximine, an inhibitor of gamma-glutamyl cysteine synthetase, was shown to produce almost complete depletion of GSH in four different human colon cancer cell lines in 24 h. Buthionine sulfoximine was also shown to be capable of producing drastic depletion of GSH in human colon cancer grown as xenografts in athymic animals.
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PMID:Sensitive enzymatic cycling assay for glutathione: measurements of glutathione content and its modulation by buthionine sulfoximine in vivo and in vitro in human colon cancer. 803 40

We examined the relationship between cellular glutathione (GSH) level and susceptibility to lymphokine-activated killer (LAK) cell-mediated cytolysis in KB human pharyngeal carcinoma cells. Treatment of KB cells with D,L-buthionine-S,R-sulfoximine (BSO), a gamma-glutamyl cysteine synthetase blocker, resulted in decreased total intracellular GSH levels associated with increased susceptibility to LAK killing. In contrast, treatment with oxothiazolidine-4-carboxylate (OTZ, a precursor of cysteine), which is known to increase cellular GSH level, decreased the susceptibility of KB cells to LAK killing. Both agents had no effects on binding frequency of KB cells to LAK cells. These results suggest that intracellular GSH in tumor cells play a protective role against LAK mediated cytolysis, specially in the post-binding killing phase.
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PMID:Relationship between cellular glutathione level and susceptibility to LAK killing in human pharyngeal carcinoma cell line. 807 61

Previous studies in our laboratory have shown that the ontogenic development of gamma-glutamyltranspeptidase (gamma-GTP) activity is delayed by the in utero administration of alcohol. gamma-GTP is responsible for the degradation and recycling of glutathione (GSH) via the gamma-glutamyl cycle. In this study, we examined the effects of the in utero administration of alcohol on GSH levels in gestational age 21-day-old (g21) rats. Pregnant rats were placed on a liquid diet containing either 35% ethanol-derived calories (35% EDC) or a pair-fed (PF) diet or a lab chow (LC) diet starting on day 1 of gestation and maintained on their respective diets until gestational day 21. On gestational day 21, the pups were delivered by Cesarean section and brains and livers removed and prepared for analysis of GSH, gamma-GTP, or gamma-glutamyl-cysteine synthetase (gamma-GCSyn). GSH levels in brain and liver were found to be significantly lower in the offspring of the 35% EDC-treated mothers than from the PF and LC controls. gamma-GTP activity was higher in brain and liver of the 35% EDC group than the PF group. gamma-GCSyn, the enzyme involved in the rate-limiting step of GSH synthesis, was not affected in liver, but was found to be decreased in brain of the 35% EDC and PF groups when compared with the LC group. GSH is involved in many cellular reactions that appear to protect the cell from damage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of in utero administration of alcohol on glutathione levels in brain and liver. 810 12

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.
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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.
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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.
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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.
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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.
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PMID:Chronic hypoxia and glutathione-dependent detoxication in rat small intestine. 892 4


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