Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1260386 (GSH)
 38,102 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the liver is recognized as a major site of glutathione (GSH) synthesis, it is thought to play only a minor role in GSH catabolism. This is primarily because in the rat, the most commonly used experimental animal, hepatic gamma-glutamyltransferase (gamma-GT) activity is very low, whereas kidney activity is quite high. gamma-GT is the only enzyme known to catalyze the initial step in GSH degradation. The present work compares gamma-GT and dipeptidase activities in liver, kidney, and gallbladder of six mammalian species to assess the importance of hepatobiliary catabolism of GSH, relative to renal degradation. Marked species differences were observed in gamma-GT activities, and in kidney to liver (K/L) ratios for both gamma-GT concentration (milliunits/mg protein) and whole organ activities (total activity per liver or two kidneys). The K/L concentration ratios for gamma-GT activities ranged from 875 in the rat to 15 in the guinea pig. Whole organ gamma-GT ratios were approximately 150 in mouse and rat, and only 2-5 in guinea pig. pig, and macaque. Human K/L ratios calculated from gamma-GT activities reported previously were similar to those of the guinea pig. Species differences were also observed in K/L ratios for dipeptidase activities, though these differences were not as large as those for gamma-GT, gamma-GT and dipeptidase activities were also measured in gallbladders of all species examined (except rat which does not have this organ), and were found to be comparable to those of liver. These results suggest that in species such as the guinea pig and perhaps humans, the liver and biliary tree play a prominent role in GSH turnover. Because of the low hepatic and high renal gamma-GT activities of the rat, and because it does not have a gallbladder, this species may not be the best model for studying the catabolism of GSH and GSH conjugates. Use of the rat model may underestimate the contribution of liver, and overestimate that of kidney, in these degradative processes.
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PMID:Glutathione-degrading capacities of liver and kidney in different species. 197 72

The mechanism of the renal uptake of methylmercury was studied in mice. Preadministration of 1,2-dichloro-4-nitrobenzene (DCNB), which is a reagent that depletes hepatic glutathione (GSH) without affecting the renal GSH level, 30 min before injection of methylmercury significantly decreased the renal accumulation of mercury. The renal accumulation of mercury in mice receiving methylmercury-GSH intravenously was significantly higher than that in mice receiving methylmercuric chloride. These results suggest the possibility that hepatic GSH, as a source of extracellular GSH, plays an important role in the renal accumulation of methylmercury. No significant difference in renal mercury accumulation between bile duct-cannulated mice and normal mice was observed, indicating that the enterohepatic circulation of methylmercury is not an important factor in the renal accumulation of methylmercury in mice. Pretreatment of mice with acivicin, a potent inhibitor of gamma-glutamyl transpeptidase (gamma-GTP), significantly depressed the renal uptake of methylmercury and increased the urinary excretion of GSH and methylmercury. In in vitro reactions, methylmercury-GSH was degraded into methylmercury-cysteinylglycine by gamma-GTP, and this product was then converted to methylmercury-cysteine by dipeptidase. These results suggest that methylmercury is transported into the kidney as a complex with GSH, and then incorporated into the renal cells after degradation of the GSH moiety by gamma-GTP and dipeptidase, although the methylmercury bound to extracellular GSH can be reversibly transferred to plasma proteins in the bloodstream.
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PMID:Possible role of hepatic glutathione in transport of methylmercury into mouse kidney. 334 85

Monolayers of LLC-PK1 cells, a cell line with features typical of proximal tubular epithelial cells, were treated at the apical and basolateral side with S-(1,2,3,4,4-pentachlorobutadienyl)glutathione (PCBD-GSH) and N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine (PCBD-NAC). Apical treatment with PCBD-GSH (greater than 20 microM) resulted in cytotoxicity, which could be inhibited by acivicin and aminooxyacetic acid (AOAA), inhibitors of gamma-glutamyltranspeptidase (gamma GT) and beta-lyase respectively. In contrast apical treatment with PCBD-NAC was only toxic at high concentrations (greater than 850 microM), and this effect could hardly be inhibited by AOAA. Basolateral treatment of confluent LLC-PK1 monolayers, grown on porous membranes, with PCBD-GSH gave a much smaller response than apical treatment, consistent with the fact that gamma GT is predominantly present at the apical side. Basolateral treatment even with high concentrations of PCBD-NAC (1.1 mM) did not show an increase in cytotoxicity when compared to the effect after apical treatment. These results suggest the absence of an organic anion transporter, by which these conjugates in vivo are transported into the cells from the basolateral side. This supposition was substantiated in a study of transcellular transport of the model ions tetraethyl ammonium (TEA) and para-aminohippurate (PAH), in LLC-PK1 monolayers, grown as indicated above. No active PAH transport could be demonstrated, whereas an active TEA transport was present. The absence of an organic anion transporter limits the usefulness of LLC-PK1 cells for the study of nephrotoxicity of compounds, like PCBD-NAc, needing this transport to enter the cells. However, the finding of an active basolateral organic cation transporter, together with the presence of gamma GT, dipeptidase and beta-lyase, makes this system especially interesting for testing all compounds that use this transporter or these enzymes in order to elicit toxicity.
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PMID:Differential toxicity as a result of apical and basolateral treatment of LLC-PK1 monolayers with S-(1,2,3,4,4-pentachlorobutadienyl)glutathione and N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine. 337 80

Murine L1210 leukemia cells resistant to the antineoplastic agent L-phenylalanine mustard have a 1.5-2.0-fold elevation in their cellular GSH and GSSG content as compared to drug-sensitive cells. Cellular uptake of L-[U-14C]cystine and its incorporation into GSH of the resistant tumor are correspondingly elevated. Synthesis of gamma-glutamylcysteine, GSH, and GSSG is elevated 1.5-2.0-fold in cell-free preparations of the resistant tumor. This increased synthesis of GSH is attributed to increased cellular content (1.6-fold) of gamma-glutamylcysteine synthetase. GSH synthetase activity is equivalent in both drug-sensitive and -resistant cells. Investigation into the hydrolysis of selected peptides by cell-free preparations of both sensitive and resistant tumors suggest that aminopeptidase M participates in the formation of L-cysteine from L-Cys-Gly. This is supported by the observation that these preparations readily degrade L-Leu-p-nitroanilide and L-Ala-L-Ala-L-Ala, known substrates for aminopeptidase M, but not dipeptidase. The failure of the tumors to degrade Gly-D-Ala, a dipeptidase substrate, and the marked inhibition of L-Ala-Gly, L-Cys-Gly, and L-Ala-L-Ala-L-Ala hydrolysis by Bestatin further support a role for aminopeptidase M in the generation of L-cysteine from L-Cys-Gly. These results suggest that the drug-resistant tumor cell has developed an efficient mechanism for maintenance of elevated GSH which involves both gamma-glutamyl transpeptidase-initiated catabolism of GSH to cysteine and its reutilization by gamma-glutamylcysteine synthetase.
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PMID:Elevation of glutathione in phenylalanine mustard-resistant murine L1210 leukemia cells. 366 23

A glutathione conjugate of aflatoxin B1 (AFB1) which has previously been identified as 8,9-dihydro-8-(S-glutathionyl)-9-hydroxy aflatoxin B1 (AFB1-GSH) (E.J. Moss, D.J. Judah, M. Przybylski and G.E. Neal, Biochem. J., 210 (1983) 227-233) has been degraded in vitro to all of the intermediates of the mercapturic acid pathway (MAP) and the chromatographic and spectral characteristics of each of these compounds investigated. The cysteinylglycyl conjugate (AFB1-Cys.Gly) was prepared by incubating the AFB1-GSH conjugate with a rat hepatoma cell line rich in gamma-glutamyl-transpeptidase (GGT). Incubations of the AFB1-Cys.Gly conjugate with dipeptidase produced a metabolite, which was purified and characterized by 1H-NMR spectroscopy as 8,9-dihydro-8-(S-cysteinyl)-9-hydroxy aflatoxin B1 (AFB1-Cys). The N-acetyl derivative of the AFB1-Cys conjugate resulted from the incubation of the AFB1-GSH conjugate in vitro with isolated rat kidney cells. Mass spectral data were consistent with the compound being 8,9-dihydro-8-(S-cysteinyl-(N-acetyl))-9-hydroxy aflatoxin B1 (AFB1-Nac.Cys). A chromatographically identical compound was obtained by the chemical acetylation of AFB1-Cys.
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PMID:The mercapturic acid pathway metabolites of a glutathione conjugate of aflatoxin B1. 393 41

The nephrotoxicity of nitrilotriacetate chelated Fe(III) (NTA-Fe(III)) has been linked to the metabolism of glutathione (GSH) by gamma-glutamyl transpeptidase and a dipeptidase. The products of these enzymes are cysteinyl-glycine (cys-gly) and cysteine (cys), which are proposed to be the reductants of NTA-Fe(III) to cause oxidative damage to various biomolecules. The ability of cys-gly and cys to cause in vitro NTA-Fe(III)-dependent lipid peroxidation correlated directly with their ability to reduce NTA-Fe(III). GSH reduced iron at a much slower rate and did not stimulate lipid peroxidation. It has been proposed that GSH, cys-gly and cys reduce iron at different rates because their thiols have different pKas. However, increasing the amount of GS-, by raising the pH, did not cause a corresponding increase in the rate of iron reduction. The monomethyl ester of GSH reduced NTA-Fe(III) at the same rate as GSH, but the dimethyl ester of GSH reduced NTA-Fe(III) approximately 30 times faster. From this we conclude that GSH does not reduce NTA-Fe(III) at the same rate as cys-gly and cys because of the liganding between GSH and the iron.
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PMID:Thiol-mediated NTA-Fe(III) reduction and lipid peroxidation. 803 Nov 28

Monocrotaline (MONO), a pyrrolizidine alkaloid, causes veno-occlusive disease of the liver, pulmonary arterial hypertension, and right ventricular hypertrophy. Toxicity is due to the hepatic formation of a pyrolic metabolite that can be detoxified by conjugation with glutathione (GSH). We have shown that the GSH content of the liver affects the quantity of the pyrrolic metabolite that is released from the liver. We have now examined whether MONO, in turn, affects GSH metabolism. Twenty-four hours after administration of MONO to rats (65 mg/kg, i.p.), the highest concentration of bound pyrrolic metabolites was found in the liver, followed by the lung and kidney. Heart and brain contained lower concentrations of these metabolites. Significantly higher levels of GSH were found in liver and lungs of MONO-treated rats than in saline-injected control animals. In the liver, activities of the following enzymes were elevated: gamma-glutamylcysteine synthetase, GSH synthetase, gamma-glutamyl transpeptidase, dipeptidase, and microsomal GSH transferase. The same changes were seen in the lung. In the heart, gamma-glutamyl transpeptidase activity was decreased markedly, and cytosolic GSH transferase activity was elevated. In the kidney, the activities of GSH synthetase, gamma-glutamyl transpeptidase, and cytosolic GSH transferase were increased. Our results establish a mutual interaction of MONO and sulfur metabolism. It appears that an early metabolic action of MONO is to modify sulfur amino acid metabolism, diverting cysteine metabolism from oxidation to taurine towards synthesis of GSH.
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PMID:Effects of monocrotaline, a pyrrolizidine alkaloid, on glutathione metabolism in the rat. 857 5

Mercury chloride (HgCl2) has a potent nephrotoxic effect. Most of Hg2+ existing in plasma following HgCl2 exposure forms a complex with sulfhydryl-containing ligands such as albumin and glutathione (GSH). The Hg(2+)-GSH complex is filtered in the glomeruli of the kidney and degraded into Hg(2+)-cysteine in the proximal tubules by the combined action of gamma-glutamyl transpeptidase and dipeptidase present in the epithelial cells. The degradation product is then incorporated and accumulated into the proximal tubule epithelial cells. The accumulated Hg2+ in the epithelial cells finally causes acute tubular necrosis (ATN) by its cytotoxic effect. At present, it is believed that tubular obstruction resulting from ATN triggers the onset of HgCl2-induced acute renal failure (ARF). A progressive fall in glomerular filtration rate (GFR) contributes to the progression of HgCl2-induced ARF. The fall in GFR may be caused by an increment in afferent arteriole resistance (RA) and a decrement in the ultrafiltration coefficient (Kf) due to mesangial cell contraction. These changes in RA and Kf may be attributed to the increased action of the vasoconstrictors, angiotensin II and endothelin-1 and to the decreased action of the vasodilator, nitric oxide observed at the glomerulus level of HgCl2-induced ARF. Accordingly, the imbalance between these vasoactive substances appears to play an important role in the progression of HgCl2-induced ARF due to reducing GFR. Further studies, however, remain to elucidate the mechanisms involved.
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PMID:[HgCl2-induced acute renal failure and its pathophysiology]. 952 59

The disposition and toxicity of methylmercury, a ubiquitous environmental pollutant, is modulated by binding to the endogenous tripeptide glutathione (GSH) and metabolism of the resulting methylmercury-glutathione complex by the ectoproteins gamma-glutamyl transpeptidase (GGT) and dipeptidase. To evaluate the role of GGT in the whole-body disposition of methylmercury, we compared the elimination of [203Hg]methylmercury in GGT-deficient mice with that in wild-type mice and mice heterozygous for this deficiency. The effects of N-acetylcysteine (NAC), a drug used to maintain the cysteine and GSH levels of GGT-deficient mice, were also examined. Female mice were treated with either 0.5 or 25 micromol of CH3 203HgCl/kg body weight, in the presence and absence of 10 mg/ml NAC in the drinking water. There were no differences in methylmercury excretion between the wild-type and heterozygous mice; however, the GGT-deficient mice excreted methylmercury more rapidly at both dose levels. Wild-type and heterozygous mice excreted from 11 to 24% of the dose in the first 48 hours, whereas the GGT-deficient mice excreted 55 to 66% of the dose, with most of the methylmercury being excreted in urine. Urinary methylmercury excretion was further accelerated in mice that received NAC. In contrast to methylmercury, the whole-body elimination of inorganic mercury was not affected by GGT deficiency, although the tissue distribution of inorganic mercury was markedly different in GGT-deficient male mice, with only 13% of the 203Hg body burden in the kidneys of GGT-deficient mice versus approximately 50% in kidneys of wild-type male mice. These findings provide direct evidence for a major role of GGT in regulating the tissue distribution and elimination of methylmercury and inorganic mercury and provide additional support for the use of NAC as an antidote in methylmercury poisoning.
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PMID:Accelerated methylmercury elimination in gamma-glutamyl transpeptidase-deficient mice. 954 65

In the gamma-glutamyl cycle, hereditary defects have been described in four of the six enzymes namely: gamma-GC synthetase; GSH synthetase; gamma-glutamyl transpeptidase and 5-oxoprolinase. Mutants are still to be found in gamma-glutamyl cyclotransferase and in the dipeptidase. Deficiency of GSH synthatase or gamma-GC synthetases results in low levels of GSH. In gamma-GC synthetase deficiency hemolytic anemia is the most prominent symptom, with or without hepatosplenomegaly. In generalized GSH synthetase deficiency 5-oxoproline is overproduced due to lack of feedback inhibition of gamma-GC synthetase. These patients have metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and about 50% of them also have progressive neurological symptoms. Treatment includes acidosis correction, high doses of vitamin E and C and avoidance of drugs precipitating hemolytic crises in G6PD deficiency. Therapeutic trials with GSH analogues, N-acetylcysteine and GSH esters have been carried out. Glutathione synthetase deficiency restricted to erythrocytes results in hemolytic anemia but no 5-oxoprolinuria. gamma-Glutamyl transpeptidase deficiency is associated with GSH-emia and GSH-uria whereas 5-oxoprolinase deficiency is associated with 5-oxoprolinuria. In diagnostic work it must be emphasized that erythrocytes contain an incomplete gamma-glutamyl cycle; they lack both gamma-glutamyl transpeptidase and 5-oxoprolinase and these enzyme activities must therefore be analyzed in other types of cells such as leukocytes and fibroblasts. It is also important to investigate other patients with inherited defects in the gamma-glutamyl cycle to learn more about the biological role of GSH in man.
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PMID:Patients with genetic defects in the gamma-glutamyl cycle. 967 48


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