Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.4.1.2 (glutamate dehydrogenase)
 4,380 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An isomeric mixture of S-[(1 and 2)-phenyl-2-hydroxyethyl]glutathione (PHEG), a glutathione conjugate of styrene, is moderately nephrotoxic. Its in vivo nephrotoxicity was characterized by significant elevations in the urinary excretion of glucose, gamma-glutamyl transpeptidase, glutamate dehydrogenase, N-acetyl-beta-D-glucosaminidase and lactic dehydrogenase 24 h after an i.v. administration of PHEG (0.5 mmol/kg) in male Fischer-344 rats. The histologic alterations consisted of moderate tubular damage with proximal tubule vacuolization and accumulation of tubular cast material, indicating an early sign of tubular necrosis. The data suggest that nephrotoxic injury induced by PHEG lies preferentially at the tubular region of the rat kidney involving several subcellular targets. The nephrotoxicity of PHEG was blocked by acivicin, a specific inhibitor of gamma-glutamyl transpeptidase, by phenylalanylglycine, an inhibitor of cysteinylglycine dipeptidase, as well as by probenecid, a competitive inhibitor of renal organic anion transport system. On the other hand, pretreatment with aminooxyacetic acid, a specific inhibitor of renal cysteine conjugate beta-lyase, failed to inhibit the nephrotoxicity of this glutathione conjugate. Similarly, prior administration of alpha-ketobutyrate, an inducer of renal cysteine conjugate beta-lyase, failed to potentiate its nephrotoxicity, suggesting an insignificant role of beta-lyase in such toxicity. A modest decline in renal cellular GSH due to PHEG but without any concomitant oxidation of GSH to GSSG and without any increase in lipid peroxidation indicates that oxidative stress may not be an important mechanism of its nephrotoxicity. Therefore, the following steps at least, are involved in the development of its nephrotoxicity: (1) renal tubular accumulation of PHEG via a probenecid-sensitive transport process; and (2) its renal metabolism via gamma-glutamyl transpeptidase and cysteinylglycine dipeptidase to the corresponding cysteine-S-conjugate.
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PMID:In vivo nephrotoxic action of an isomeric mixture of S-(1-phenyl-2-hydroxyethyl)glutathione and S-(2-phenyl-2-hydroxyethyl)glutathione in Fischer-344 rats. 167 68

The activities of lactate dehydrogenase, glutamate dehydrogenase, aspartate aminotransferase, beta-galactosidase, N-acetyl-beta-D-glucosaminidase, leucine aminopeptidase, gamma-glutamyltransferase and alkaline phosphatase in renal tissue and urine of rats treated with sodium tetrathionate were determined. A decrease of enzyme activities in renal tissue and an increase in urine were observed. The largest decrease in the glutamate dehydrogenase of renal tissue amounted to 0.7 times the control value, and was correlated with an appropriate increase in the urine. Increases in urinary enzyme activity were especially marked for beta-galactosidase and N-acetyl-beta-D-glucosaminidase (3 and 6 times the control values, respectively). The increase in enzyme activities was not accompanied by a corresponding change in the urinary protein. Characterization of urinary lactate dehydrogenase and N-acetyl-beta-D-glucosaminidase isoenzymes also indicates the renal origin of these enzymes. The abnormally high enzyme activities of the urine correlated with the nature and degree of renal damage shown by electron microscopy.
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PMID:Effect of sodium tetrathionate on the activities of some enzymes in kidney and urine. 611 89

The clinical use of gentamicin (G) is limited because of its nephrotoxic potential. The administration of G (50 mg/kg) to rats in a 10-day daily treatment gave a biphasic pattern of lactate dehydrogenase (LDH) and N-acetyl-beta-D-glucosaminidase (NAG) excretion. Alkaline phosphatase (ALP) was highly elevated during the corresponding second phase while a slight and statistically insignificant increase in glutamate dehydrogenase (GDH) was obtained. The kidneys of such rats were isolated and tubules prepared and incubated for a specific period of time at 37 degrees C in Kreb's Henseleit bicarbonate buffer, pH 7.4. Results indicate a considerable loss of protein (P < 0.01) after the 3rd and 10th days of treatment with G, elevated and significant increase of ALP after the 1st (P < 0.05) and 3rd (P < 0.01) days and significant increase (P < 0.05) of GDH after the 10th day of treatment. The release of GDH, LDH and NAG from tubules of rats after a single dose of G was lower than the control rats while other treatments produced a significant increase in ALP, LDH and NAG over the period of incubation. In vitro incubation of tubules in the presence of several concentrations (5, 50, 500, 5000 micrograms/g of wet cortex) of G indicated a time-dependent leakage of enzyme only at the highest concentration of G. Our results clearly indicate that cellular damage caused by G as evidenced by urinary enzyme excretion and marker enzyme release from isolated tubules occurs at very high concentration in vivo or in vitro and is time-dependent.
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PMID:Renal damage caused by gentamicin: a study of the effect in vitro using isolated rat proximal tubular fragments. 786 40

The two conjugates, S-[N-(2-hydroxyethyl)carbamoylmethyl]glutathione (GSAAE), and its corresponding mercapturic derivative N-acetyl-S-[N-(2-hydroxyethyl)carbamoylmethyl]cysteine (NCySAAE) were administered to fasted Sprague-Dawley rats as putative metabolites of vinylidene chloride (VDC). Methylthioacetylaminoethanol (MAAE) was identified in the urine of GSAAE- or NCySAAE-treated rats (0.5-2.0 mmol/kg, i.p.), as well as in the urine of VDC-treated rats (0.5-2.0 mmol/kg, p.o.). The effects of VDC, GSAAE and NCySAAE on the kidney and liver were also examined using aspartate aminotransferase (ASAT). N-acetyl-beta-D-glucosaminidase (NAG) and beta 2-microglobulin (beta 2-m) as urinary parameters of nephrotoxicity, and glutamate dehydrogenase (GLDH), sorbitol dehydrogenase (SDH) and alanine aminotransferase (ALAT) as serum parameters of hepatotoxicity. Unlike treatment with VDC, treatment with both GSAAE and NCySAAE failed to cause kidney and liver toxicity. The results support the hypothesis that MAAE originates from the formation of GSAAE and further metabolization to NCySAAE, and that MAAE excretion does not reveal a pathway of reactive intermediates.
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PMID:Formation of GSH-derivatives as a pathway for inactive intermediates in vinylidene chloride-treated rats. 900 91

The consumption of plants containing the diterpenoid atractyloside (ATR) causes selective proximal tubule injury, renal failure and death in humans. We have compared the effects of ATR in freshly isolated renal proximal tubules and glomeruli from rat and also in cell lines: NRK, derived from the proximal tubules, and MDBK and MDCK more closely representing the distal nephron. The effects of ATR (10-500 microM) on proximal tubules and glomeruli were assessed by changes in lipid peroxidation, de novo protein synthesis and the leakage of alkaline phosphatase (ALP), lactate dehydrogenase (LDH), glutamate dehydrogenase (GDH) and N-acetyl-beta-D-glucosaminidase (NAG). The susceptibility of NRK, MDBK and MDCK cell lines to ATR was assessed by the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, measuring mitochondrial reduction. Enzyme leakage was the most sensitive of the markers of cell injury in fresh fragments and ranked LDH > GDH > ALP > NAG in proximal tubules. As little as 20 microM ATR caused significant enzyme leakage from proximal tubules, but there were no increases in enzyme leakage from glomeruli at concentrations < and = 500 microM ATR. De novo protein synthesis was only inhibited 50% at ATR concentration > 5 mM in the proximal tubules, but there were no effects in glomeruli. Malondialdehyde production was significantly elevated at 1 mM ATR for proximal tubules, and 500 microM for glomeruli. NRK cells were sensitive to ATR (IC50, 120 microM), but MDBK or MDCK cells were unaffected by < and = 1 mM of this diterpenoid. Both freshly isolated fragments and continuous cell lines representing the proximal tubules are more sensitive to ATR than either glomeruli or cells representing the distal nephron. These data also show that protein synthesis is a less specific and sensitive measure of ATR cytotoxicity than enzyme leakage in fragments. MTT reduction to formazan was the most sensitive in the NRK cell line. The low levels of lipid peroxidation products in proximal tubular fragments or sensitive renal cell lines at toxic levels of ATR suggest that oxidative injury is not a key mechanism.
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PMID:Selective cytotoxicity associated with in vitro exposure of fresh rat renal fragments and continuous cell lines to atractyloside. 901 May 90

Male Sprague-Dawley rats (8 per group) were administered a single oral dose of cyclosporine A (10, 30 and 50 mg/day) for 5 days or vehicle (corn oil, 1.5 mL/kg) and urinary enzymes excretion was monitored. Only minor changes in enzymuria were observed in the 10 and 30 mg/kg group. However, in the 50 mg/kg group, nephrotoxicity was evident by significant increase in the excretion of N-acetyl-beta-D-glucosaminidase (NAG), glutamate dehydrogenase (GDH), and lactate dehydrogenase (LDH on day 2 of treatment. As chemotherapeutic drug interaction with cyclosporine A (CyA) is thought to aggravate its nephrotoxicity, the effect of combined CyA (30 mg/kg) and the antibiotic gentamicin (50 mg/kg) for 5 days was investigated. Gentamicin alone caused a significant enzymuria, whilst co-treatment of rats with CyA gave rise to increased changes in enzymuria on days 1 and 2, between the groups receiving gentamicin+vehicle and those receiving CyA+gentamicin. This was particularly marked by significant changes in LDH excretion. In contrast these observed differences were not paralleled by changes in serum creatinine and other functional parameters. Treatment with gentamicin, appears to enhance CyA nephrotoxicity, but only in the first 2 days, after this there was no significant differences between the two groups. Our data suggest that urinary enzyme measurements could serve as a valuable non-invasive means of monitoring renal performance in animals or humans who may be exposed to combination of drugs. CyA is found not to potentiate the nephrotoxic effect of gentamicin in the animal model used in this study. It therefore appears safe to use the combined therapy particularly in the treatment of transplant patients.
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PMID:The combined effect of cyclosporine a and gentamicin on enzymuria in the Sprague-Dawley rat. 1084 39