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

Previously, the synthesis and validation of [32P]2N3NAD+ as an active site directed photoaffinity probe for glutamate dehydrogenase (GDH) was reported (8). This report shows that 2N3NAD+ is also an effective probe for the NAD+ binding site of lactate dehydrogenase (LDH). With the appropriate photolabeling procedures and immobilized boronate column chromatography the active site peptides of GDH and LDH involved in the adenine base binding domain have been isolated and sequenced. With both GDH and LDH a single photolabeled peptide, which contained the majority of the photoinserted radiolabel, was isolated. Additionally, these peptides had UV spectra that were markedly different from the nonphotolabeled peptides. The modified peptide from GDH corresponded to Cys270 through Lys289. Both sequencing and compositional analysis identified Glu275 as the site of photoinsertion. Sequencing of this peptide aborted at Glu275 after five rounds of analysis, indicating that insertion was blocking further progress. Compositional analysis showed that the entire sequence from residues 270 to 289 was present except that the single Glu residue was missing. This is interpreted as indicating that the photoinsertion is into the polypeptide backbone at the Glu site. The peptide isolated from LDH corresponded to Asp82 through Arg90. Sequencing of this peptide could be completed throughout with only the round at Tyr83 giving no identifiable residue. Compositional analysis of this peptide was in agreement with the peptide from Asp82 to Arg90 with the exception that the single Tyr residue was missing. This indicates that the photoinsertion is into the tyrosine side chain. This data was found to be in agreement with X-ray crystallographic results identifying the NAD(+)-binding domains.
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PMID:Identification of peptides in the adenine ring binding domain of glutamate and lactate dehydrogenase using 2-azido-NAD+. 168 10

Treatment of rats with the vitamin B12 analogue hydroxy-cobalamin[c-lactam] (HCCL) impairs methylmalonyl-CoA mutase function and leads to methylmalonic aciduria due to intracellular accumulation of propionyl and methylmalonyl-CoA. Since accumulation of these acyl-CoAs disrupts normal cellular regulation, the present investigation characterized metabolism in hepatocytes and liver mitochondria from rats treated subcutaneously with HCCL or saline (control) by osmotic minipump. Consistent with decreased methylmalonyl-CoA mutase activity, 14CO2 production from 1-14C-propionate (1 mM) was decreased by 76% and 82% after 2-3 wk and 5-6 wk of HCCL treatment, respectively. In contrast, after 5-6 wk of HCCL treatment, 14CO2 production from 1-14C-pyruvate (10 mM) and 1-14C-palmitate (0.8 mM) were increased by 45% and 49%, respectively. In isolated liver mitochondria, state 3 oxidation rates were unchanged or decreased, and activities of the mitochondrial enzymes, citrate synthetase, succinate dehydrogenase, carnitine palmitoyltransferase, and glutamate dehydrogenase (expressed per milligram mitochondrial protein) were unaffected by HCCL treatment. In contrast, activities of the same enzymes were significantly increased in both liver homogenate (expressed per gram liver) and isolated hepatocytes (expressed per 10(6) cells) from HCCL-treated rats. The mitochondrial protein per gram liver, calculated on the basis of the recovery of the mitochondrial enzymes, increased by 39% in 5-6 wk HCCL-treated rats. Activities of lactate dehydrogenase, catalase, cyanide-insensitive palmitoyl-CoA oxidation, and arylsulfatase A in liver were not affected by HCCL treatment. Hepatic levels of mitochondrial mRNAs were elevated up to 10-fold in HCCL-treated animals as assessed by Northern blot analysis. Thus, HCCL treatment is associated with enhanced mitochondrial oxidative capacity and an increased mitochondrial protein content per gram liver. Increased mitochondrial oxidative capacity may be a compensatory mechanism in response to the metabolic insult induced by HCCL administration.
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PMID:Increased hepatic mitochondrial capacity in rats with hydroxy-cobalamin[c-lactam]-induced methylmalonic aciduria. 170 51

One hundred and one young-adult female Sprague-Dawley rats were acclimatized to metabolic cages for 2 days. After that time 24-hour urine was collected at a constant cooling temperature of 0-4 degrees C. After gel filtration the enzyme activities were determined, and the resulting values were used to calculate 24-hour excretions. The following reference ranges (2.5 and 97.5 percentiles) were determined (in mU/24 h): lactate dehydrogenase 43-181; phosphohexoseisomerase 45-1445; glutathione-S-transferase 1-299; alkaline phosphatase 27-1239; leucine arylamidase 72-377; gamma-glutamyltransferase 1334-9188; arylsulphatase A 59-309; beta-galactosidase 76-305; beta-glucuronidase 20-2756; beta-N-acetyl-D-glucosaminidase 66-491; glutamate dehydrogenase 7-711. There was a significant (though not very high) correlation with diuresis for the lysosomal enzymes beta-N-acetyl-D-glucosaminidase, arylsulphatase A and beta-galactosidase, and for glutamate dehydrogenase, lactate dehydrogenase, phosphohexoseisomerase and alkaline phosphatase. The relation to creatinine excretion was markedly close for the lysosomal enzymes beta-N-acetyl-D-glucosaminidase, arylsulphatase A and beta-galactosidase (r = 0.71-0.83), as well as for alkaline phosphatase, leucine arylamidase and gamma-glutamyltransferase. There was a relatively high correlation between the excretion of beta-N-acetyl-D-glucosaminidase, arylsulphatase A and beta-galactosidase among themselves (r = 0.63-0.81) as well as between leucine arylamidase and gamma-glutamyltransferase (r = 0.75).
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PMID:Excretion of urinary enzymes in female Sprague-Dawley rats in relation to cellular compartment, creatinine excretion and diuresis. 179 3

Haemonchus contortus, incubated in 10 micrograms/ml and 50 micrograms/ml concentrations of Nilzan and albendazole in Tyrode solution were stained for histoenzymatic demonstration of various phosphatases, oxido-reductases and esterases. The intestine showed major alterations after drug treatments. The alkaline phosphatases (AkPase), adenosine triphosphatase (ATPase), glucose-6-phosphatase, succinic dehydrogenase (SDH), glutamate dehydrogenase (GDH), reduced nicotinamide adenine dinucleotide phosphate diaphorase and reduced nicotinamide adenine dinucleotide diaphorase showed a decreased activity in intestine after Nilzan treatment, whereas lactic dehydrogenase (LDH), glucose-6-phosphate dehydrogenase (G-6-PD) and monoamine oxidase resisted increased reaction. The albendazole treatment resulted in altered distribution pattern of the AkPase, ATPase, SDH, and GDH; while LDH, G-6-PD, and non-specific esterases exhibited slightly enhanced activity in the epithelium. The functional significance of these changes has been fully discussed.
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PMID:Effect of Nilzan and albendazole on the absorptive surfaces of Haemonchus contortus (Nematoda)--a histoenzymic study. 196 79

The toxic potential of sodium orthovanadate towards isolated perfused rat livers was investigated at a dose of 2 mmol/l. In livers from fasted rats, vanadate led to a release of cytosolic (glutamate-pyruvate-transaminase (GPT) and lactate dehydrogenase (LDH] and mitochondrial (glutamate dehydrogenase (GLDH] enzymes, an accumulation of calcium in the liver, a marked depletion of hepatic glutathione and an enhanced release of it into the perfusate, as well as an augmented formation and release of thiobarbituric acid-reactive material by the liver. Furthermore, a marked inhibition of oxygen consumption was observed. Vanadate-induced vasoconstriction resulted in a progressive decrease in perfusate flow rate. Control experiments with similarly reduced flow rates led to a comparable reduction in oxygen consumption. GPT and LDH release and hepatic glutathione depletion were also evident, though to a lesser extent than in the presence of vanadate, but no increase in GLDH release, in tissue calcium content or TBA-reactive material in the liver or the perfusate were observed. Thus, indirect toxic effects due to a reduced flow rate contribute only partly to vanadate hepatotoxicity and do not affect mitochondrial integrity. Omission of calcium from the perfusate did not prevent hepatotoxic responses to vanadate, although less calcium was present in the treated livers than in the control organs, indicating that calcium influx is not involved in vanadate-induced hepatotoxicity in the intact organ, in contrast to isolated hepatocytes. Feeding the animals, resulting in an activation of anaerobic energy conservation reactions, strongly attenuated vanadate hepatotoxicity indicating that the energetic status of the liver is the main target of vanadate. Superoxide dismutase did not affect the hepatotoxic responses of livers from fasted rats towards vanadate, while allopurinol and deferrioxamine inhibited lipid peroxidation and hepatotoxicity due to vanadate. The strong correlation between induction of lipid peroxidation and hepatotoxicity and the inhibition of both processes in parallel by antioxidants are suggestive of a causative role for lipid peroxidation in vanadate-induced hepatotoxicity.
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PMID:Vanadate-induced toxicity towards isolated perfused rat livers: the role of lipid peroxidation. 199 68

The phospholipid and fatty acid compositions of the host infected erythrocyte plasma membrane (IEPM) have been determined for erythrocytes infected with the human malaria parasite Plasmodium falciparum. IEPM were prepared by selective lysis of the host erythrocyte (but not of the parasite membranes) with 0.1% saponin, followed by differential centrifugation. The purity of the IEPM was determined by measuring the membrane-specific enzyme markers acetylcholinesterase, glutamate dehydrogenase and lactate dehydrogenase, and by immunoelectron microscopy using monoclonal antibodies specific for human erythrocyte glycophorin A (4E7) and for a 195 kDa parasite membrane glycoprotein (Pf6 3B10.1). Both approaches demonstrated that the host erythrocyte plasma membrane preparation was free from contamination by parasite membranes. During intra-erythrocytic development of the parasite, the phospholipid composition of the erythrocyte membrane was strikingly altered. IEPM contained more phosphatidylcholine (38.7% versus 31.7%) and phosphatidylinositol (2.1% versus 0.8%) and less sphingomyelin (14.6% versus 28.0%) than normal uninfected erythrocytes. Similar alterations in phospholipid composition were determined for erythrocyte membranes of parasitized cells isolated by an alternative method utilizing polycationic polyacrylamide microbeads (Affigel 731). The total fatty acid compositions of the major phospholipids in IEPM were determined by g.l.c. The percentage of polyunsaturated fatty acids in normal erythrocyte phospholipids (39.4%) was much higher than in phospholipids from purified parasites (23.3%) or IEPM (24.0%). The unsaturation index of phospholipids in IEPM was considerably lower than in uninfected erythrocytes (107.5 versus 161.0) and was very similar to that in purified parasites (107.5 versus 98.5). Large increases in palmitic acid (C16:0) (from 21.88% to 31.21%) and in oleic acid (C18:1) (from 14.64% to 24.60%), and major decreases in arachidonic acid (C20:4) (from 17.36% to 7.85%) and in docosahexaenoic acid (C22:6) (from 4.34% to 1.8%) occurred as a result of infection. The fatty acid profiles of individual phospholipid classes from IEPM resembled in many instances the fatty acid profiles of parasite phospholipids rather than those of uninfected erythrocytes. Analysis of IEPM from P. falciparum-infected erythrocytes (trophozoite stage) revealed that, during intra-erythrocytic maturation of the parasite, the host erythrocyte phospholipid composition was markedly refashioned. These alterations were not dependent on the method used to isolate the IEPM, with similar results obtained using either a saponin-lysis method or binding to Affigel beads. Since mature erythrocytes have negligible lipid synthesis and metabolism, these alterations must occur as a result of parasite-directed metabolism of erythrocyte lipids and/or trafficking of lipids between the parasite and erythrocyte membranes.
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PMID:Modification of host cell membrane lipid composition by the intra-erythrocytic human malaria parasite Plasmodium falciparum. 200 Dec 27

5-Ethylphenazine-poly(ethylene glycol)-glutamate dehydrogenase conjugate (EP(+)-PEG-GluDH) was prepared by linking poly(ethylene glycol)-bound 5-ethylphenazine to glutamate dehydrogenase. The average number of the ethylphenazine moieties bound/enzyme subunit was 0.7. This conjugate is a semisynthetic enzyme having NADH oxidase activity; the ethylphenazine moiety works as a catalytic group, and the coenzyme-binding site of glutamate dehydrogenase works as a substrate-binding site. The effects of the presence of the substrate-binding site near the catalytic group were studied by using EP(+)-PEG-GluDH. Before the preparation of the conjugate, the reactivity of NADH bound in the coenzyme-binding site toward the ethylphenazine moiety was estimated for glutamate and lactate dehydrogenases. The results show that the NADH molecule bound in the site of glutamate dehydrogenase reacts with EP(+)-PEG at a rate of 43% of that of free NADH, but the NADH molecule bound in lactate dehydrogenase does not react with 1-(3-carboxypropyloxy)-5- ethylphenazine. Therefore, glutamate dehydrogenase was used as the substrate-binding site of the semisynthetic NADH oxidase. The results of the kinetic analysis of the activity of EP(+)-PEG-GluDH show that the apparent turnover number of the active site is 0.38 s-1, which corresponds to the apparent intramolecular rate constant of the oxidation of NADH bound in the active site. The apparent effective concentration of bound NADH for the catalytic group of the ethylphenazine moiety is 0.33 mM. This means that the presence of the substrate-binding site near the catalytic group increases the local NADH concentration by at most 0.33 mM, and this is the rate-accelerating effect of the binding site.
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PMID:Preparation and kinetic properties of 5-ethylphenazine-poly(ethylene-glycol)-glutamate-dehydrogenase conjugate. A semisynthetic NADH oxidase. 200 3

No interactions related to the analytical method were observed between chlorpromazine (1) or carbamazepine (2) and activities of alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), glutamate dehydrogenase (GLDH) or lactate dehydrogenase (LDH). With respect to its cytotoxic potential 1 in cultures of isolated rat hepatocytes increased markedly the release of enzymes into the culture medium, whereas the overall activities of the enzymes were not influenced. 2 in cultured hepatocytes caused no significant effects on the activities of the enzymes investigated. Besides the investigation of methodically related interactions in pooled human serum the methodic procedure including the use of cultures of isolated hepatocytes allows to study also pharmacologically and toxicologically related interactions between drugs and diagnostically relevant liver enzymes.
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PMID:[The effect of chlorpromazine and carbamazepine on diagnostically relevant liver enzymes]. 208 Feb 2

It is well known that brain function is critically dependent upon energy metabolism and that the brain has a relatively high metabolic rate. Experiments using intact brain preparations do not provide information about metabolism in the different cell types that constitute brain tissue. Progress in primary culture techniques has facilitated biochemical investigations and analysis of the metabolic pathways prevailing in specific cerebral cell types. We found that, in the presence of pyruvate or succinate as the substrate, oxygen consumption by neurons grown in culture was always higher than that by glial cells. The relatively low values of hexokinase, malate dehydrogenase and glutamate dehydrogenase activities observed in glial cells and, in contrast, the high levels of lactate dehydrogenase and enolase activities may be the result of a less aerobic metabolism prevailing in this type of brain cell, compared to neurons. On the other hand, the predominance of the aerobic, lactate dehydrogenase, isoenzymatic form in neurons can be associated with a more aerobic metabolism in this type of cell. In the case of severe hypoxia, we observed that astrocytes were the most damaged cells. An increased lactate dehydrogenase level with a modification of its isoenzymatic profile and a decreased glutamine synthetase activity under hypoxic conditions indicated severe derangement of important biochemical functions within the astrocytes. By antagonizing some of these changes, almitrine and raubasine (both present in Duxil) seem to exert some protective effect. One may consider that, among the different cell types present in brain tissue, astroglial cells may represent a target particularly sensitive to hypoxia-induced injury.
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PMID:[Neuronal and astrocytic plasticity: metabolic aspects]. 208 81


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