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:1.1.1.41 (isocitrate dehydrogenase)
3,101 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoid-induced cataract formation appears to proceed via oxidation or peroxidation steps possibly caused by multiple activities of glucocorticoid in the living system. Attempts were made to modify GC-induced metabolic changes and prevent cataract formation using intermediates of the citric acid cycle. The compounds were applied to the embryos at 3, 10 and 20 hr after the administration of hydrocortisone succinate sodium (HC:0.25 mumol/egg) to 15-day-old eggs. At 48 hr after HC treatment the lenses were classified and analyzed. Almost all lenses were classified as stage IV-V (greater than 94%). However, the application of sodium isocitrate (IC:15 mumol/egg) which was the most potent among several intermediates tested showed a significant preventive effect against cataract formation. The administration of IC prevented the decline of GSH, the elevations of LPO and reduced the marked elevation of glucose in the lens caused by HC. The IC treatment also diminished the elevation of LPO in blood and liver. The above effects by IC on HC-induced events may be due to the action of IC in preventing the early decline of hepatic GSH caused by HC. Possibly IC was utilized as an intermediate of the citric acid cycle and a substrate for isocitrate dehydrogenase in cytosol to modify GC-induced metabolic changes.
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PMID:Preventive effect of isocitrate on glucocorticoid-induced cataract formation of developing chick embryo. 191 99

Acetaminophen (APAP) with or without ascorbyl stearate (AS) or ascorbyl palmitate (AP) was administered by gavage to male Swiss-Webster mice at a dose of 600 mg/kg for each chemical. The biochemical markers of hepatotoxicity, serum transaminases (serum glutamate pyruvate transaminase [SGPT], serum glutamate oxaloacetic transaminase [SGOT]) and serum isocitrate dehydrogenase (SICD) activities were monitored after APAP and APAP + AP or AS dosing. There were significant reductions in serum transaminase and SICD activities in the APAP- + ascorbate ester-treated animals as compared to APAP-positive controls. Oral coadministration of APAP with AP or AS did not prevent the initial hepatic GSH depletion (15 min-4 hr postdosing). However, hepatic GSH content began to rise in the APAP + AS or AP-treated animals at 4 hr and reached control values within 12 hr postdosing. Urinary mercapturate conjugates were also significantly higher in the APAP + AP or AS-treated animals as compared to APAP alone when measured over a 60-min postdosing period. Plasma sulfobromophthalein (BSP) retention was approximately eight times higher in APAP-treated animals as compared to the APAP + ascorbate ester treatments indicating maintenance of hepatic excretory functions in presence of AP or AS. Prior depletion of hepatic GSH by diethyl maleate (DEM) did not alter hepatoprotective effects of AP or AS in the presence of APAP. Hepatic ascorbate levels also peaked at 4 hours after APAP + AP or AS treatments. The possible role of L-ascorbic acid esters in GSH regeneration following co-administration of a hepatotoxic dose and APAP is discussed.
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PMID:Effect of ascorbic acid esters on hepatic glutathione levels in mice treated with a hepatotoxic dose of acetaminophen. 194 4

1. The activities of enzymes participating in the regeneration of reduced glutathione (GSH), and their subcellular distribution were studied in cultured rat adrenal cells. 2. It has previously been shown that the adrenocorticolytic agent 7-hydroxymethyl-12-methylbenz[a]anthracene (7-hydroxymethyl-12-MBA) causes a drastic and selective oxidation of mitochondrial GSH in rat adrenal cells. Treatment of the adrenal cells with 7-hydroxymethyl-12-MBA, resulted in a minor decrease in the content of cytochrome c oxidase, nicotinamide nucleotide transhydrogenase, isocitrate dehydrogenase and cytosolic GSH reductase, whereas the activity of lactate dehydrogenase and citrate synthase was unaffected. None of these effects were considered to be responsible for the massive oxidation of mitochondrial GSH induced by 7-hydroxymethyl-12-MBA. 3. 1,3-Bis-(2-chloroethyl)-1-nitrosourea (BCNU) was used to obtain rat adrenal cells cultures with inactivated cytosolic and mitochondrial GSH reductase. The oxidation of mitochondrial GSH, induced by 7-hydroxymethyl-12-MBA, was not dramatically enhanced by the inactivation of GSH reductase, indicating that this enzyme was not rate-limiting in the regeneration of GSH. 4. Fractionation of rat adrenal cells with increasing concentrations of digitonin resulted in an earlier release of citrate synthase in cells treated with 7-hydroxymethyl-12-MBA compared with controls. These results may indicate damage to mitochondrial membranes as a result of 7-hydroxymethyl-12-MBA treatment.
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PMID:Effect of 7-hydroxymethyl-12-methylbenz[a]anthracene and 1,3-bis-(2-chloroethyl)-1-nitrosourea on enzyme activities and oxidation of glutathione in cultured rat adrenal cells. 254 26

Glutathione (GSH), together with NADPH-producing pathways and glutathione reductase, provides a defense system against oxidants. Oxidation of GSH causes stimulation of the hexose monophosphate shunt and increased production of NADPH. We have asked if hexose monophosphate shunt activity is required for the recovery of GSH following exposure of the isolated rat retina to an oxidant. Hexose monophosphate shunt activity was decreased by depleting the retina of hexose stores, before exposing the tissue to diamide (0.04-1.0mM), an oxidant for GSH, for 30 min. After exposure, retinas were transferred to either glucose-containing or glucose-free recovery medium for an additional 30 min. Control retinas kept in glucose-free, oxygenated medium (no diamide) for 90-120 min maintained GSH at 90% of the value found in retinas incubated with glucose. After exposure of hexose-depleted retinas to 0.4 mM diamide, a nearly 90% decrease in GSH was observed. When the oxidant was removed, the level of GSH returned to more than 80% of the control value in the presence or absence of glucose. In contrast, no recovery of GSH was observed after diamide treatment if the retinas were transferred to ice-cold (1-5 degrees C) media with or without glucose or if the retinas were pre-treated with 2 mM 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to inhibit glutathione reductase. Measurements of two NADPH-producing cytosolic enzymes, namely NADP+-dependent malic enzyme and NADP+-dependent isocitrate dehydrogenase, revealed high activities. Optimum production of NADPH from malic enzyme was 0.90 nmol NADPH produced min-1 per retina, while with isocitrate dehydrogenase the average rate was 6.9 nmol NADPH produced min-1 per retina. We suggest that these enzymes together with a long-lived endogenous substrate (probably glutamate) are responsible for the recovery of GSH in hexose-depleted retinas. The present results suggest that more than one NADPH-producing system is capable of controlling the GSH concentration in retina. Studies that have focused on the hexose monophosphate shunt pathway as the sole source of NADPH for glutathione reductase in retina and other tissues may require re-evaluation depending on the overall metabolic capacity and substrate utilization of the particular tissue. Thus, the present findings are significant not only with respect to the retina but also for other tissues whose metabolic characteristics are similar to those found in the retina.
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PMID:Multiple NADPH-producing pathways control glutathione (GSH) content in retina. 380 64

Cellular metabolism and, in particular, oxidation-reduction systems are linked to responses to drugs and toxic agents in several ways. Major connections are given by the NADPH/NADP+ system and the GSH/GSSG system. Intracellular reductive pathways generally use NADPH as the electron donor. From a toxicological point of view, NADPH can be considered both as a "detoxicant" and as a "toxicant". In the former case, NADPH supports the glutathione redox cycle by maintaining a negative redox potential of GSH to permit its detoxication functions to occur. NADPH is also the main donor for reducing equivalents in drug oxidations by the cytochrome P-450-dependent monooxygenase system which, with some notable exceptions, serves important purposes in detoxication. The sources of NADPH reducing equivalents depend on the nutritional state: major sources in the fed state are represented by the cytosolic pentose phosphate shunt dehydrogenases, whereas mitochondrial sources linked to isocitrate dehydrogenase provide the bulk of NADPH reducing equivalents in the fasted state. As a "toxicant", NADPH supports redox cycling reactions involving various drugs and other compounds of quinoid structure, aromatic nitro compounds and iron chelates with formation of superoxide anion radicals and subsequent formation of other oxygen derived radical species. This presentation focuses on recent work carried out with isolated hepatocytes and perfused rat liver with respect to "oxidative stress". The noninvasive techniques of measurement of low-level chemiluminescence and of volatile hydrocarbons (ethane, pentane) as well as glutathione release and calcium release have been employed.
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PMID:Cellular redox changes and response to drugs and toxic agents. 635 19

Paracetamol metabolism and toxicity were studied in isolated rat hepatocytes. Cell damage, due to paracetamol, was shown to be dose dependent and was worse in cells from animals pre-treated with phenobarbitone. Exposure to 10 mM paracetamol for 1 hr caused a loss of intracellular reduced glutathione (GSH) and a later progressive leakage of isocitrate dehydrogenase (ICD). Treatment with (+)catechin, 3-O-methyl(+)catechin and promethazine reduced or prevented the paracetamol-induced ICD leakage. Similarly, studies on covalent binding of paracetamol showed that 3-O-methyl(+)catechin, which "protected" the cells, did so without affecting the amount of material bound covalently to cellular protein. Incubation in tissue culture for 24 hr, after prior treatment with paracetamol +/- the protective agent, showed that the protected cells remained viable and attached to tissue culture plates much better than did the "unprotected" cells. These results suggest that the protective effect is much more than just a temporarily delayed cell death. GSH loss and covalent binding of paracetamol metabolites to cell protein are not sufficient causes of cell death, although they may act as starting points in the chain of events leading to cell death.
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PMID:Dissociation of cell death from covalent binding of paracetamol by flavones in a hepatocyte system. 715 57

Hyperplastic nodular cirrhosis was induced in rats by long-term (6 month) i.p. administration of thioacetamide at doses of 2.66 mmol/kg body wt, three times per week. The survival rate of animals at the end of the treatment was 90%. To follow the temporal changes samples at 0, 7, 15, 30, 45, 60, 90, 150 and 180 days from rats during thioacetamide intoxication and from chronological controls were obtained. The cirrhogenic ability of this treatment was assessed on the basis of morphological changes: the development of macronodular cirrhosis and the appearance of fibrous septa of collagen through portal spaces. Parameters of liver injury and cholestasis were obtained by assaying the serum activities of isocitrate dehydrogenase and gamma-glutamyltransferase. Enzymes and metabolites related to glutathione redox systems, as well as other antioxidant enzymes, were tested. Catalase and glutathione peroxidase, the two enzymes involved in the elimination of peroxides, and glutathione reductase decreased significantly at the end of the 6 months of intoxication, while Cu-Zn and Mn superoxide dismutases increased progressively during the long-term thioacetamide treatment. Protein thiol levels profile showed a biphasic change increasing from the 7th day and were insensitive to the 30% depletion of intracellular glutathione (GSH). To study the relationship of the intracellular thiols on the mechanisms of cell proliferation and differentiation during the cirrhogenic process, DNA content was assayed by flow cytometry in isolated hepatocytes, and DNA ploidy and distribution between G0-G1, S and G2 + M phases were determined. Remarkable changes in relation to a sharp increase in diploid population from 7 to 180 days (24.5%-->85.5%), a pronounced decrease in polyploid populations (tetraploid+octoploid) in the same period (73.7%-->12.3%), and elevations in the populations in S phase (S1 + S2) were observed in thioacetamide-treated rats. The results obtained indicate that hepatocytes isolated from thioacetamide-treated rats showed a marked tendency to diploidy, an enhancement in DNA replication parallel to the hepatic content of protein sulphydryl groups and a significant decline in antioxidant enzyme activities. The increase in protein thiols was independent of GSH level and of the thiol redox state.
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PMID:Relationship between antioxidant systems, intracellular thiols and DNA ploidy in liver of rats during experimental cirrhogenesis. 761 93

Oxidative stress is associated with the formation of oxidized glutathione (GSSG) in the cells, which can form mixed disulfide with proteins leading to alteration of their function. The present study looks at the effect of in vitro exposure of GSSG on intestinal mitochondria and brush border membrane (BBM). Incubation with 1 mM GSSG increased the protein bound GSH in mitochondria by 15-fold. This was associated with loss of activity of certain mitochondrial enzymes such as succinic dehydrogenase, isocitrate dehydrogenase, total ATPase and NADH dehydrogenase whereas NADH oxidase was not affected. A similar treatment of BBMV with GSSG increased the protein bound GSH by 4.7-fold without altering its enzyme activity. Exposure to GSSG had no effect on the Na(+)-dependent glucose transport by BBMV. These studies suggest that GSSG formed during oxidative stress may modify thiol groups in proteins by forming mixed disulfides leading to functional alteration of certain cellular proteins.
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PMID:Effect of oxidized glutathione on intestinal mitochondria and brush border membrane. 767 Nov 37

Liver injury was induced by a single dose (60 mg/kg) of cocaine in male albino Swiss mice untreated or pretreated with phenobarbital (in drinking water 1 gm/L), for 5 days before cocaine administration. One parameter of liver injury, serum isocitrate dehydrogenase activity, showed sharp increases at 24 hr of cocaine treatment; we also noted decrease hepatic levels of ATP, GSH, cytochrome P-450 and NADPH/NADP+ ratio and increases in malondialdehyde concentration. Histopathological study of liver slices showed perivenous and periportal necrosis induced by cocaine in untreated mice and mice pretreated with phenobarbital, respectively. A regenerative postnecrotic response, which peaked at 48 hr, was demonstrated by the appearance of mitotic cells. Mitotic index analysis showed that proliferative cells appear to be unevenly distributed in the hepatic acinus and were mainly located in the vicinity of the damaged acinar region. Genomic DNA ploidy and the distribution of DNA in the phases of the cell cycle were studied in nuclei of isolated hepatocytes. At 12 hr of cocaine administration, both in untreated and phenobarbital-pretreated mice, the following changes were observed: a sharp decrease in tetraploid (4N) cells (40% to 17% and 25% to 6%, respectively) and octoploid (8N) cells (5% to 2% and 2% to 1%, respectively), together with the appearance of a hypodiploid population (13% and 31%, respectively). Hypodiploid population was characterized as apoptotic cells by detection of DNA fragmentation in agarose gel. These results suggest that a significant percentage of cell death induced by cocaine occurs by means of the apoptosis death program. Comparison of the initial values of DNA ploidy with those obtained at 7 days of cocaine administration showed remarkable increases in polyploid populations (4N and 8N) and a decrease in diploid cells (2N), indicating that the process of differentiation occurs when liver restores its functionality.
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PMID:Cocaine-induced liver injury in mice elicits specific changes in DNA ploidy and induces programmed death of hepatocytes. 792 41

Arsenazo III (AIII) (100 mg/kg ip in saline) administration to Sprague-Dawley male rats 30 min before or 6 or 10 hr after CCl4 [1 ml/kg ip as a 20% (v/v) solution in olive oil] significantly prevented liver necrosis but not fatty liver caused by the hepatotoxin at 24 hr as demonstrated either by histology or by determination of isocitric acid dehydrogenase in plasma. AIII did not modify the CCl4 concentrations reaching the liver, the intensity of the covalent binding of CCl4-reactive metabolites to hepatic microsomal lipids, or the CCl4-promoted lipid peroxidation process at either 1 or 3 hr of poisoning. AIII administration enhanced glutathione (GSH) levels in liver and significantly prevented the CCl4-induced minor decreases in GSH content and the CCl4-induced increases in calcium content at 24 hr of intoxication. AIII treatment further enhanced the CCl4-induced decreases in body temperature of the poisoned rats. Results suggest that AIII's preventive effects might be related to its very well-known calcium-chelating properties, but that additional factors related to AIII's ability to increase GSH content in liver or to decrease body temperature of CCl4-intoxicated animals may also play a role.
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PMID:Prevention of CCl4-induced liver necrosis by the calcium chelator arsenazo III. 851 46


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