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:1.4.1.2 (glutamate dehydrogenase)
4,380 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sequential pattern of lipid accumulation and associated biochemical changes were studied in two commonly used experimental models of nutritional fatty liver in rats. Female rats were maintained for 8 weeks on high fat, low protein diets containing adequate methionine and choline, and drinking water ad libitum (Diet 1), or deficient in methionine and choline and containing 20% ethanol as a substitute for drinking water (Diet 2). Histologically, there was a progressive increase in liver lipids, mainly in the periportal areas. Occasional foci of liver cell necrosis with lipogranuloma formation occurred in areas of severe fatty change. These changes appeared earlier and were more marked in rats maintained on Diet 2. Electron micrographs revealed large lipid droplets in the liver cells, which sometimes contained myelin figures. The mitochondria were enlarged, distorted and appeared as amorphous structures with disorientated cristae in rats on Diet 1, whereas they had a condensed conformation in rats maintained on Diet 2. Rough endoplasmic reticulum was fragmented and degranulated particularly in rats on Diet 1, and smooth endoplasmic reticulum showed hyperplasia and vesiculation in rats on Diet 2. There was a progressive increase in the total liver lipids and triglycerides in both the groups of rats. This fatty change was accompanied by a significant increase in hepatic 3-hydroxybutyrate, acetoacetate, malate, 2-oxoglutarate, citrate, lactate, ammonia, glutamate, alanine and aspartate, and a significant decrease in oxaloacetate, urea and glucose concentrations. The mass action ratios for alanine aminotransferase, aspartate amino transferase, and glutamate dehydrogenase, generally moved in a parallel direction. Hepatic ATP content was considerably reduced accompanied by a decrease in [ATP]/[ADP] ratios and a significant increased in [lactate]/[pyruvate] and [3-hydroxybutyrate]/[acetoacetate] ratios. There was a corresponding decrease in the [NAD+]/[NADH] ratios both in the cytoplasmic and mitochondrial compartments. These biochemical changes were particularly severe in rats maintained on Diet 1 and Diet 2 for 8 weeks. There was a very good relationship between impaired mitochondrial and endoplasmic reticulum functions, redox and phosphorylation states, and the relevance of their changes to the fate of fatty liver cells.
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PMID:Lipid accumulation in the rat liver: a histological and biochemical study. 23

The metabolism of proline was studied in liver cells isolated from starved rats. The following observations were made. 1. Consumption of proline could be largely accounted for by production of glucose, urea, glutamate and glutamine. 2. At least 50% of the total consumption of oxygen was used for proline catabolism. 3. Ureogenesis and gluconeogenesis from proline could be stimulated by partial uncoupling of oxidative phosphorylation. 4. Addition of ethanol had little effect on either proline uptake or oxygen consumption, but strongly inhibited the production of both urea and glucose and caused further accumulation of glutamate and lactate. Accumulation of glutamine was not affected by ethanol. 5. The effects of ethanol could be overcome by partial uncoupling of oxidative phosphorylation. 6. The apparent K(m) values of argininosuccinate synthetase (EC 6.3.4.5) for aspartate and citrulline in the intact hepatocyte are higher than those reported for the isolated enzyme. 7. 3-Mercaptopicolinate, an inhibitor of phosphoenolpyruvate carboxykinase (EC 4.1.1.32), greatly enhanced cytosolic aspartate accumulation during proline metabolism, but inhibited urea synthesis. 8. It is concluded that when proline is provided as a source of nitrogen to liver cells, production of ammonia by oxidative deamination of glutamate is inhibited by the highly reduced state of the nicotinamide nucleotides within the mitochondria. 9. Conversion of proline into glucose and urea is a net-energy-yielding process, and the high state of reduction of the nicotinamide nucleotides is presumably maintained by a high phosphorylation potential. Thus when proline is present as sole substrate, the further oxidation of glutamate by glutamate dehydrogenase (EC 1.4.1.3) is limited by the rate of energy expenditure of the cell.
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PMID:Prolone metabolism in isolated rat liver cells. 64 9

The hypothesis that mictochondrial damage is a significant factor in the pathogenesis of alcoholic liver disease (ALD) was investigated by enzymic analysis of mitochondrial fractions isolated from needle biopsy specimens from control patients, patients with fatty liver due to chronic alcoholism, and from patients with other forms of liver disease. Enzymes associated with the inner and outer mitochondrial membranes showed normal levels in ALD. Enzymes associated with the mitochondrial matrix, glutamate dehydrogenase, malate dehydrogenase and aspartate aminotransferase showed significantly raised levels in ALD, but the levels in patients with non-alcoholic liver disease was normal. In addition, analysis of the mitochondria by sucrose density gradient centrifugation revealed no differences between control tissue and liver from patients with alcoholic liver disease. These results do not indicate that there is significant mitochondrial damage in ALD. The raised mitochondrial matrix enzymes may represent an adaptive response to the ethanol load.
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PMID:Mitochondrial enzyme activities in liver biopsies from patients with alcoholic liver disease. 65 61

The influence of potassium on ethanol production by Saccharomyces cerevisiae wild type and AR5 cells carrying the plasmid pCYG4 was investigated. This plasmid carries the glutamate dehydrogenase gene conferring an 11-fold higher level of expressed enzyme activity over the wild type cells. All experiments were carried out in batch culture with medium supplemented to different potassium concentrations up to 180 mM. Maximum ethanol production rate was observed in the AR5 cells grown in medium supplemented with 3.5 mM of potassium ions. Glucose uptake rate increased with increasing potassium up to 60 mM, but higher concentrations depressed glucose uptake rate in both strains. Furthermore, the wild type cells showed higher growth rate, ethanol production, and glucose consumption rate than the AR5 cells. These lower rates in the AR5 cells could be explained by repression of potassium uptake by an enhancement of ammonium feeding, and greater energy requirements by these cells due the presence of the plasmid.
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PMID:Effects of potassium on the ethanol production rate of Saccharomyces cerevisiae carrying the plasmid pCYG4 related with ammonia assimilation. 128 12

The inability of the 'ethanol/high vitamin A Lieber-DeCarli diet' to induce liver fibrosis in two different rat strains was further evaluated by determining changes in parameters of liver cell damage and of retinoid and lipid metabolism. In the ethanol/vitamin A-treated group, slight but constant hepatic cell damage, as indicated by elevated alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase activities in blood, was already observed at 6 months and maintained until the time of death at 16 months. Serum gamma-glutamyl transaminase activities were not raised. Moderate parenchymal liver cell damage was not accompanied by fibrosis. Hypertriglyceridemia or hypercholesterolemia were observed at 6-16 months of chronic alcohol administration. This response was strain dependent. In ethanol-treated rats of both strains, total liver retinoids and serum retinol concentrations were not altered. Therefore, the hypothesis that interaction between alcohol and retinoids is a major factor in the pathogenesis of alcoholic liver disease, needs to be reconsidered.
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PMID:Chronic administration of ethanol with high vitamin A supplementation in a liquid diet to rats does not cause liver fibrosis. 2. Biochemical observations. 174 28

To study the effects of ethanol on the hepatotoxicity of N-nitrosodimethylamine (NDMA), 5 mg NDMA/kg body weight was injected intraperitoneally 3 times a week for 6 weeks into rats pair-fed liquid diets containing 36% of energy either as ethanol or as additional carbohydrates. Another group of rats was pair-fed with the same diets but injected with saline instead of NDMA. Co-administration of ethanol and NDMA produced much higher elevations of serum alanine and aspartate aminotransferase and glutamic dehydrogenase activities than the administration of either agent alone. The combined treatment also slightly increased focal necrosis, whereas other liver lesions (steatosis and fibrosis) and the functional impairment of mitochondrial respiration were not affected significantly. Microsomal low Km NDMA demethylation, as well as NDMA denitrosation, were inhibited markedly by incubation with an antibody against P450IIE1, suggesting the involvement of this alcohol-inducible P450 in both NDMA bioactivation reactions. The addition of ethanol inhibited P450-dependent demethylation and denitrosation of NDMA in liver microsomes, whereas both activities were enhanced markedly by chronic ethanol administration. At ethanol concentrations similar to those prevailing in the blood of alcohol-fed animals at the time of NDMA administration, hepatic microsomal demethylation and denitrosation remained significantly higher in ethanol-fed rats given NDMA than in controls. Our results suggest that bioactivation plays a critical role in the hepatotoxicity of NDMA and its aggravation by chronic alcohol consumption.
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PMID:Effects of ethanol consumption on bioactivation and hepatotoxicity of N-nitrosodimethylamine in rats. 185 64

Two decades of research in ethanol metabolism have culminated in the molecular elucidation of an ethanol-inducible cytochrome P450 (P450IIE1) which is not only involved with ethanol metabolism and ethanol tolerance, but also with the activation of a number of xenobiotics. The unique ability of P450IIE1 to activate xenobiotic agents now appears to be responsible for the increased susceptibility of the heavy drinker to hepatotoxic industrial solvents, commonly used drugs, over-the-counter medications and chemical carcinogens. It also explains some of the interaction of ethanol with nutritional factors, such as hepatic vitamin A: enhanced microsomal degradation of retinoids (together with hepatic mobilisation) promotes depletion. Treatment, however, is complicated by the fact that ethanol also enhances the toxicity of excess vitamin A. All pathways of ethanol metabolism result in the production of acetaldehyde, the toxicity of which has been reviewed (Lieber 1982). New aspects discussed here include the formation of acetaldehyde-protein adducts and an associated immune response that may play a pathogenic role. Also discussed are the implications of ethanol-induced alterations in microtubules, mitochondria and plasma membranes, as they relate, in part, to accompanying acetaldehyde-induced toxicity, to the production of free radicals or to lipid peroxidation-mediated injury associated with glutathione depletion. There is also depletion of S-adenosyl-L-methionine (SAMe). Administration of synthetic SAMe results in a partial correction of the SAMe depletion and a consequent restoration of glutathione levels. Other beneficial effects of SAMe include a significant attenuation of the increase in plasma aspartate transaminase and glutamate dehydrogenase activities. Mitochondrial damage, including giant forms, documented by light and electron microscopy, is also attenuated by SAMe. Thus, the new understanding of the pathophysiology of alcohol-induced liver damage has led to more successful therapy with drugs and nutritional factors.
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PMID:Interaction of alcohol with other drugs and nutrients. Implication for the therapy of alcoholic liver disease. 208 78

Administration of enflurane (EF), a widely-used anesthetic agent, sometimes results in occult liver injury. As hepatic cytochromes P450 oxidize EF to a reactive intermediate, we assessed whether one such microsomal enzyme, ethanol-inducible P450IIE1, plays an obligatory role in EF metabolic activation and hepatotoxicity. Liver microsomes from rats fed ethanol (36% of total calories for 14 days) oxidized 1 mM EF (measured by its defluorination) at rates nearly 10-fold greater than those from control rats, reflecting the markedly enhanced content of immunoreactive microsomal P450IIE1 in the former animals. P450IIE1 involvement in hepatic EF oxidation was further suggested by the pronounced inhibition of microsomal defluorination noted with P450IIE1 antibodies and with ethanol, a specific substrate for this enzyme. EF administration to rats treated chronically with ethanol caused significant elevations in plasma levels of aspartate and alanine aminotransferases and glutamate dehydrogenase, indicative of hepatic injury, whereas concurrent treatment of naive rats with EF and ethanol failed to produce the same effect. Our results imply that ethanol-inducible P450IIE1 is the primary catalyst of hepatic EF bioactivation and that the increased bioactivation occurring in vivo secondary to chronic ethanol consumption is attendant with an increased incidence of EF hepatotoxicity.
Alcohol Clin Exp Res 1990 Apr
PMID:Interaction of ethanol with enflurane metabolism and toxicity: role of P450IIE1. 219 Apr 81

A single administration to rats of cyanamide (60 mg/kg, for 1 hour) was found to decrease the contents of cysteate, serine, glutamate, glycine, alanine, valine, methionine, isoleucine, tyrosine, ethanolamine, ornithine and histidine that may be considered as a manifestation on the drug hepatotoxicity. The activities of transaminases, glutamate dehydrogenase, pyruvate dehydrogenase remained unchanged. Cyanamide effects were considerably abolished by the supplementary ethanol administration (0.5 g/kg). Cyanamide failed to affect vitamin-dependent enzymes reflecting thiamine pyrophosphate, pyridoxal phosphate and flavine adenine dinucleotide status of the rat organism.
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PMID:[Free amino acids of the liver and the characteristics of the amino acid metabolism in the liver and brain after cyanamide administration to rats]. 222 67

Chronic ethanol consumption by baboons (50% of energy from a liquid diet) for 18 to 36 mo resulted in significant depletion of hepatic S-adenosyl-L-methionine concentration: 74.6 +/- 2.4 nmol/gm vs. 108.9 +/- 8.2 nmol/gm liver in controls (p less than 0.005). The depletion was corrected with S-adenosyl-L-methionine (0.4 mg/kcal) administration (102.1 +/- 15.4 nmol/gm after S-adenosyl-L-methionine-ethanol, with 121.4 +/- 11.9 nmol/gm in controls). Ethanol also induced a depletion of glutathione (2.63 +/- 0.13 mumol/gm after ethanol vs. 4.87 +/- 0.36 mumol/gm in controls) that was attenuated by S-adenosyl-L-methionine (3.89 +/- 0.51 mumol/gm in S-adenosyl-L-methionine-methanol vs. 5.22 +/- 0.53 mumol/gm in S-adenosyl-L-methionine controls). There was a significant correlation between hepatic S-adenosyl-L-methionine and glutathione level (r = 0.497; p less than 0.01). After the baboons received ethanol, we observed the expected increase in circulating levels of the mitochondrial enzyme glutamic dehydrogenase: 95.1 +/- 21.4 IU/L vs. 13.4 +/- 1.8 IU/L; p less than 0.001, whereas in a corresponding group of animals given S-adenosyl-L-methionine with ethanol, the values were only 30.3 +/- 7.1 IU/L (vs. 9.6 +/- 0.7 IU/L in the S-adenosyl-L-methionine controls). This attenuation by S-adenosyl-L-methionine of the ethanol-induced increase in plasma glutamic dehydrogenase (p less than 0.005) was associated with a decrease in the number of giant mitochondria (assessed in percutaneous liver biopsy specimens), with a corresponding change in the activity of succinate dehydrogenase, a mitochondrial marker enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:S-adenosyl-L-methionine attenuates alcohol-induced liver injury in the baboon. 230 95


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