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:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, we demonstrated the hepatoprotective effects of nicotinic acid amide, a selective inhibitor of poly(ADP-ribose) polymerase (PARP; EC 2.4.2.30) on mice suffering from acetaminophen (AAP)-hepatitis, suggesting that the AAP-induced liver injury involves a step which depends on adenoribosylation. The present study investigates the effects of a diet free of precursors of NAD, the substrate on which PARP acts, in female NMRI mice with AAP hepatitis and evaluates the influence of simultaneous ethanol consumption in these animals. Liver injuries were quantified as serum activities of glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT). While AAP caused a 117-fold elevation of serum transaminase activities in mice kept on a standard laboratory diet, which was significantly exacerbated by ethanol and inhibited by nicotinic acid amide (NAA), adverse effects were noted in animals fed a diet free of precursors of NAD. In these animals, only minor increases of serum transaminase activities were measured in the presence of AAP, and unlike the exacerbation caused by ethanol in mice on a standard diet, the liver damage was inhibited by 50% by ethanol. A further 64% reduction of hepatitis was observed, when NAA was given to ethanol/AAP-mice. Our results provide evidence that the AAP-induced hepatitis and its exacerbation by ethanol can either be reduced by end-product inhibition of PARP by NAA or by dietary depletion of the enzyme's substrate NAD. We see the main application of NAA as for the combinational use in pharmaceutical preparations of acetaminophen in order to avoid hepatic damage in patients treated with this widely used analgesic.
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PMID:Influence of diet free of NAD-precursors on acetaminophen hepatotoxicity in mice. 874 98

An array of therapeutically used analgetic and antirheumatic drugs causes severe liver damage. The present study investigates the hepatoprotective effects of inhibitors of NAD-dependent adenoribosylation reactions in analgesics-induced hepatic injury. Male NMRI mice were treated perorally with 500 mg/kg of acetaminophen, and the activities of both glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) were determined in serum. In addition, the activity of poly(ADP-ribose)polymerase (PARP) was quantified in liver cell nuclei. While the PARP-activity remained essentially unchanged, the acetaminophen-induced release of both GOT and GPT from injured liver cells could be inhibited by 90-99%, when mice were injected additionally with the selective PARP-inhibitors nicotinic acid amide, benzamide, caffeine, theophyline, and thymidine, respectively. We see the main application of inhibitors of adenoribosylation reactions as for the combinational use in pharmaceutical preparations of analgesics and antirheumatic drugs in order to avoid hepatic damage.
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PMID:The influence of antagonists of poly(ADP-ribose) metabolism on acetaminophen hepatotoxicity. 874 16

1. An array of therapeutically used analgetic and antirheumatic drugs cause severe liver damage. The present study investigates the hepatoprotective effects of inhibitors of NAD-dependent adenoribosylation reactions and of antioxidants in analgesic-induced hepatic injury. 2. Male NMRI mice were treated PO with 500 mg/kg of acetaminophen, and the activities of both glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) were determined in serum. 3. The acetaminophen-induced release of both GOT and GPT from injured liver cells could be inhibited in a dose-dependent manner, when mice were injected additionally either with increasing amounts (from (25 mg/kg to 100 mg/kg i.p.) of the PARP-inhibitor nicotinamide, with increasing amounts (from 25 mg/kg to 100 mg/kg i.p.) of the antioxidant N-acetylcysteine, or with increasing amounts (from 50 mg/kg to 300 mg/kg i.p.) of the amino acid L-methionine. 4. A combination of both nicotinamide and N-acetylcysteine (at the low dose of 12.5 mg/kg i.p. each) results in a complete protection from acetaminophen-induced release of GOT and GPT from injured liver cells. 5. A combination of both L-methionine and N-acetylcysteine or nicotinamide (at the low dose of 12.5 mg/kg IP each) resulted also in complete protection from acetaminophen-induced release of GOT and GPT.
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PMID:Protection from acetaminophen-induced liver damage by the synergistic action of low doses of the poly(ADP-ribose) polymerase-inhibitor nicotinamide and the antioxidant N-acetylcysteine or the amino acid L-methionine. 901 4

The anaerobic fungus Piromyces sp. strain E2 appeared restricted in nitrogen utilization. Growth was only supported by ammonium as source of nitrogen. Glutamine also resulted in growth, but this was due to release of ammonia rather than to uptake and utilization of the amino acid. The fungus was not able to grow on other amino acids, albumin, urea, allantoin, or nitrate. Assimilation of ammonium is very likely to be mediated by NADP-linked glutamate dehydrogenase (NADP-GDH) and glutamine synthetase (GS). One transaminating activity, glutamate-oxaloacetate transaminase (GOT), was demonstrated. Glutamate synthase (GOGAT), NAD-dependent glutamate dehydrogenase (NAD-GDH), and the transaminating activity glutamate-pyruvate transaminase (GPT) were not detected in cell-free extracts of Piromyces sp. strain E2. Specific enzyme activities of both NADP-GDH and GS increased four- to sixfold under nitrogen-limiting conditions.
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PMID:The anaerobic fungus Piromyces sp. strain E2: nitrogen requirement and enzymes involved in primary nitrogen metabolism. 908 17

The idea of a metabolic coupling between neurons and astrocytes in the brain has been entertained for about 100 years. The use recently of simple and well-compartmentalized nervous systems, such as the honeybee retina or purified preparations of neurons and glia, provided strong support for a nutritive function of glial cells: glial cells transform glucose to a fuel substrate taken up and used by neurons. Particularly, in the honeybee retina, photoreceptor-neurons consume alanine supplied by glial cells and exogenous proline. NH4+ and glutamate are transported into glia by functional plasma membrane transport systems. During increased activity a transient rise in the intraglial concentration of NH4+ or of glutamate causes a net increase in the level of reduced nicotinamide adenine dinucleotides [NAD(P)H]. Quantitative biochemistry showed that this is due to activation of glycolysis in glial cells by the direct action of NH4+ and of glutamate, probably on the enzymatic reactions controlled by phosphofructokinase alanine aminotransferase and glutamate dehydrogenase. This activation leads to a massive increase in the production and release of alanine by glia. This constitutes an intracellular signal and it depends upon the rate of conversion of NH4+ and of glutamate to alanine and alpha-ketoglutarate, respectively, in the glial cells. Alanine and alpha-ketoglutarate are released extracellularly and then taken up by neurons where they contribute to the maintenance of the mitochondrial redox potential. This signaling raises the novel hypothesis of a tight regulation of the nutritive function of glia.
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PMID:The nutritive function of glia is regulated by signals released by neurons. 929 50

The oxidative metabolism of glutamine in HeLa cells was investigated using intact cells and isolated mitochondria. The concentrations of the cytoplasmic amino acids were found to be aspartate, 8.0 mM; glutamate, 22.2 mM; glutamine, 11.3 mM; glycine, 9.8 mM; taurine, 2.3 mM; and alanine, < 1 mM. Incubation of the cells with [14C]glutamine gave steady-state recoveries of 14C-label (estimated as exogenous glutamine) in the glutamine, glutamate, and aspartate pools, of 103%, 80%, and 25%, respectively, indicating that glutamine synthetase activity was absent and that a significant proportion of glutamate oxidation proceeded through aspartate aminotransferase. No label was detected in the alanine pool, suggesting that alanine aminotransferase activity was low in these cells. The clearance rate of [14C]glutamine through the cellular compartment was 65 nmol/min per mg protein. There was a 28 s delay after [14C]glutamine was added to the cell before 14C-label was incorporated into the cytoplasm, while the formation of glutamate commenced 10 s later. Aspartate was the major metabolite formed when the mitochondria were incubated in a medium containing either glutamine, glutamate, or glutamate plus malate. The transaminase inhibitor AOA inhibited both aspartate efflux from the mitochondria and respiration. The addition of 2-oxoglutarate failed to relieve glutamate plus malate respiration, indicating that 2-oxoglutarate is part of a well-coupled truncated cycle, of which aspartate aminotransferase has been shown to be a component [Parlo and Coleman (1984): J Biol Chem 259:9997-10003]. This was confirmed by the observation that, although it inhibited respiration, AOA did not affect the efflux of citrate from the mitochondria. Thus citrate does not appear to be a cycle component and is directly transported to the medium. Therefore, it was concluded that the truncated TCA cycle in HeLa cells is the result of both a low rate of citrate synthesis and an active citrate transporter. DNP (10 microM) induced a state III-like respiration only in the presence of succinate, which supports the evidence that NAD-linked dehydrogenases were not coupled to respiration, and suggests that these mitochondria may have a defect in complex I of the electron transport chain. Arising from the present results with HeLa cells and results extant in the literature, it has been proposed that a major regulating mechanism for the flux of glutamate carbon in tumour cells is the competitive inhibition exerted by 2-oxoglutarate on aspartate and alanine aminotransferases. This has been discussed and applied to the data.
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PMID:Oxidation of glutamine in HeLa cells: role and control of truncated TCA cycles in tumour mitochondria. 944 77

Enzyme activity modulation by cadmium in the liver of the teleost fish Sparus aurata was investigated in vivo following 3 and 6 days of CdCl2 administration (2.5 mg/kg body wt). The specific activities of the mitochondrial enzymes NAD-isocitrate dehydrogenase, succinate dehydrogenase, and malate dehydrogenase were stimulated by approximately 20% after 3 days administration and were further increased (by about 40%) after 6 days treatment. In comparison with these enzymes, the activities of glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) in mitochondria were less stimulated after the two indicated intervals of treatment. Cadmium significantly reduced the activities of liver cytoplasmic GOT and GPT while a simultaneous increase occurred in the serum activities of these same enzymes. The activity of liver NADPH-cytochrome P450 reductase was stimulated by 25 and 40% after 3 and 6 days cadmium intoxication, respectively. Lastly, the antioxidant enzymes glutathione peroxidase and glutathione reductase in liver and catalase in both liver and blood were strongly reduced after 3 and 6 days cadmium administration. These data suggest that cadmium in fish hepatocytes alters cell membrane structure and concomitantly induces some perturbation in the integrity of the mitochondrial membrane.
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PMID:Changes in liver enzyme activity in the teleost Sparus aurata in response to cadmium intoxication. 1033 Mar 29

The effect of various metabolic inhibitors on the rate of oxygen consumption by procyclic culture forms of Trypanosoma congolense utilizing proline as substrate was investigated. Cyanide inhibited the rate of oxygen consumption by 81.0 +/- 6.7%, malonate inhibited the rate by 51.6 +/- 1.6% and Antimycin A by 73.1 +/- 5.9%. A combination of cyanide and malonate inhibited the rate of oxygen consumption by 84.9 +/- 6.7% while a combination of antimycin A and malonate inhibited the rate by 81.6 +/- 7.6%. Rotenone had no effect on the rate of respiration except when the intact cells were first permeabilized by digitonin after which rotenone decreased the rate of respiration by 20-30%. Salicylhydroxamate (SHAM) did not have any effect on the rate of oxygen consumption. Enzymes involved in the catabolism of proline with high activities were: proline dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, fumarase, NADP-linked malic enzyme, alanine aminotransferase and malate dehydrogenase. Activities of 1-pyrroline-5 carboxylate dehydrogenase, glutamate dehydrogenase, aspartate aminotransferase and NAD-linked malic enzyme were detectable but lower. The end products of proline catabolism were alanine and glutamate. Unlike the case in Trypanosoma brucei brucei aspartate was not detected. Possible pathways of proline catabolism in procyclic culture forms of T. congolense and of electron transfer are proposed.
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PMID:Catabolism of proline by procyclic culture forms of Trypanosoma congolense. 1042 13

The compartmentation of key processes in sugar, organic acid and amino acid metabolism was studied during the development of the flesh and seeds of grape (Vitis vinifera L.) berries. Antibodies specific for enzymes involved in sugar (cell wall and vacuolar invertases, pyrophosphate: fructose 6-phosphate phosphotransferase, aldolase, NADP-glyceraldehyde-P dehydrogenase, cytosolic fructose 1,6-bisphosphatase), photosynthesis (Rubisco, fructose 1,6-bisphosphatase, sedoheptulose 1,7-bisphosphatase), amino acid metabolism (cytosolic and mitochondrial aspartate aminotransferases, alanine aminotransferase, glutamate dehydrogenase, glutamine synthetase), organic acid metabolism (phosphoenolpyruvate carboxylase, NAD- and NADP-dependent malic enzyme, ascorbate peroxidase), and lipid metabolism (acetyl CoA carboxylase, isocitrate lyase) were used to determine how their abundance changed during development. There were marked changes in the abundance of many of these enzymes in both the flesh and seeds. The intercellular location of some enzymes was investigated using immunohistochemistry. Several enzymes (e.g. phosphoenolpyruvate carboxylase and those involved in amino acid metabolism) were associated with tissues likely to function in the transport of imported assimilates, such as the vasculature. Although other enzymes (e.g. NADP-malic enzyme and soluble acid invertase, involved in the metabolism of sugars and organic acids) were largely present in the parenchyma cells of the flesh, their distribution was extremely heterogeneous. This study shows that when considering the metabolism of complex structures such as fruit, it is essential to consider how metabolism is compartmentalized between and within different tissues, even when they are apparently structurally homogeneous.
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PMID:An immunohistochemical study of the compartmentation of metabolism during the development of grape (Vitis vinifera L.) berries. 1093 59

We investigated the antiischemic properties of a new compound, S-15176, in an experimental model of rat liver subjected to 120-min normothermic ischemia followed by 30-min reperfusion. Rats were divided into groups, pretreated with different doses of S-15176 (1.25, 2.5, 5 and 10 mg/kg/day by intramuscular injection) or solvent alone, and subjected to the ischemia--reperfusion process. Another group served as the sham-operated controls. Ischemia--reperfusion induced huge alterations of hepatocyte functions, namely, a decrease in ATP content and bile flow, and membrane leakage of alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT). These effects were associated with alterations in mitochondrial functions characterized by (1) a decrease in ATP synthesis, (2) a decrease in NAD(P)H levels and mitochondrial membrane potential, and (3) an increase in mitochondrial swelling reflecting the generation of permeability transition. Pretreatment of rats with S-15176 alleviated these deleterious ischemia--reperfusion effects at both the cellular and mitochondrial levels in a dose-dependent manner. The protection of mitochondrial functions was almost complete at a dosage of 10 mg/kg/day. In addition, in vitro, S-15176 totally abolished the swelling of isolated mitochondria induced by a calcium overload with an IC(50) value of 10 microM. These data demonstrate that S-15176 protects mitochondria against the deleterious effects of ischemia-reperfusion and suggest that this protective effect could be related to the inhibition of the mitochondrial permeability transition.
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PMID:Attenuation of liver normothermic ischemia--reperfusion injury by preservation of mitochondrial functions with S-15176, a potent trimetazidine derivative. 1144 61


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