Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The retina of honeybee drone is a nervous tissue with a crystal-like structure in which glial cells and photoreceptor neurons constitute two distinct metabolic compartments. The phosphorylation of glucose and its subsequent incorporation into glycogen occur in glia, whereas O2 consumption (QO2) occurs in the photoreceptors. Experimental evidence showed that glia phosphorylate glucose and supply the photoreceptors with metabolic substrates. We aimed to identify these transferred substrates. Using ion-exchange and reversed-phase HPLC and gas chromatography-mass spectrometry, we demonstrated that more than 50% of 14C(U)-glucose entering the glia is transformed to alanine by transamination of pyruvate with glutamate. In the absence of extracellular glucose, glycogen is used to make alanine; thus, its pool size in isolated retinas is maintained stable or even increased. Our model proposes that the formation of alanine occurs in the glia, thereby maintaining the redox potential of this cell and contributing to NH3 homeostasis. Alanine is released into the extracellular space and is then transported into photoreceptors using an Na(+)-dependent transport system. Purified suspensions of photoreceptors have similar alanine aminotransferase activity as glial cells and transform 14C-alanine to glutamate, aspartate, and CO2. Therefore, the alanine entering photoreceptors is transaminated to pyruvate, which in turn enters the Krebs cycle. Proline also supplies the Krebs cycle by making glutamate and, in turn, the intermediate alpha-ketoglutarate. Light stimulation caused a 200% increase of QO2 and a 50% decrease of proline and of glutamate. Also, the production of 14CO2 from 14C-proline was increased. The use of these amino acids would sustain about half of the light-induced delta QO2, the other half being sustained by glycogen via alanine formation. The use of proline meets a necessary anaplerotic function in the Krebs cycle, but implies high NH3 production. The results showed that alanine formation fixes NH3 at a rate exceeding glutamine formation. This is consistent with the rise of a glial pool of alanine upon photostimulation. In conclusion, the results strongly support a nutritive function for glia.
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PMID:Glial cells transform glucose to alanine, which fuels the neurons in the honeybee retina. 812 Jun 29

An inverse relation is known to link blood potassium with renal synthesis and the release of ammonia. Given the liability of hyperammonemia for precipitating hepatic encephalopathy (HE), 28 patients affected by stage I HE were equally divided into two groups and maintained up to their death at the highest (5.4-5.5 mEq/l) or the lowest (3.5-3.6 mEq/l) normokalemia levels. When compared with the lowest normokalemia group, the highest one showed an early, albeit transient, improvement in the mental state (as assessed by both EEG and psychiatric investigations) and to a lesser extent in hepatic functions (as assessed by the variations in serum bilirubin, GPT, GGT and plasma prothrombin time). In the highest normokalemia group the survival was also prolonged. The cause of this improvement may be related to the induced decrease in blood pH, the consequent depression of renal ammoniagenesis and the rise in the arterial and urine NH+4/NH3 ratios. These factors reduce the entry of ammonia into the cells and enhance the urinary excretion of this metabolite, respectively.
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PMID:The importance of the highest normokalemia in the treatment of early hepatic encephalopathy. 816 17

Plasma hyaluronan (HA) concentration and the rate of HA uptake by the isolated, perfused liver were measured in rats treated with saline, D-galactosamine (GaI-NH2, 50 mg/100 g body wt), gadolinium chloride (GdCl3) (0.5 mg/100 g body wt), and GdCl3 + GaI-NH2. GdCl3 was given 24 hr before GaI-NH2 or saline. Plasma L-alanine:2-oxoglutarate aminotransferase (EC 2.6.1.2), a marker for hepatocyte damage, was increased by 8 hr and remained elevated for 24 hr after GaI-NH2 injection. GdCl3 did not affect plasma enzyme levels when given alone or in association with, but prior to, GaI-NH2. Plasma HA levels were increased (200%) within 24 hr after GaI-NH2 administration. A plateau was reached at 8 hr, which was maintained for at least 24 hr. Although GdCl3 alone did not affect plasma HA levels, it slightly delayed the increase in HA concentration in GaI-NH2-treated rats. Livers, isolated 24 hr after GaI-NH2 treatment, exhibited a severe depression (approximately 67%) of HA uptake. GdCl3 did not prevent this suppression. The data presented indicate that: (1) one of the sinusoidal endothelial cell-dependent functions of the liver, i.e. removal of HA from the blood stream, is profoundly impaired during galactosamine-induced hepatitis, and (2) the adverse effect of GaI-NH2 on this sinusoidal endothelial cell function may not be dependent on CdCl3-suppressible Kupffer cell functions.
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PMID:Association of galactosamine-induced hepatitis in the rat with hyperhyaluronanaemia and decreased hyaluronan uptake by the isolated, perfused liver. 836 40

To determine the effect of varying levels of dietary protein with a constant intake of vitamin B-6 (B-6) on B-6 status, nine women were fed diets providing daily intakes of 1.25 mg B-6 and 0.5, 1.0 and 2.0 g protein/kg body weight. After an 8-d adjustment period, the women consumed each level of dietary protein for 14 d in a Latin-square design. Several direct and indirect B-6 status indicators were measured in blood and urine. Significant differences among protein levels were found for urinary 4-pyridoxic acid (4-PA) excretion (P < 0.01), plasma pyridoxal 5'-phosphate (PLP) concentration (P < 0.05), and urinary excretion of volatile amines (VA, kynurenine plus acetylkynurenine) after a 2-g L-tryptophan load (P < 0.05). Nitrogen intake was significantly negatively correlated with urinary 4-PA excretion (r = -0.619, P < 0.001) and plasma PLP concentration (r = -0.549, P < 0.01), and positively correlated with erythrocyte alanine aminotransferase percentage stimulation (r = 0.418, P < 0.05) and urinary post-tryptophan load excretion of xanthurenic acid (r = 0.535, P < 0.05), kynurenic acid (r = 0.563, P < 0.05) and VA (r = 0.626, P < 0.01). Compared with men consuming diets with similar B-6 to protein ratios In a previous study, the women excreted a greater percentage of the B-6 intake as 4-PA, had lower plasma PLP concentrations and excreted greater amounts of postload urinary tryptophan metabolites at all three protein levels. If the Recommended Dietary Allowance (RDA) of vitamin B-6 is to be based on the dietary B-6 to protein ratio, gender differences in response to varying protein intakes should be considered. For the levels of protein intake used in this study and a B-6 intake of 1.25 mg/d, a B-6 to protein ratio of greater than 0.020 mg/g is required for adequate vitamin B-6 status in women.
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PMID:Vitamin B-6 status of women with a constant intake of vitamin B-6 changes with three levels of dietary protein. 868 52

Muscle proteins turn over slowly and there are minimal diurnal changes in the size of the muscle protein pool in response to feeding and fasting. Nitrogen balance and tracer studies indicate that protein oxidation and net protein breakdown (degradation--synthesis) is not increased during dynamic exercise at intensities of < or = 70% VO2max. An imbalance between muscle protein synthesis and degradation does exist during one leg knee extensor exercise and during two legged cycling in patients with glycogen phosphorylase deficiency. In these latter cases amino acids liberated from the protein pool are used for synthesis of TCA-cycle intermediates and glutamine. Six amino acids are metabolized in resting muscle: leucine, isoleucine, valine, asparagine, aspartate and glutamate. Only leucine and part of the isoleucine molecule can be converted to acetylCoA and oxidized. The carbon skeleton of the other amino acids is used for synthesis of TCA-cycle intermediates and glutamine. The six amino acids provide the amino groups and the ammonia for synthesis of glutamine and alanine, which are released by muscle in excessive amounts. About half of the glutamine release from muscle originates from glutamate taken up from the blood. Glutamine produced by muscle is an important fuel and regulator of DNA and RNA synthesis in mucosal cells and immune system cells and fulfils several other important functions in human metabolism. The alanine aminotransferase reaction functions to establish and maintain high concentrations of TCA-cycle intermediates and a high TCA cycle flux in the first minutes of exercise. A gradual increase in leucine oxidation subsequently leads to a carbon drain on the TCA-cycle in glycogen depleted muscles and may thus reduce the maximal flux in the TCA-cycle and lead to fatigue. Deamination of amino acids and glutamine synthesis present alternative anaplerotic mechanisms in glycogen depleted muscles but only allow exercise at 40-50% of Wmax. It is proposed that the maximal flux in the TCA-cycle is reduced in glycogen depleted muscles due to insufficient TCA-cycle anaplerosis and that this presents a limitation for the maximal rate of fatty acid oxidation. Interactions between the amino acid pool and the TCA-cycle thus seem to play a central role in the energy metabolism of the exercising muscle.
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PMID:Protein and amino acid metabolism in human muscle. 978 36

Forty patients, scheduled for abdominal surgery, were randomized to receive postoperatively either a structured or a physical mixture of long-chain triacylglycerols/medium-chain triacylglycerols (LCT/MCT) emulsions to assess the tolerance and the effectiveness of the structured triacylglycerol emulsion. Total parenteral nutrition started the day after surgery and covered 100% of measured energy expenditure with nitrogen (0.2 g N.kg-1.d-1) and non-protein calories: glucose (50%) and lipids (50%). Blood samples for liver function tests, albumin, transthyretin, and triacylglycerols were checked at 0800 h on the day before surgery and on day 1, day 3, and day 6 after surgery. Urine samples were taken each day from day 1 to day 7 for 3-methylhistidine (3 Me His) and total nitrogen measurements. Aspartate transaminase (ASAT), alanine transaminase (ALAT), and triacylglycerol plasma levels in routine clinical biochemistry increased significantly in the physical mixture group. Nitrogen balance and 3 Me His excretion were not significantly different between groups. Structured triacylglycerol (STG) lipid emulsions are as efficacious as the physical mixture on nitrogen balance in postoperative patients. They could have some advantages: no disturbances were found to occur in liver function tests or plasma triacylglycerol levels.
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PMID:Medium- and long-chain triacylglycerols in postoperative patients: structured lipids versus a physical mixture. 1031 58

Our bioartificial liver (BAL) consists of porcine hepatocytes attached to beads and plasma perfused through the system. The function of our BAL lasts for approximately 7 hours. The objective of the present study was to investigate the efficacy of Nafamostat Mesilate (NM), a protease inhibitor and potent complement inhibitor, for improving the performance of the BAL. The experimental groups were divided as follows; the NM group (n=7) where the BAL had porcine hepatocytes with 3.8x10(-4) M, of NM, and the control group where the BAL had no NM. Plasma obtained from patients suffering from hepatic failure was perfused through the BAL for 10 hours. The viability of the porcine hepatocytes and the levels of alanine aminotransferase (ALT) in the human plasma were measured during perfusion. After the 10-hour perfusion, another human hepatic failure plasma was perfused for an additional 1 hour and then the function of the BAL was evaluated. After the 10-hour perfusion, the viability of the hepatocytes in the NM group was 51 +/- 7%, whereas that in the control group was rapidly reduced by 35 +/- 5%. Although the levels of ALT in the human plasma in both groups increased with the perfusion time, those in the NM group were significantly lower than those in the control group (p < 0.05). These results suggest that NM prevented damage to the porcine hepatocytes in human hepatic failure plasma as compared to the control group. In the human hepatic failure plasma before perfusion, the partial thrombin time (PT) and the plasma ammonia (NH3) levels were 19.8 +/- 12% and 288 +/- 102 microg/dl, respectively. Fischer's ratios were 0.98 +/- 0.39. Even after the 10-hour perfusion, the BAL in the NM group significantly improved the levels of PT (38 +/- 10%; p < 0.05), NH3 (214 +/- 34 microg/dl; p < 0.05) and Fischer's ratios (1.4 +/- 0.3; p < 0.05). On the other hand, the BAL in the control group did not show any improvement in those parameters. In conclusion, NM was found to help in maintaining the viability of porcine hepatocytes in human hepatic failure plasma, thereby allowing the porcine hepatocyte-based BAL to function much better.
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PMID:Efficacy of Nafamostat Mesilate for improving the performance of a bioartificial liver using porcine hepatocytes. 1049 59

DT388GMCSF, a fusion toxin composed of the NH2-terminal region of diphtheria toxin (DT) fused to human granulocyte-macrophage colony-stimulating factor (GMCSF) has shown efficacy in the treatment of acute myeloid leukemia. However, the primary dose-limiting side effect is liver toxicity. We have reproduced liver toxicity in rats using the rodent cell-tropic DT-murine GMCSF (DT390mGMCSF). Serum aspartate aminotransferase and alanine aminotransferase were elevated 15- and 4-fold, respectively, in DT390mGMCSF-treated rats relative to controls. Histologic analysis revealed hepatocyte swelling; however, this did not lead to hepatic necrosis or overt histopathologic changes in the liver. Immunohistochemical staining showed apoptotic cells in the sinusoids, and depletion of cells expressing the monocyte/macrophage markers, ED1 and ED2, indicating that Kupffer cells (KC) are targets of DT390mGMCSF. In contrast, sinusoidal endothelial cells seemed intact. In vitro, DT390mGMCSF was directly cytotoxic to primary KC but not hepatocytes. Two related fusion toxins, DT388GMCSF, which targets the human GMCSF receptor, and DT390mIL-3, which targets the rodent IL-3 receptor, induced a less than 2-fold elevation in serum transaminases and did not deplete KC in vivo. In addition, DTU2mGMCSF, a modified form of DT390mGMCSF with enhanced tumor cell specificity, was not hepatotoxic and was significantly less toxic to KC in vivo and in vitro. These results show that DT390mGMCSF causes liver toxicity by targeting KC, and establish a model for studying how this leads to hepatocyte injury. Furthermore, alternative fusion toxins with potentially reduced hepatotoxicity are presented.
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PMID:Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor-induced hepatotoxicity is mediated by Kupffer cells. 1563 63

There have been many fatal occupational accidents of skin exposure to monochloroacetic acid (MCA). However, there have been no reports of dermatological findings and the lethal consequences have not yet been demonstrated. Therefore, harmful local and systemic effects were investigated after dermal exposure to MCA. A 0.5 mL aliquot of MCA solution (40% w/w) was applied to the abdominal skin of ten 10-week-old male SD rats under anesthesia. The exposure area (25 x 25 mm2) was 1.6% of the total surface area. The dose of MCA per area was 34.1 mg/cm2. Saline was similarly administered to 10 control rats. Histopathological findings after 10 min were observed by light microscopy. Blood samples were collected by exsanguinations from the carotid arteries after 4 h. Skin samples were collected 10 min after the initial exposure. Histological findings showed severe degeneration of collagen bundles in the epidermis and subcutaneous tissues. P(CO2), HCO(3)-, TCO2, BE and glucose levels were decreased in the MCA group. AST, m-AST, ALT, BUN, Cr, NH3, lactic acid, pyruvic acid, RBC, Hb, Hct, total protein and albumin were increased in the MCA group. The burn was determined to be a third-degree burn on the basis of the histopathological findings. The severe toxicity was probably a consequence of the rapid permeability. Biochemical parameters were a consequence of hepatocellular injuries, renal dysfunction, dysglyconeogenesis and dysfunction of ammonia metabolism. MCA reportedly enters the TCA cycle and inhibits aconitase. MCA metabolites also inhibit pyruvate carboxylase in the gluconeogenesis pathway. Therefore, the important serum biochemical abnormalities such as hypoglycemia and lactic acidosis should be monitored to find the acute systemic disorders.
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PMID:Systemic effects and skin injury after experimental dermal exposure to monochloroacetic acid. 1574 77

Total plasma exchange (TPE) corrects coagulopathy in patients with liver disease and removes hepatotoxins/cytokines. This improvement is transient but can be used as a bridge until an organ is identified for liver transplantation (LTx) or the liver itself regenerates. Our aim was to retrospectively assess the efficacy of TPE in fulminant hepatic failure (FHF) and its impact on liver function tests. Between 1995-2001, 39 patients with FHF who had undergone TPE were reviewed. FHF was defined according to the O'Grady criteria based on the duration of encephalopathy as well as jaundice. TPE was performed using the Cobe Spectra TPE (Gambro) in Liver Intensive Care Unit, continued on a daily basis, until either adequate clinical response was achieved, the patient expired, or transplantation occurred. INR, PTT, Fibrinogen, ALT, AST, GGT, BUN, Ammonia, and Total Bilirubin were analyzed before and after TPE. Student's t-test and chi-square test and ANOVA were used for statistical analysis. Thirty-nine patients with FHF (31 females, 8 males with mean age of 32.3, range: 7-64) underwent TPE. Coagulopathy, hyperbilirubinemia, hyperammonemia were significantly improved (P < 0.05). Twenty-one patients survived (54%), 12 required LTx, and 18 patients (including one after LTx) expired. TPE was found to be significantly effective for correction of coagulopathy and improvement of liver tests. This intervention can be considered for temporary liver support until recovery or liver transplantation.
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PMID:The effect of total plasma exchange on fulminant hepatic failure. 1614 21


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