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)

The purposes of this study were to clarify the role of neutrophilic proteases in the pathogenesis of hepatic ischemia/reperfusion injury and to determine whether urinary trypsin inhibitor (UTI) pretreatment attenuated liver ischemia/reperfusion injury in rats. Livers from male Sprague-Dawley rats were subjected to 90 min of no-flow warm ischemia followed by 120 min of reperfusion. Rats were divided into a UTI group and a control group. In the control group, 120-min reperfusion of the liver produced a significant increase in myeloperoxidase activity, a significant decrease in ATP and energy charge, and a marked increase in the serum aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase levels. In the UTI group, the myeloperoxidase activity was significantly attenuated (P < 0.01), ATP and energy charge were significantly improved (P < 0.01 and P < 0.05, respectively), and the elevation in serum aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase was also markedly suppressed (P < 0.05, P < 0.01, and P < 0.05, respectively) compared with the control group. Sections through the livers of control rats showed severe hepatocyte necrosis with neutrophil infiltration. In the UTI group, there was slight congestion and hepatocyte necrosis. The survival rate after 90-min liver ischemia was significantly improved compared with that in the control group (P < 0.05). The results of this study suggest that pretreatment with UTI significantly attenuates liver reperfusion injury, perhaps by inhibiting neutrophil proteases.
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PMID:Effect of protease inhibitor on ischemia/reperfusion injury of the rat liver. 827 98

Studies have shown that ethanol at moderate concentrations inhibits epidermal growth factor-dependent replication of fetal rat hepatocytes in culture. This may account for the growth/development impairment associated with fetal alcohol syndrome and decreased liver regeneration in alcoholic liver disease. In this study, we further define the mechanism(s) of the negative impact of ethanol on fetal rat hepatocytes and provide evidence that ethanol-induced injury to these cells is associated with membrane damage caused by lipid peroxidation, altered cell glutathione homeostasis and deranged mitochondrial structure and function. Exposure of fetal rat hepatocyte replication to ethanol (2 mg/ml) promptly resulted in blockade of replication, as indicated by a 40% reduction in DNA synthesis (p < 0.05). Assessment of cell injury on the basis of lactate dehydrogenase and ALT leakage indicated a statistically significant but not appreciable effect, whereas 51Cr leakage was more substantially increased (p < 0.05). Within 6 hr of ethanol exposure, superoxide radical levels increased more than twofold (p < 0.05). We noted a 56% increase in levels of diene conjugates, a 131% increase in malonaldehyde concentration and a 66% increase in fluorescent products of lipid peroxidation (all p < 0.05). Glutathione levels were decreased to 47% below control values (p < 0.05). Electron microscopic studies illustrated a slight disruption of mitochondrial structure (enlargement of mitochondria and dilation of cristae). This disruption was accompanied by mitochondrial swelling (increased permeability), altered mitochondrial membrane potential (a 16% decrease in rhodamine uptake), a 28% decrease in succinate dehydrogenase activity and a 30% decrease in cellular ATP level (p < 0.05). Pretreatment of fetal rat hepatocytes with 0.1 mmol/L N-acetylcysteine or S-adenosylmethionine for 24 hr prevented the ethanol-induced reduction of ATP and glutathione levels, essentially restored cell replication, ameliorated 51Cr leakage and decreased malonaldehyde and diene conjugate levels to 41% to 65% and 25% above control values, respectively. Pretreatment with 0.1 mmol/L vitamin E fully normalized malonaldehyde and diene conjugate levels and 51Cr leakage but failed to improve ATP levels or to increase significantly cell replication and glutathione levels. Concomitant administration of glutathione precursors with ethanol, rather than pretreatment, did not alter the impaired cell replication. Thus our data underscore the importance of cellular glutathione and ATP in preventing ethanol-induced decreases in fetal cell replication and suggest that alleviation of cellular lipid peroxidation alone is not sufficient to prevent this abnormality in fetal rat hepatocyte function.
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PMID:Effect of ethanol on rat fetal hepatocytes: studies on cell replication, lipid peroxidation and glutathione. 835 6

We have investigated the relationship between ATP levels and the onset and progression of cell injury induced by paracetamol overdose both in vivo and in vitro. Liver slices obtained from phenobarbitone-induced and non-induced rats were used in a model in vitro system. Slices were exposed to paracetamol (2-10 mM), for 120 min and then incubated without paracetamol for a further 240 min. ATP levels are reduced upon exposure to paracetamol in liver slices from both phenobarbitone-induced and non-induced rats. Cell injury, as quantified by measuring leakage of lactate dehydrogenase (LDH) and potassium (K+), does not become apparent until 240 min, some 120 min after exposure to paracetamol had ended. This irreversible cell injury is not observed in liver slices from non-induced rats. For in vivo studies rats were phenobarbitone-induced and received i.p. injections of 800 mg/kg body weight paracetamol. Hepatic ATP levels were measured and are found to drop sharply by 3 h post-injection. Development of irreversible hepatic cell injury was assessed by measuring serum enzyme (ALT) activity. ALT levels do not rise until 12 h have elapsed. Paracetamol in overdose gives rise to ATP depletion in liver cells, that is early, independent of paracetamol metabolism and probably spread throughout the lobule. In contrast cell injury is found late and only in our phenobarbitone-induced rats. No cell injury is observed in liver slices from non-induced rats. This suggests that while the level of ATP depletion which is observed may be a necessary part of cell injury by paracetamol, it is not a sufficient cause.
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PMID:Adenosine triphosphate (ATP) levels in paracetamol-induced cell injury in the rat in vivo and in vitro. 856 May 7

Oxygen free radicals have been shown to be implicated in ischemic tissue injury, and free radical-induced reactions may also play an important role in the pathophysiology of circulatory shock. The present study was designed to investigate the potential use of ascorbic acid as an exogenous antioxidant on the liver's recovery from hemorrhagic shock in situ. Rats (fasted overnight) were subjected to 60 min of hemorrhagic shock (HS) (mean arterial pressure = 40 mmHg) under pentobarbital anesthesia, followed by retransfusion of the shed blood. One-half of the animals (n = 6) were injected with 10 mg/kg of ascorbic acid prior to induction of shock, while untreated animals (n = 6) received the same volume of saline solution. in untreated animals, systemic plasma levels of malondialdehyde rose from 1.07 +/- .08 during normotension (NT) to 1.36 +/- .18* 60 min after resuscitation (RS), documenting oxygen free radical-induced lipid peroxidation. Accordingly, plasma levels of alanine aminotransferase (16.5 +/- 2.5; 34.9 +/- 12.3*; 105.8 +/- 68.7* U/L; NT/HS/RS) and ammonia (127 +/- 40; 532 +/- 160*; 304 +/- 244* micrograms/dL) rose significantly during the experiment. Hepatic ATP content of the liver fell from 4.8 +/- .83 to .56 +/- .27* after HS and recovered partially to 2.7 +/- 1.6* mumol/g after RS. Leukocyte infiltration in the liver, indicated by tissue levels of myeloperoxidase, remained constant during HS but rose during RS (37.9 +/- 18.5; 38.6 +/- 16.4; 81.4 +/- 30.7*, arbitrary units), thus documenting an inflammatory reaction after HS. In the ascorbic acid group, plasma levels of malondialdehyde were comparable to those of untreated animals after RS, as were enzyme concentrations and ammonia. No differences were observed with regard to the tissue concentrations of ATP or myeloperoxidase. Mean arterial blood pressure as well as liver tissue perfusion, as measured by Laser Doppler flowmetry, did not show significant differences between the groups. It was concluded that, although an effect of oxygen free radicals on liver tissue could be found during and after HS, treatment with ascorbic acid alone, in our model, failed to ameliorate the recovery of the animals upon resuscitation (values are mean +/- SD; *, p < .05 vs. NT; one-way ANOVA).
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PMID:No evidence for a protective effect of ascorbic acid on free radical generation and liver injury after hemorrhagic shock in rats. 872 88

Delayed fluid resuscitation of burn shock may lead to many harmful effects. We investigated the injury of liver and kidney of rats sustaining non-fluid perfusion, immediate perfusion, and delayed perfusion of burn shock. The electron spin reonance (ESR) was used to determine the existence of oxygen free radicals (OFR) successfully. We tested the activity of ATP enzyme in kidney, lactate dehydrogenase isoenzyme 5 (LDH5), GPT and GOT. We also tested the contents of malonaldehyde (MDA) and ATP in liver and kidney, urea nitrogen (BUN) and creatinine (Cr) in blood. We found that OFR plays an important role in the injury of liver and kidney sustaining delayed fluid resuscitation of burn shock. Immediate fluid perfusion can not protect the liver and kidney perfectely. And some OFR scavengers should be added to the fluid resuscitation of burn shock.
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PMID:[The injury of liver and kidney of rats sustaining delayed fluid resuscitation of burn shock]. 876 54

The effect of antithrombin III (AT III) supplementation on energy status, microcirculation, cytoprotection, and prostacyclin (PGI2) production during and after a period of warm ischemia of the rat liver was investigated. AT III supplementation (250 units/kg) stimulate prostaglandin I2 (PGI2) production from 1 hour after administration, with maximal production observed at 3 hours. Ischemia was induced by occluding the hepatoduodenal ligament for 30 minutes, and experiments were continued for 60 minutes after reperfusion. The rats received AT III (250 units/kg IC) 30 minutes before induction of liver ischemia (AT III group). In the AT III group, recovery of the beta-ATP/inorganic phosphate ratio measured by 31P nuclear magnetic resonance showed significant improvement (p < 0.01), and the recovery of tissue blood flow markedly improved (p < 0.01) compared to the saline-treated group (control group). Leakages of aspartame aminotransferase, alanine aminotransferase, and lactate dehydrogenase were mitigated in the AT III group (p < 0. 05). Ultrastructural alterations of sinusoidal endothelial cells were markedly reduced in the AT III group. The PGI2 level at the end of reperfusion was significantly elevated (p < 0.01) in the AT III group compared to the control group. The results of this study indicated that pretreatment with AT III significantly improved the energy status and microcirculation, as well as histologic damage, after liver ischemia and reperfusion. One of the fundamental effects of AT III might be mediated through the production of prostacyclin.
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PMID:Protective effects of antithrombin III supplementation on warm ischemia and reperfusion injury in rat liver. 879 66

The importance of arterial reconstruction in experimental orthotopic rat liver transplantation is widely acknowledged in the literature. Non-rearterialization of the graft leads to impaired microcirculation and, in chronic models, to severe hepatobiliary damage, together with bile duct proliferation and fibrosis in such livers. The aim of the current study was to investigate the impact of rearterialization on hepatic oxygen tension (pO2), hepatic tissue content of adenine nucleotides, early graft function, and postoperative outcome. Orthotopic liver transplantation was performed in 27 male inbred rats. Ten rats underwent rearterialization and while 17 did not. A group of sham-operated animals (n = 6) served as controls. After reperfusion, liver grafts without arterial reconstruction showed significantly reduced levels of oxygen tension (mean +/- SD, 3.79 +/- 2.20 vs. 10.03 +/- 2.84 mmHg; P < 0.05) and a clear shift toward lower pO2 values in the pO2 histograms, as compared with arterialized grafts. Without arterialization, the level of liver ATP was 65% of that in sham animals, compared with 84% in arterialized livers. Without arterialization, bile secretion was reduced (0.42 +/- 0.04 vs. 0.71 +/- 0.06 mg/min x g liver; (P < 0.001), and the postoperative course of serum alanine transaminase, bilirubin, and alkaline phosphatase revealed severe hepatobiliary damage. These findings allow us to conclude that graft rearterialization is essential to ensure both an adequate oxygen supply and maintenance of tissue ATP. Arterialization may thus be a necessary part of liver transplantation models in this animal species, and should be considered when designing studies on the biochemical, microcirculatory, and histopathological status of the graft.
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PMID:Impact of arterialization on hepatic oxygen supply, tissue energy phosphates, and outcome after liver transplantation in the rat. 883 Aug 19

The putative hepatoprotective effect of cyclosporine A (CyA) against the hepatic injury associated with ischemia and reperfusion was studied in rats after a two-thirds hepatectomy following a 60-minute period of ischemia of the unresected liver. Animals were divided into three distinct groups of 10 rats each Group 1 (controls) received 0.5 ml saline solution intravenously (i.v.) while group 2 animals were injected with CyA (5 mg/kg) i.v., 24 hours before the induction of hepatic ischemia. The hepatic ATP content and serum levels of ALT and LDH were determined in each animal. Rats in group 3 were subjected to two-thirds hepatectomy only without the induction of ischemia. All controls died within 72 hours (group 1). Pretreatment of CyA improved the 7-day survival to 60% (p < 0.01). All group 3 animals survived through seven days. The improved survival seen in CyA pretreated animals as compared to controls was reflected by a restoration of hepatic ATP content and reduction in the serum levels of ALT and LDH postoperatively. Based on these results, it may be concluded that CyA ameliorates the hepatic injury associated with ischemia and reperfusion and allows the liver to recover and regenerate. Subsequently, survival is enhanced.
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PMID:Protective effect of cyclosporine A (CyA) against the hepatic injury associated with ischemia and reperfusion. 891 89

The red blood cell metabolic parameters ATP, ADP, sigma AN, ATP/ADP, ATP/ATP, energy charge, PAD, 2,3-DPH, Pn were studied in 106 patients with generalized meningococcus infection (GMI) and meningitis of other etiology over their natural history. There was a typical adaptative red blood cell response that featured glycolytic stimulation on hypoxia that ran with impaired red blood cell energy metabolism (RBCEM), negative energy balance. It was the most pronounced at the peak of disease. RBCEM changes occurred in the presence of antioxidative disorders of red blood cells as lowered PAD levels. When early complications, such as shock, brain edema, death developed, there was a high incidence of signs of erythrocytic biochemical disadaptation. The RBCEM changes were associated with the magnitude of cytolysis, i.e. serum AST and AST/ALT levels. The significance of the metabolic changes found in the red blood cells in the pathogenesis and clinical picture of GMI and purulent meningitis is discussed in the paper.
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PMID:[Erythrocyte metabolism in meningococcal infection and purulent meningitis]. 899 64

We describe a 76-year-old male patient who developed a life-threatening acute hepatotoxicity possibly caused by flutamide, an antiandrogen drug given during the previous 10 months, in the scenario of a brief moderate hypotension secondary to atrial flutter. There was a sudden increase of liver enzyme levels AST = 4.521 IU/L, ALT = 1.716 IU/L (normal values 0-37 and 0-40 respectively), prothrombin activity decreased to 16%, and also felt the platelet count, with significant haemorrhages. We hypothesize this was triggered as a consequence of the transient diminished supply of oxygen to the subclinically flutamide-damaged hepatocytes by the well-known mechanism of the cytochrome P450 (3A and 1A)-mediated formation of electrophilic metabolites, and the inhibitory effect of flutamide on mitochondrial respiration and ATP formation.
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PMID:[Hepatoxicity caused by flutamide increased by hypotensive situation?]. 901 17


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