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:2.6.1.1 (aspartate aminotransferase)
21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is well recognized that consumption of alcohol leads to liver disease in a dose-dependent manner; however, the exact mechanisms remain unclear. Hypoxia subsequent to a hypermetabolic state may be involved; therefore, when it was observed recently that inactivation of Kupffer cells prevented stimulation of hepatic oxygen uptake by alcohol, the idea that Kupffer cells participate in early events that ultimately lead to alcohol-induced liver disease became a real possibility. The purpose of this study was to test that hypothesis. Male Wistar rats were exposed to ethanol continuously by means of intragastric feeding for up to 4 weeks using the model developed by Tsukamoto and French. In this model, ethanol causes fatty liver, necrosis and inflammation--changes characteristic of alcohol-induced liver disease in human beings. Kupffer cells were inactivated by twice weekly treatment with gadolinium chloride (GdCl3), a selective Kupffer cell toxicant. AST levels were elevated to 192 +/- 13 and 244 +/- 56 IU/L in rats exposed to ethanol for 2 and 4 wk, respectively (control value, 88 +/- 7). This injury was prevented almost completely by GdCl3 treatment. Fatty changes, inflammation and necrosis were also all reduced dramatically by GdCl3 treatment. The average hepatic pathological score of rats treated with ethanol for 4 wk was 4.3 +/- 0.6, which was reduced significantly in ethanol- and GdCl3-treated rats to 1.8 +/- 0.5 (p < 0.05). Rates of ethanol elimination were elevated 2- to 3-fold in rats exposed to ethanol for 2 to 4 wk. This elevation was blocked by GdCl3 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inactivation of Kupffer cells prevents early alcohol-induced liver injury. 804 7

S-Adenosylmethionine (SAMe) and N-acetylcysteine (NAC), two agents with known benefit for reducing hepatic injury, were used to treat ischemic injury in a rat liver perfusion model. We compared cold ischemic injury with sequential periods of cold and warm ischemia that equate to episodes during the storage and implantation of liver grafts. The additional period of 20 min warm ischemia after 24 hr cold ischemia profoundly impaired initial (15 min) mean blood flow (1.8 +/- 0.1 vs. 2.7 +/- 0.4 ml/min/g liver for cold ischemia, P < 0.001) and bile flow (2.31 +/- 0.74 vs. 10.6 +/- 3.96 mg/hr/g liver for cold ischemia, P < 0.001) and increased the oxygen extraction ratio (OER) (0.53 +/- 0.03 vs. 0.29 +/- 0.08 for cold ischemia, P < 0.01) and acid release from glycolysis (0.18 +/- 0.02 vs. 0.11 +/- 0.02 mmol/g liver for cold ischemia, P < 0.05). Impairment of blood flow, bile flow, and OER was sustained throughout the 3-hr perfusion. In the same model, SAMe restored hepatic blood flow to control values when administered to the donor, included in the UW, and added as a bolus to the perfusate on reperfusion. SAMe also improved OER (P < 0.001 vs. sequential cold and warm ischemia) and initial bile flow (9.63 +/- 2.01 mg/hr/g liver, P < 0.01), returning values to control levels by 3 hr. SAMe reduced the initial release of glucose upon reperfusion (P < 0.01) and improved subsequent glucose uptake, but corresponding benefits on enzyme release from damaged hepatocytes (AST) or endothelial cells (purine nucleoside phosphorylase) were not observed. Equimolar concentrations of NAC induced transitory improvements in blood and bile flow but these were not sustained beyond 30 min of reperfusion.
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PMID:Evidence that S-adenosylmethionine and N-acetylcysteine reduce injury from sequential cold and warm ischemia in the isolated perfused rat liver. 817 41

Reactive oxygen metabolites generated from xanthine oxidase play an important role in the pathogenesis of ischemia-induced tissue injury. In a hemorrhagic shock model of ischemia-reperfusion, the intracellular enzyme xanthine oxidase was released into the vasculature. This intravascular source of superoxide (O2.-) and hydrogen peroxide (H2O2) interacted reversibly with glycosaminoglycans of vascular endothelium and markedly concentrated xanthine oxidase at cell surfaces, enhancing its ability to produce extensive damage to remote tissues. Rats were made hypotensive by hemorrhage, maintained for 2h, and reinfused with shed blood. Blood samples were obtained prior to hemorrhage and 15, 30, 60, and 90 min after reperfusion for determination of xanthine oxidase (XO), lactate dehydrogenase (LDH), and alanine transaminase (AST). These enzymes were not significantly elevated in control animals. Reperfusion after hemorrhage-induced ischemia resulted in significantly elevated AST and LDH in both low heparin (100 U/h) and high heparin (1000 U/h) groups. Xanthine oxidase was detected in the circulation only after 90 min reperfusion in the low heparin group and was elevated during the entire reperfusion period in the high heparin group. Studies with cultured vascular endothelium showed significant heparin-reversible binding of XO to cellular glycosaminoglycans. These results suggest that XO can gain access to the circulation following ischemia, where it then binds to the vascular endothelial cells to produce site-specific oxidant injury to organs remote from the site of XO release.
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PMID:Xanthine oxidase activity in the circulation of rats following hemorrhagic shock. 822 22

The present study set out to investigate whether plasma phosphatidylcholine hydroperoxide (PCOOH) levels could accurately reflect lipid peroxidation linking to liver damage due to ischemia--reperfusion. PCOOH is a primary peroxidative product of phosphatidylcholine (PC), which is the most important functional lipid in the hepatocellular membrane, and may mediate oxidative stress. We quantified PCOOH and PC in the plasma and liver of rats subjected to hepatic ischemia-reperfusion by chemiluminescence detecting HPLC (CL-HPLC) method. Plasma PCOOH levels showed no significant rise in either the ischemia only group or in the sham-operation group, compared to controls (0.7 nmol/mL plasma). At 60 min subsequent to reperfusion, the PCOOH levels in plasma and liver, as well as the levels of several serum markers of liver injury [lactic dehydrogenase (LDH), glutamic-oxalacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT)] increased in proportion to the duration of ischemia (up to 60 min). During periods of reperfusion following 30 min of ischemia, plasma PCOOH increased biphasically (2 nmol/mL; 12-24 hr duration of reperfusion), and generally ran parallel to that in the liver after more than 60 min of reperfusion. Dose-dependent protective effects against warm ischemia (30 min)-reperfusion (12 hr) injury were clearly demonstrated in the groups treated with allopurinol, diclofenac Na, ascorbic acid (V.C), alpha-tocopherol and coenzyme Q10, but not in those treated with r-h-superoxide dismutase or betamethasone. The rises in plasma PCOOH and serum GOT, GPT and LDH of the ischemia-reperfused rats were ameliorated most in the group pretreated with diclofenac Na, and next most in the group pretreated with V.C. These results indicate that the plasma PCOOH levels are a useful index both for liver cell damage induced by oxygen free radicals generated during ischemia-reperfusion, and to investigate the efficacy of drugs against oxidative stress.
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PMID:Effects of anti-free radical interventions on phosphatidylcholine hydroperoxide in plasma after ischemia-reperfusion in the liver of rats. 825 Sep 60

Six healthy horses were anaesthetised with halothane (1.2 times the horse minimal alveolar concentration) in oxygen for more than 12 hours. Serum bilirubin, aspartate aminotransferase, alkaline phosphatase and L-iditol dehydrogenase values were significantly (P < 0.05) increased for up to nine days after anaesthesia. These changes suggest an anaesthesia related liver dysfunction. Creatine kinase increased to an average of more than 1400 IU litre-1 24 hours after anaesthesia and this change is indicative of muscle cell disruption. Renal-associated biochemical results, (that is serum creatinine and inorganic phosphate concentrations) were significantly increased transiently and are indicative of reduced renal function during and immediately after anaesthesia. Plasma concentrations of eicosanoids (6-keto-PGF1a, PGF2a, PGE and thromboxane) following anaesthesia were not different from preanaesthetic values. The magnitude of liver and muscle cell related increases in serum enzyme activities resulting from prolonged halothane anaesthesia was in excess of that previously reported for anaesthesia of shorter duration.
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PMID:Biochemical and haematological changes following prolonged halothane anaesthesia in horses. 828 98

Quinidine in vitro significantly reduced accumulation of TEA (tetraethyl ammonium) and PAH (p-amino hippurate) and inhibited oxygen consumption in renal cortical slices. Mitochondrial respiratory control index (RCI) and ADP/O ratio were decreased. Intraperitoneal administration of quinidine at 75 mg/kg twice a day for four days inhibited TEA transport in renal cortical slices and decreased oxygen consumption. Mitochondria showed a reduction in ADP/O ratio but no change in RCI. Serum biochemical measurements indicated a significant elevation in serum creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST).
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PMID:In vitro and in vivo effects of quinidine on the kidneys in Fischer-344 rats. 830 84

The purpose of this study was to develop a simple new method for rearterialization to compare rearterialized and nonarterialized models of liver transplantation in the rat in the same laboratory with the same surgeon. Hepatic rearterialization in the rat was completed by connecting the proper hepatic artery with a splint of polyethylene tubing (PE 10). With this technique, no extrahepatic arteries or modification of other organs was required. Further, the recipient's gastroduodenal artery remained intact to minimize bile duct hypoxia, and the anastomosis was completed rapidly (< 3 min). Postoperative arterial thrombosis and bile duct necrosis occurred with low frequencies with this model (< 15%). For comparison, the nonarterialized model of Kamada was used. With the nonarterialized method, survival of livers stored for 24 hr in cold University of Wisconsin solution was approximately 85% (6/7), whereas survival of livers stored for 48 hr was poor (< 10%; 1/16). Rearterialization improved survival following 48 hr of storage in UW solution from less than 10% to 50% (3/6), and reduced early enzyme release (AST) by about 50%. Rearterialization also reduced enzyme release following 24 hr of cold storage by about 50%. We conclude that this new technique is a simple and reliable method for hepatic artery reconstruction that may be particularly useful in studying the mechanism of primary graft non-function. These data are consistent with the hypothesis that hepatic rearterialization minimizes hypoxic injury to parenchymal cells postoperatively, most likely by increasing oxygen delivery.
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PMID:Development of a new method for hepatic rearterialization in rat orthotopic liver transplantation. Reduction of liver injury and improvement of surgical outcome by arterialization. 833 41

The number of clinical liver transplants that can be performed is limited by the availability of suitable donor organs. If it were possible to harvest and use livers after cardiac arrest, the supply could be improved. The mechanisms of damage in warm ischemia are not yet well understood and the consequences of transplanting a liver that is unable to provide immediate life-support are unacceptable. This study aims to identify areas for more detailed study in an attempt to improve the quality of livers harvested after significant warm ischemia, and to select acceptable organs for transplantation. Porcine livers were subjected to 75 min of warm ischemia and then perfused at 37 degrees C for 3 hr, during which period biochemical monitoring was carried out. At the end of the perfusion, histological and transmission electron microscopical studies were made. Large amounts of the intracellular enzymes ALT, AST, and LDH were released into the perfusate during the first 30 min of perfusion, but this--and the further amounts released during the subsequent 2.5 hr--was influenced by the composition of the perfusate. The inclusion of the substrates fructose and oleate, plus amino acids, substantially reduced this release and also improved the ability of the livers to metabolize ammonia. Oxygen free-radical scavengers had a significant, but smaller, beneficial effect. Electron microscopy confirmed the value of perfusion in improving cell morphology, and the additional value of including metabolic substrates. This study shows that hepatocellular structure and function can be improved by appropriate perfusion methods that also provide a simple means of monitoring some important functions. Both metabolic support and neutralization of oxygen free-radical action have a role to play in this approach to rendering ischemically injured livers acceptable for clinical use.
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PMID:The possibility of resuscitating livers after warm ischemic injury. 833 57

Reoxygenation of rat-liver mitochondria after anoxic incubation induced release of matrix proteins. As assessed by release of a matrix enzyme, it was proportional to the rate of H2O2 production. The release was not observed with low concentrations of extramitochondrial free Ca2+, indicating a Ca(2+)-dependent pathway. Phospholipase A2 was not involved in the reoxygenation injury, because non-esterified fatty acids did not increase on reoxygenation even when re-acylation was inhibited and because inhibitors of phospholipase A2 had little effect on enzyme release. Cyclosporin A, ATP, ADP and inhibitors of pyridine nucleotide oxidation had a protective effect, strongly suggesting involvement of so-called Ca(2+)-dependent permeability transition. Ca2+ was also released from reoxygenated mitochondria and inhibition of reuptake of released Ca2+ attenuated the enzyme release. Similar releases of aspartate aminotransferase and Ca2+ were observed with mitochondria in an oxygen radical-generating system, hypoxanthine and xanthine oxidase. In this system, lecithin-cardiolipin liposomes also released entrapped Ca2+ without disruption of the membrane. From these results, we conclude that during reoxygenation, Ca2+ release and subsequent reuptake induced permeability transition of mitochondria, resulting in reoxygenation injury.
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PMID:Ca(2+)-induced, phospholipase-independent injury during reoxygenation of anoxic mitochondria. 841 80

In vivo and ex vivo liver function was compared using the same livers to exclude interanimal variation in hepatic function. Six male pigs were anesthetized, and catheters and perivascular flow probes placed for transhepatic sampling and hepatic arterial and portal venous flow measurement. After a 2-h in vivo study period, the livers were resected and studied immediately afterwards for a further 2 h ex vivo as an isolated perfused preparation (Experiment A). Hepatic function in a further 6 pig livers (Experiment B) was studied ex vivo only for comparison with the ex vivo livers from Expt. A to determine whether the prior in vivo study had affected hepatic function. Despite using the same livers with similar total hepatic blood flows, (0.91 +/- 0.16 ml.g-1 x min-1) in vivo and (0.84 +/- 0.03 ml.g-1 x min-1) ex vivo, hepatic oxygen consumption (6.5 +/- 0.9 vs 2.6 +/- 0.2 ml O2 x 100 g-1), adenosine-5-triphosphate content (5.22 +/- 0.62 vs 4.14 +/- 0.71 microM.g liver-1) and bile flow (15.1 +/- 1.2 vs 6.0 +/- 1.0 ml.h-1) were initially less ex vivo and remained so throughout the study, while perfusate potassium (initially) (3.7 +/- 0.1 vs 6.4 +/- 0.3 meq.l-1), and aspartate aminotransferase (50 +/- 9 vs 76 +/- 5UL-1) was consistently higher than in vivo values. Initial hepatic energy charge (0.620 +/- 0.034 vs 0.552 +/- 0.061) and total adenine nucleotides 12.49 +/- 0.60 vs 11.66 +/- 0.62 microM.g liver-1) were not different and remained so subsequently.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of in vivo and ex vivo porcine liver function using the same liver. 844 16


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