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)

While the clinical results of orthotopic liver transplantation have greatly improved, the viability of liver grafts and extension of the safe time for preservation are necessary factors in need of improvement. The liver is one of the organs most sensitive to anoxia. The addition of an oxygen carrying agent to the preservation solution was evaluated. Pyridoxalated hemoglobin-polyoxyethylene conjugate (PHP) is used as an oxygen carrier. Viaspan (UW) served as a control solution. Test solution (PHP+UW) composition was composed of a 1:1 mixture of PHP and UW solutions with hemoglobin 4.0g%, hydroxyethyl starch 2.5g%, osmolality 320 mOsm/kg H2O, and colloidal osmotic pressure 33 mmHg. The oxygen carrying capacity of PHP+UW solution is about 10 times higher than UW solution at 4 degrees C. Male Lewis rats (BW: 250-300 g) were divided into five groups. After flushing the solution via the portal vein, rat livers were harvested. Two preservation methods, simple storage and perfusion (0.1 ml/min/g liver), were studied at 4 degrees C for 24 or 48 hours. OxyHb, MetHb, pO2, pH, Na, K, GOT, and GPT of perfusate, hepatic mitochondrial functions after preservation, and tissue adenine nucleotides by HPLC were measured. Light microscopy on the tissue was also performed. No significant differences were noted in perfusate biochemical parameters. Oxygen consumption during the perfusion was significantly higher in the PHP+UW than in the UW group. Hepatic mitochondrial functions and tissue ATP levels were better preserved in perfusion than in simple storage, and in PHP+UW than in UW at 48 hours. The oxygen carrying agent, PHP, can provide significantly higher levels of oxygen to liver grafts and improve graft viability.
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PMID:Does oxygen supply improve graft viability in liver preservation? 139 76

This study was designed to clarify the effects of changes in liver tissue glutathione (GSH) concentration on postischemic liver injury together with the effects of gamma-glutamylcysteine ethyl ester (GCE), a prodrug of GSH, and GSH. Rats were pretreated with GSH (50 mg/kg, i.v.), or GCE (50 mg/kg, i.v.), or untreated. In each rat, liver was isolated, and liver mitochondria were prepared after 2 h of ischemia or 1 h of reperfusion following 2 h of ischemia. Mitochondrial function was measured polarographically. Liver adenine nucleotide concentrations were also determined using high-performance liquid chromatography. Liver tissue GSH, an oxidized form of glutathione (GSSG) concentrations, and activities of GSH peroxidase and GSSG reductase were determined enzymatically. Liver hypoxanthine and xanthine concentrations were determined by HPLC. Liver tissue concentration of lipid peroxide was measured. Leakages of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and adenine nucleotides into the hepatic vein after reperfusion were also measured. Administration of GCE improved the recovery of mitochondrial function and maintained tissue GSH concentration concomitantly. Increases in liver lipid peroxide concentration after reperfusion, and leakage of liver cell enzymes and adenine nucleotides were mitigated by administration of GCE. Administration of GSH itself failed to maintain tissue GSH concentration and had no protective effects. From these results, it is concluded that in the postischemic process, free radical formation might be enhanced, and the radical scavenging system deteriorated. To enhance the radical scavenging system is a possible maneuver to prevent radical-related cell damage associated with reperfusion, because pharmacological reduction of breakdown of ATP to hypoxanthine and xanthine seems to be difficult. GCE maintained liver GSH concentrations and mitigated postischemic liver injury, concomitantly. Clinical use of GCE might be recommended.
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PMID:The effects of gamma-glutamylcysteine ethyl ester, a prodrug of glutathione, on ischemia-reperfusion-induced liver injury in rats. 833 63

Forty-three male mongrel dogs (12.5 +/- 2.5 kg) were divided into normal control (n = 7), immediate infusion (n = 8), non-infusion (n = 13) and delayed infusion (n = 15) groups. A 50% TBSA third degree surface burn was produced by igniting 3% napalm for 30 seconds on the shaved back. Cardiac, pulmonary, hepatic, renal and gastrointestinal functions were monitored following the thermal injury. The findings of these studies showed that mean arterial pressure, cardiac index, left ventricular work, right ventricular work, ADP/O ratio and ATP were all significantly decreased (P less than 0.05). However pulmonary artery wedge pressure, pulmonary vascular resistance, systemic vascular resistance, P(A-a)O2, Beef, Cr, UN, ALT, LDH, TB, DB, and MDA were markedly increased (P less than 0.05). Severe shock occurred soon after burns. Thirteen dogs died within 12 hours in the non-infusion group. All the dogs were resuscitated when immediate infusion of lactic acid Ringers solution was given according to Parkland formula, and all of them tide over shock stage smoothly without obvious changes in visceral functions. However, dogs were not resuscitated when infusion was delayed 6 hours postburn. The changes in visceral were even more severe in this group than those in non-infusion group. These results demonstrated that delayed resuscitation was an important factor of MOF in the early postburn stage. The marked increase in MDA in the myocardiac, lung, liver, renal and gastrointestinal tissues indicated that lipoperoxidation by free oxygen radicals was closely related with visceral damages.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Experimental study on early multiple organ failure after severe burns]. 159 85

Allyl alcohol injury to hepatocytes in the perfused liver is oxygen-dependent. It is not known if this injury involves direct action of allyl alcohol on hepatocytes or requires participation of other cell types (e.g., Kupffer cells) present in the liver. Accordingly, the action of allyl alcohol (100-500 microM) on isolated hepatocytes was studied using cells maintained at either 95 or 21% O2. Allyl alcohol toxicity, as indexed by trypan blue uptake, lactate dehydrogenase release, and ATP content, did not differ in the two groups of cells, suggesting that O2 dependency of allyl alcohol toxicity involves other cell types. Administration of allyl alcohol (30 or 40 mg/kg, ip) to rats caused extensive hepatic necrosis localized primarily to periportal regions. To test the involvement of Kupffer cells in the genesis of this injury, male rats (200-350 g) were treated with gadolinium chloride (GdCl3, 10 mg/kg, iv) which diminishes Kupffer cell function and number. The extent of hepatic damage assessed by light microscopy and serum enzymes, aspartate aminotransferase and alanine aminotransferase, was markedly attenuated by pretreatment of rats with GdCl3 24 hr prior to allyl alcohol injection. Thus, O2-dependent hepatic necrosis caused by allyl alcohol involves the presence of Kupffer cells. Since GdCl3 did not prevent toxicity in the perfused liver, circulating blood elements may also contribute to injury of the liver by allyl alcohol in vivo.
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PMID:Involvement of nonparenchymal cells in oxygen-dependent hepatic injury by allyl alcohol. 163 94

In order to elucidate the role of mitochondrial dysfunction in paracetamol-induced hepatotoxicity, the effects of paracetamol on the oxygen consumption and ATP content of the isolated perfused rat liver were correlated with parameters of hepatic viability and hepatotoxicity. Paracetamol at 5 g/L reduced the oxygen consumption of the livers by about 80% and hepatic ATP content by 96%. Hepatotoxicity was evident from the nearly complete interruption of bile secretion, a marked release of enzymes [glutamate-pyruvate transaminase (GPT), lactate dehydrogenase (LDH)] in the perfusate, a depletion of hepatic glutathione and an accumulation of calcium in the liver. Paracetamol-induced hepatotoxicity could be prevented completely by using livers from non-fasted rats as well as by addition of fructose to the perfusate of livers from fasted animals. Both treatments resulted in an increased energy supply from anaerobic glycolysis as evidenced by a large release of lactate and pyruvate into the perfusate, but did not inhibit paracetamol-induced decline of oxygen consumption. The decrease in hepatic oxygen consumption depended on the dose of paracetamol and occurred first at a concentration of 0.2 g/L (-10%). LDH and GPT release, on the other hand, was elevated at 2 and 5 g/L and calcium accumulation occurred at 5 g/L paracetamol only. Inhibition of mixed-function oxidases by dithiocarb did not prevent the decrease in oxygen consumption and the resulting hepatic injury induced by paracetamol. The oral administration of the high dose of 5 g/kg paracetamol in vivo to rats exerted strong hepatotoxicity but produced maximal serum levels of 800 mg/L paracetamol only and did not decrease hepatic oxygen consumption as measured in vitro. Our results show that in the isolated perfused rat liver in vitro, only high concentrations of paracetamol can produce "chemical hypoxia" by attacking mitochondria so as to cause hepatic injury. Such high concentrations of paracetamol are not attained in vivo, however. "Chemical hypoxia", thus, seems not to be relevant to the well-known hepatotoxic action of paracetamol.
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PMID:The toxicological relevance of paracetamol-induced inhibition of hepatic respiration and ATP depletion. 163 30

Chlordecone (CD) pretreatment is well known to greatly potentiate CCl4 toxicity. Previous work has shown that suppression of hepatocellular regeneration permits an ordinarily limited liver injury to progress in an irreversible manner. Insufficient hepatocellular energy has been proposed as a mechanism for suppressed hepatocellular regeneration. Since cyanidanol reportedly increases cellular ATP, this compound was employed to test the above hypothesis. The present study was designed to investigate the sequential biochemical and histological changes over a time course of 120 hr after CCl4 administration. Male Sprague-Dawley rats (125-150 g) were maintained on 10 ppm CD diet for 15 days and were challenged with either a standard protocol dose (100 microliters/kg) or a low (50 microliters/kg, L) dose of CCl4. Cyanidanol pretreatment at 48, 24, and 2 hr before CCl4 administration to rats maintained on CD diet resulted in 100 or 70% animal survival, for CCl4 (L) or the standard dose of CCl4, respectively. Preliminary studies indicated that neither simultaneous nor subsequent administration of cyanidanol with CCl4 challenge affords such protection. Prior treatment with cyanidanol and a latency period were found necessary for protection. Without cyanidanol, CD + CCl4 combination caused 50 and 100% lethality after CCl4 (L) and the standard dose, respectively, while the same doses of CCl4 alone did not cause lethal effects. Plasma enzymes (alanine aminotransferase, aspartate aminotransferase, sorbitol dehydrogenase) in control rats showed only moderate and transient increases after CCl4 challenge. The combination of CD + standard dose of CCl4 resulted in progressive and marked elevations of all three serum enzymes at all time intervals until the death of animals. Cyanidanol pretreatment resulted in significant decline in the plasma enzyme elevations at later time points. Cyanidanol pretreatment increased hepatic ATP synthesis in control or CD rats. CCl4 administration to control rats did not alter hepatic ATP levels, while in CD-fed rats hepatic ATP levels were significantly decreased. Cyanidanol pretreatment to CD + CCl4 combination-treated rats did not significantly prevent the decline in hepatic ATP and glycogen levels. However, in the surviving rats a recovery in these parameters was observed. Light microscopic examination of livers from animals that received CCl4 alone revealed only marginal cellular injury, at early time points only. However, CCl4 challenge to rats maintained on CD resulted in progressive injury, characterized by the appearance of ballooned cells, necrotic cells, and cells with lipid droplets in the liver. Cyanidanol pretreatment to these rats caused decreased vacuolation and significantly reduced the progression of liver necrosis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Protection from chlordecone-amplified carbon tetrachloride toxicity by cyanidanol: biochemical and histological studies. 170 39

The effect of FK 506 on regeneration of the liver was studied in rats after a two-thirds partial hepatectomy after 60 min of ischemia of the unresected liver. The animals were divided into three distinct groups of 10 rats each. Group 1 (controls) received 0.5 ml saline solution intravenously 30 min after the induction of ischemia. Groups 2 and 3 were injected with FK 506 (0.3 mg/kg) intravenously 30 min after and 24 min before the induction of hepatic ischemia, respectively. The hepatic content of ATP and serum levels of ALT and lactate dehydrogenase were determined on each animal. In addition, the histological appearance and mitotic activity of the remnant liver was determined at regular 24-hr intervals after hepatic ischemia. All 10 control animals died within 72 hr. Treatment with FK 506 resulted in improved survival in groups 2 and 3 (30% and 80%, respectively). The improved survival seen in the FK 506-treated animals was reflected by a restoration of hepatic ATP content, a reduction in the serum levels of ALT and lactate dehydrogenase, an amelioration of hepatic necrosis and neutrophilic infiltration and an increase in the mitotic activity of the liver. These results suggest that FK 506 ameliorates the hepatic injury associated with ischemia/reperfusion and has a potent stimulatory effect on liver cell regeneration that may make it valuable as a hepatoprotective agent when administered to organ donors before graft harvesting.
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PMID:FK 506 ameliorates the hepatic injury associated with ischemia and reperfusion in rats. 170 12

The purine nucleotide content of lymphocytes of normal subjects and asymptomatic HIV-1 seropositive patients was analyzed by HPLC. An increase in IMP and a decrease in ADP, GDP, ATP and GPT were observed in the HIV-infected patients with respect to healthy subjects. The changes may depend on different factors and indicate that the virus influences purine nucleotide metabolism of the cell. The finding sheds light on the metabolic situation of the infected cell, and could be applied to monitoring the disease.
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PMID:Purine nucleotide content of lymphocytes from healthy subjects and asymptomatic HIV-1 seropositive patients. 176 29

Although several studies suggest that hepatic graft failure after cold ischemia results from nonparenchymal cell damage, other data indicate that hepatocellular ATP content is significantly correlated with the transplantation success rate. In this study, we have conducted a systematic investigation of various aspects of cell viability and function of isolated hepatocytes stored at 4 degrees C for 24 and 48 hr in either University of Wisconsin solution or Hanks' HEPES buffer, a control solution clinically unsuitable for organ preservation. After 24 hr, hepatocytes stored in Hanks' HEPES buffer had viability (measured by trypan blue exclusion and ALT and lactic dehydrogenase leakage), transport function (measured by 22Na+ and [3H]taurocholate uptake) and cell size similar or only slightly altered when compared with freshly isolated and University of Wisconsin solution-stored hepatocytes. ATP content was decreased in both groups; however, the reduction was much greater in Hanks' HEPES buffer-stored cells. Furthermore, ATP regenerating capacity was greatly reduced in Hanks' HEPES buffer- stored but not in University of Wisconsin solution-stored hepatocytes. By 48 hr viability and function of Hanks' HEPES buffer-stored hepatocytes were decreased; University of Wisconsin solution afforded partial protection. When examined by light and electron microscopy, cells stored in both University of Wisconsin solution and Hanks' HEPES buffer for 24 hr appeared essentially normal except for the presence of numerous membrane blebs in the Hanks' HEPES buffer group. Tissue sections of livers preserved in Hanks' HEPES buffer but not in University of Wisconsin solution revealed the presence of extensive amounts of blebs in the sinusoidal lumen and loss of endothelial elements.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Functional and morphological features of isolated hepatocytes preserved in University of Wisconsin solution. 186 Jun 90

The biochemical mechanism of cocaine hepatotoxicity is thought to involve enzymatic formation of reactive metabolites. The exact hepatocellular effects of these metabolites have yet to be established. This study was designed to monitor, in a time course after an acute cocaine dose, biochemical parameters that are important in cellular defense and homeostasis in vivo. The hepatic parameters measured were ATP as an indicator of cellular energetic status, reduced and oxidized glutathione, NADH and NADPH as measures of redox changes, and thiobarbituric acid-reactive products and microsomal conjugated dienes to determine the extent of lipid peroxidation. In addition, serum ALT levels were determined at each time point to assess the extent of toxicity. Inbred mouse strains selected for their relative sensitivity (male DBA/2Ibg) and resistance (male C57BL/6Ibg) to cocaine-mediated hepatotoxicity were used in this study. Animals were given an acute 50 mg/kg intraperitoneal dose of cocaine, and at various times after administration the hepatic and serum determinations were made. The results of this study confirm the strain difference in cocaine-induced hepatotoxicity and also indicate that there are changes in the biochemistry of the liver that are brought about by acute cocaine administration. In particular, depletions of hepatic GSH, NADH, NADPH and ATP coupled with significant increases in oxidized glutathione were observed in the DBA mouse. C57BL mice showed similar decreases in reduced glutathione, NADH and NADPH but exhibited no significant depletion of hepatic ATP. A similar extent of lipid peroxidation was seen in both mouse strains after cocaine administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hepatic biochemical changes as a result of acute cocaine administration in the mouse. 195 71


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