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)

Swiss Webster male mice, 22 +/- 3 g, killed 17-18 h following the concomitant oral administration of acetaminophen (350 mg/kg) and N-acetyl-cysteine (NAC, 100-500 mg/kg, treated) had statistically significant lower plasma transaminases (GOT and GPT) than control mice (acetaminophen + water). Possible mechanisms underlying this protective effect of NAC were examined. NAC (500 mg/kg) reduced [14C]acetaminophen-derived radioactivity in the blood and tissues but increased the percentage of the dose in the gastrointestinal tract. Depletion of hepatic sulphydryl compounds below 75% of the control value was prevented by NAC treatment, whereas urinary excretion of mercapturate and sulfate, metabolites derived from sulphydryls, were proportionally increased and excretion of unchanged drug was decreased by NAC. Absorption of acetaminophen from the small intestine was prevented by NAC and this was attributed to an inhibition in gastric emptying. Since all changes observed following NAC treatment could be attributed to inhibition of gastric emptying, it was considered the major mechanism responsible for affording in mice protection from acetaminophen-induced hepatocellular damage following concomitant oral administration.
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PMID:N-acetylcysteine-induced inhibition of gastric emptying: a mechanism affording protection to mice from the hepatotoxicity of concomitantly administered acetaminophen. 726 84

Acute acetaminophen (ACM) toxicosis was induced in cats and the therapeutic benefit of N-acetylcysteine (NAC) was demonstrated. Groups of 4 adult cats were treated as follows: group A-given ACM only; group B- given ACM and then treated with NAC, starting at 0 hour; group C-given ACM and then treated with NAC, starting at 4 hours; and group D-treated with NAC only. Acetaminophen was given as a single oral dose or 143 mg/kg, and the NAC regimen consisted of 4 oral doses (200 mg/kg, given 3 times and 100 mg/kg, given once) with 2 hours between doses. Group A cats developed increased methemoglobin concentration, depletion of erythrocyte reduced glutathione, and increased Heinz body formation. Group B cats also developed methemoglobinemia, depletion of glutathione, and increased Heinz body formation, but the magnitude of these changes was significantly less (P less than 0.05) than in group A. In group C, the findings were similar to group A through 4 hours, but thereafter, significant hematologic improvement was noted. The level of Heinz bodies in group C was intermediate between the values for groups A and B. In group D cats, no significant changes from base line were noted. Evidence of hepatotoxicity was not seen in any group as based on daily determinations of plasma alanine aminotransferase and sorbitol dehydrogenase activities.
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PMID:Clinicopathologic evaluation N-acetylcysteine therapy in acetaminophen toxicosis in the cat. 733 95

Intravenous (IV) acetylcysteine, cysteamine, and methionine treatments were compared in patients with severe acetaminophen poisoning; a control group consisted of patients receiving supportive therapy only. Acetylcysteine proved the safest and most effective mode of treatment. Acetylcysteine was effective in preventing liver damage, hepatic failure, renal damage, and death when given eight to ten hours after poisoning. When treatment was delayed for ten to 24 hours, results were the same as in the supportive-therapy group. The alanine aminotransferase (ALT) activity remained normal in 76% of the patients treated within ten hours, as compared with 40% in both cysteamine- and methionine-treated groups and with 16% in the supportive-therapy group. The ingestion-treatment interval for complete protection with all three drugs was eight hours; beyond that time, the incidence of damage increased steadily. After 15 hours, all treatments were pointless. Based on my experience, IV administration is preferable, since nausea and vomiting may limit the effectiveness of oral therapy.
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PMID:Treatment of severe acetaminophen poisoning with intravenous acetylcysteine. 746 30

We investigated whether intraportal injection of 150 mg/kg N-acetylcysteine (NAC) into rats reduced hepatic ischemia-reperfusion injury after 48 hours of cold storage and 2 hours of reperfusion. The organ was isolated and perfused to evaluate liver function. The control group received an intraportal injection of 5% dextrose. NAC increased L-cysteine concentrations 15 minutes after injection (1.29 +/- 0.11 mumol/g vs. 2.68 +/- 0.4 mumol/g, P < .05). However, neither treatment modified glutathione liver concentrations relative to preinjection values. After 48 hours of cold storage and 2 hours of reperfusion, livers from NAC-treated rats produced larger amounts of bile than those in the control group (5.04 +/- 1.92 vs. 0.72 +/- 0.37 microL/g liver; P < .05), and showed a significant reduction in liver injury, as indicated by reduced release of lactate dehydrogenase (679.4 +/- 174.4 vs. 1891.3 +/- 268.3 IU/L/g; P < .01), aspartate transaminase (AST) (13.94 +/- 3.5 vs. 38.75 IU/L/g; P < .01), alanine transaminase ALT) (14.92 +/- 4.09 vs. 45.91 +/- 10.58 IU/L/g; P < .05), and acid phosphatase, a marker of Kupffer cell injury (344.4 +/- 89.6 vs. 927.3 +/- 150.8 IU/L/g; P < .01) in the perfusate. Reduced glutathione concentrations in the perfusate were similar in the two groups (805 +/- 69 vs. 798 +/- 252 nmol/L/g), whereas oxidized glutathione (GSSG) concentrations were higher in the control group (967 +/- 137 vs. 525 +/- 126 nmol/L/g; P < .05). Reduced glutathione (GSH) concentrations in liver tissue collected at the end of perfusion were significantly higher in the NAC group (7.3 +/- 0.9 vs. 4.1 +/- 1.0 mumol/g; P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protective effects of N-acetylcysteine on hypothermic ischemia-reperfusion injury of rat liver. 763 22

There is evidence that an increase in cytosolic Ca++ concentration is a terminal event in the progression to cell death in toxic liver injury. We have compared the hepatoprotective effects of N-acetylcysteine (1 g/kg) and the calcium channel blocking agent, diltiazem (24 mg/kg), when given at 30 min, 3 h and 6 h after single intraperitoneal overdoses of acetaminophen (500 mg/kg) in mice. Overall beneficial effects on mortality, liver necrosis score, and plasma alanine aminotransferase (ALT) activity were found in diltiazem-treated mice 24 h after acetaminophen overdose. However, the most marked effects were obtained when diltiazem was given 6 h after acetaminophen. N-acetylcysteine was more effective than diltiazem at 30 min and 3 h, although it was less effective at 6 h. Mean plasma concentrations of the mercapturate metabolite (hepatic oxidative metabolism) were not significantly different among animals receiving acetaminophen alone or in combination with diltiazem, which suggests that the hepatoprotective effects of diltiazem are not exerted by inhibition of drug metabolic enzymes.
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PMID:Protective effect of diltiazem against acetaminophen hepatotoxicity in mice. 777 52

From 1989 to 1991, 104 Chinese patients were admitted to the Prince of Wales Hospital with paracetamol poisoning. Only 11 subjects had a plasma paracetamol concentration above the published treatment line. Intravenous N-acetylcysteine (NAC) was completely effective when given within 8 hours (3 patients), while late treatment with NAC at 16 and 26 hours after overdose (2 patients) was ineffective in preventing liver damage as evidenced by elevations in plasma alanine transaminase concentrations. Of the 6 patients receiving NAC between 10 to 15 hours, two had liver damage. Two other subjects who presented late or in whom a plasma paracetamol concentration was not measured also developed liver damage. Fortunately, none of these 6 subjects developed hepatic encephalopathy. We recommend that a standard protocol be readily available for junior hospital staff to use when treating patients with paracetamol overdosage.
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PMID:Paracetamol poisoning and hepatotoxicity in Chinese--the Prince of Wales Hospital (Hong Kong) experience. 826 95

A substantial fraction of the cysteine added to total parenteral nutrition (TPN) solutions is converted to the corresponding thiazolidine derivative, while in solution with relatively large concentrations of glucose typical of TPN (700 mM and higher). It was recently reported (Roberts et al. (1987) J. Med. Chem. 30, 1891-1896) that this thiazolidine, D-glucose-L-cysteine (DGC), offered no significant protection against the hepatic injury caused by 5 mmol/kg of acetaminophen in mice, suggesting that the cysteine present as DGC is poorly bioavailable in vivo. In the present study, fasted male ICR mice given 1.6 or 2.6 mmol/kg of acetaminophen sustained hepatic injury, estimated by elevations in plasma alanine aminotransferase (ALT) activities. Administration of 2.5 mmol/kg of N-acetylcysteine (NAC) 1 h before acetaminophen given i.p. prevented the rise in plasma ALT activities, apparently through support of glutathione (GSH) synthesis. Administration of 2.5 mmol/kg of DGC prior to acetaminophen resulted in slightly lower mean plasma ALT activities than were observed in animals given saline before acetaminophen, but the effect was not statistically significant. When DGC was given 1 h before p.o. administration of 1.6 or 2.6 mmol/kg of acetaminophen, the protective effects of DGC were statistically significant (P < 0.01, 0.025, respectively), although NAC afforded significantly greater protection than did DGC at the higher dose of acetaminophen. Given 4 h before acetaminophen, DGC attenuated acetaminophen-induced increases in plasma ALT activities significantly, whereas NAC was without effect. These results indicate that the cysteine in DGC is at least partially bioavailable in vivo and, further, that DGC may function as a slow release formulation of cysteine.
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PMID:Attenuation of acetaminophen hepatotoxicity in mice as evidence for the bioavailability of the cysteine in D-glucose-L-cysteine in vivo. 831 Apr 51

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 reviewed 15 cases of poisoning from ingestion of yellow phosphorus-containing fireworks and analyzed its associated acute hepatotoxic effects. Two patients (13%) had no clinical or biochemical evidence of hepatic damage, four (27%) had subclinical hepatic injury, five (33%) manifested varying degrees of hepatocellular necrosis and cholestasis, and four (27%) had fulminant hepatic failure. Jaundice was not associated with mortality (p > 0.05), but it appeared to predict the length of hospital confinement. Early elevations in transaminase and alkaline phosphatase, a more than tenfold increase in alanine aminotransferase, and a severe derangement in prothrombin time all indicate poor prognosis. Metabolic acidosis and hypoglycemia were significantly associated with mortality (p < 0.01 and p < 0.05, respectively). The use of intravenous N-acetylcysteine did not significantly alter disease outcome (p > 0.05). Our mortality rate was 27%, confirming that yellow phosphorus is extremely lethal when ingested. Its indiscriminate use in the manufacture of fireworks should be eliminated.
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PMID:Acute hepatotoxicity from ingestion of yellow phosphorus-containing fireworks. 858 80

The therapeutic application of zinc sulphate as an antidote to acetaminophen overdose was examined in ICR mice. Hepatotoxicity was induced by a single oral dose of acetaminophen (750 mg/kg). Various treatments (normal saline, 15 or 30 mg/kg zinc sulphate, 150 mg/kg N-acetylcysteine, 15 mg/kg zinc sulphate + 150 mg/kg N-acetylcysteine) were given i.p. 1 h after acetaminophen overdose. Serum alanine aminotransferase, hepatic glutathione and malondialdehyde levels were measured before experiments and at various intervals after the administration of acetaminophen. Serum acetaminophen levels were also measured at different different intervals. Zinc sulphate showed protection by dose-dependently reducing alanine aminotransferase and malondialdehyde levels. The drug also partially prevented the depletion of hepatic glutathione. These effects were not as good as those of N-acetylcysteine. However, the combination of zinc sulphate with N-acetylcysteine produced even better protective effects. Furthermore, drug treatments did not affect serum acetaminophen levels. It is concluded that both drugs attenuate acetaminophen-induced hepatic toxicity, and the action is likely to be mediated through replenishment of hepatic glutathione levels. The use of zinc sulphate alone or in combination with N-acetylcysteine could be another alternative for the treatment of acetaminophen overdose in view of possible side effects produced by N-acetylcysteine.
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PMID:Evidence for potential application of zinc as an antidote to acetaminophen-induced hepatotoxicity. 866 38


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