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)

N-acetylcysteine (NAC) is a glutathione precursor used to treat several clinical conditions where intracellular oxidant-antioxidant balance is disturbed, among which, acetaminophen induced hepatotoxicity may be counted. In this study, administering thioacetamide (TAA) as a hepatotoxic agent, a rat model of hepatotoxicity has been established, to investigate some of the immune mediated basic oxidant-antioxidant homeostatic mechanisms involved, and potential serum markers for follow-up of disease and treatment. To do this, four experimental groups receiving saline/saline, saline/NAC, saline/TAA and NAC/TAA as intraperitoneal injections, have been formed. Rat serum tumor necrosis factor-alpha (TNF-alpha), Interleukin1-beta (IL1-beta), malondialdehyde (MDA) as a measure of final oxidant damage and the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) have been assayed. Hepatocellular damage has been measured via the biochemical estimates ALT, AST and LDH as well as histopathological grading. It was found that both TNF-alpha and IL1-beta were significantly elevated in saline/TAA receivers (P<0.01) when compared to NAC/TAA receivers. Serum MDA was also increased in TAA receivers in addition to SOD (P<0.05) and GSH-Px (P<0.05). Serum nitrite levels have also been assayed to give an estimate of nitric oxide that is suggested as a counter-balancer of oxidant stress. NAC/saline receivers had the highest levels of nitrites in the serum (P<0.05). Our results indicate that part of the hepatocellular injury to rat liver, induced by TAA is mediated by oxidative stress caused by the action of cytokines imparted by the enzymatic SOD and GSH-Px and non-enzymatic gaseous nitric oxide mechanisms causing an alleviation on administration of NAC. In addition, TNF-alpha, IL1-beta, MDA, SOD, GSH-Px and nitrites are potential candidates of serum indicators for monitorization of pathophysiological stage of liver disease.
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PMID:Serum cytotoxin and oxidant stress markers in N-acetylcysteine treated thioacetamide hepatotoxicity of rats. 1060 91

Methanol is oxidized in-vivo to formaldehyde and then to formate, and these processes are accompanied by the generation of free radicals. We have studied the effect of N-acetylcysteine on liver cell membrane from rats intoxicated with methanol (3.0 g kg(-1)). Evaluation of the effect was achieved by several methods. Lipid peroxidation and surface charge density were measured. An ultrastructural study of the liver cells was undertaken. The concentration of marker enzymes of liver damage (alanine aminotransferase and aspartate aminotransferase) in blood serum was measured. Methanol administration caused an increase in lipid peroxidation products (approximately 30%) as well as in surface charge density (approximately 60%). This might have resulted in the membrane liver cell damage visible under electron microscopy and a leak of alanine aminotransferase and aspartate aminotransferase into the blood (increase of approximately 70 and 50%, respectively). Ingestion of N-acetylcysteine with methanol partially prevented these methanol-induced changes. Compared with the control group, lipid peroxidation was increased by approximately 3% and surface charge density by approximately 30%. Alanine aminotransferase and aspartate aminotransferase activity increased by 9 and 8%, respectively, compared with the control group. The results suggested that N-acetylcysteine was an effective antioxidant in methanol intoxication. It may have efficacy in protecting free radical damage to liver cells following methanol intoxication.
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PMID:Protective effect of N-acetylcysteine on rat liver cell membrane during methanol intoxication. 1086 43

Acetaminophen is a widely used nonprescription analgesic and antipyretic agent. It is also a dose-related hepatotoxin that can cause fulminant liver failure when taken in massive overdoses or, much less commonly, at therapeutic doses in susceptible individuals. Persons who regularly consume alcohol or persons who have been fasting may be more susceptible to this hepatotoxicity. This liver injury is due not to the drug itself but to the formation of the toxic metabolite N-acetyl-p-benzoquinine imine generated through the cytochrome P-450 drug-metabolizing system. Normally, hepatic stores of glutathione combine with the toxic metabolite and prevent liver cell injury. When glutathione stores are depleted by overproduction of this metabolite, however, the reactive metabolite binds to liver cell proteins and causes hepatic necrosis. P-450 2E1 is induced by alcohol consumption and possibly starvation, and glutathione depletion can occur due to the inadequate nutrition occurring in chronic alcohol use or in starvation. Recent studies have shown that activated Kupffer cells and their secreted toxic agents such as cytokines may also play a role in this liver injury. This liver injury is characterized by extremely high levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (> 1000), and bad prognostic signs include severe prolongation of the prothrombin time, renal dysfunction, and, most importantly, acidosis. N-acetylcysteine is a highly effective antidote when given early (within 15 hours) of overdose. Some patients may develop such fulminant liver injury that they require transplantation. Unfortunately, many such patients have a course so rapid that a donor liver may not become available in time. Thus, both the medical community and the general public require a heightened understanding of this clinical problem in order to initiate prevention measures and to implement early therapeutic measures if an overdose situation occurs.
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PMID:Acetaminophen hepatotoxicity: An update. 1098 Sep 26

This study investigated the hepatoprotective effects of N-acetylcysteine and different doses of S-adenosyl-L-methionine after a single intraperitoneal overdose of paracetamol in mice. Plasma concentrations of paracetamol metabolites were also determined. Female mice (Souris OFl strain) 16 weeks old and weighing 30 g were fasted for 18 h prior to intraperitoneal (i.p.) administration of 375 mg/kg (2.5 mmol/kg) of paracetamol. Experimental subgroups included mice administered paracetamol only (control group), those given of N-acetylcysteine 1 g/kg (6.13 mmol/kg) i.p. immediately after paracetamol overdose (T0) and 6 h after dosing (T6) and those administered S-adenosyl-L-methionine at doses of 20 mg/kg (0.05 mmol/kg) and 1 g/kg (2.5 mmol/kg) i.p. at T0 and T6. Twenty-four hours after paracetamol overdose, mortality and liver necrosis were significantly lower (p < 0.01) in mice treated with 2.5 mmol/kg of S-adenosyl-L-methionine and N-acetylcysteine at T0 as compared with the remaining subgroups. Plasma ALT concentrations were significantly lower (p < 0.01) in mice treated with 2.5 mmol/kg of S-adenosyl-L-methionine than in those given N-acetylcysteine. Plasma concentrations of paracetamol metabolites showed an increase in the glucuronide conjugate and a decrease in the mercapturic acid conjugate in N-acetylcysteine-treated mice and an overall decrease in the conjugation pathway without changes in the oxidative pathway in S-adenosyl-L-methionine-treated animals. We conclude that S-adenosyl-L-methionine at doses of 1 g/kg (2.5 mmol/kg) i.p. was equally effective as 1 g/kg (6.13 mmol/kg) N-acetylcysteine for preventing hepatotoxicity after paracetamol overdose in mice. S-adenosyl-L-methionine may be a therapeutic alternative to N-acetylcysteine as an antidote for poisoning with paracetamol.
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PMID:Effect of different doses of S-adenosyl-L-methionine on paracetamol hepatotoxicity in a mouse model. 1134 94

N-acetylcysteine (NAC) has been used safely in humans and in other mammals as an antidote against several toxic and carcinogenic agents, including aflatoxin B1 (AFB1). The aim of this study was to evaluate the capability of dietary supplementation with NAC to ameliorate the effects of subacute intoxication with AFB1 in broiler chickens. One hundred twenty male Hubbard 1-d-old chickens were allocated into one of four dietary treatments: 1) control group without treatment, 2) purified AFB1 added to diet (3 mg/kg of feed) for 21 d, 3) NAC (800 mg/kg BW, daily), or 4) AFB1 plus NAC at the same doses as Groups 2 and 3. Broilers treated with AFB1 plus NAC were shown to be partially protected against deleterious effects on BW (57.8%), daily weight gain (49.1%), feed conversion index (21.4%), plasma and hepatic total protein concentration (45.2, 66.7%), plasma alanine aminotransferase (67.4%), hepatic glutathione-S-transferase (18.8%), and reduced glutathione liver concentration (75.0%). In addition, they showed less intense liver fading, friable texture, and microvesicular steatosis. In the kidney, thickening of glomerular basement membrane was also less severe in NAC+AFB1-treated chickens than in AFB1-treated chickens. Our results suggest that NAC provided protection against negative effects on performance, liver and renal damage, and biochemical alterations induced by AFB1 in broiler chickens. Effects of NAC alone on chick performance were also evaluated. Addition of NAC to diet (800 mg/kg BW) did not negatively affect feed consumption, conversion index, or serum chemistry and did not induce structural changes in the liver or kidney.
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PMID:Efficacy of N-acetylcysteine to reduce the effects of aflatoxin B1 intoxication in broiler chickens. 1144 39

Prostaglandin E1 (PGE1) and N-acetylcysteine (NAC) have been used as single agents to decrease reperfusion injury and improve outcome after solid-organ transplantation (Tx). We hypothesized that combined treatment with NAC and PGE1 would be safe and reduce reperfusion injury. We therefore carried out a pilot study to assess the safety of this drug combination and gain information regarding the efficacy of treating pediatric liver transplant recipients with NAC and PGE1. The pilot study took the form of an open-label study incorporating 25 pediatric liver transplant recipients (12 children in the treatment group and 13 children as controls). NAC (70 mg/kg) was given intravenously over 1 h following reperfusion and then every 12 h for 6 days. PGE1 (0.4 mg/kg/h) was given as a continuous intravenous infusion for 6 days, starting after the first NAC dose. The primary outcome was the safety of combined treatment with NAC and PGE1. Patient survival, graft survival, allograft rejection within the first 90 days after Tx, peak post-transplant serum alanine aminotransferase (ALT) concentration, post-transplant length of hospitalization, and post-operative complications were secondary outcomes. Post-operative complications occurred at similar rates in both control and treated groups. No complications or adverse events occurred in the treated group as a result of study drugs. The 3-month patient survival rate was 100% for both groups. For the group treated with NAC and PGE1, peak serum ALT was lower and median length of stay was shorter but the differences did not reach statistical significance. The proportion of patients with allograft rejection was not significantly different between the two groups. However, rejection was more severe in the control group than in the treated group. In summary, infusions of NAC and PGE1 were safely administered to pediatric liver transplant recipients. However, a randomized controlled study is needed to determine the efficacy of treatment with NAC and PGE1.
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PMID:Effect of treatment with prostaglandin E1 and N-acetylcysteine on pediatric liver transplant recipients: a single-center study. 1173 62

OBJECTIVE: To evaluate the pharmacokinetics of cefetamet pivoxil and possible interaction with N-acetylcysteine and cisapride in healthy volunteers. METHODS: In a double-blind, randomized three-way crossover study with 12 healthy male volunteers, serum and urine concentrations of cefetamet were determined over 12 h by a validated bioassay method after oral administration of 0.5 g cefetamet pivoxil and, randomly, placebo, 5x20 mg cisapride, or 0.6 g N-acetylcysteine. RESULTS: The study medications were well tolerated, although there were 10 cases of altered bowel movements, two cases of mild, transient headache and one case of increased serum transferase levels (AST and ALT). The mean peak serum level of cefetamet pivoxil in the placebo group was 4.86plus minus1.35 mg/L. The urine recovery/24 h in the placebo group was 41.9plus minus3.8% of the oral dose. The elimination half-life was 3.56plus minus0.92 h. N-Acetylcysteine had no effect on the pharmacokinetics of cefetamet pivoxil. With concomitant administration of cisapride there was an accelerated absorption of cefetamet pivoxil and a slightly increased Cmax of cefetamet. The Cmax values differed significantly (p<0.05) only between the cisapride group (5.76plus minus1.50 mg/L) and the N-acetylcysteine group (4.53plus minus1.18 mg/L). CONCLUSION: None of the small pharmacokinetic differences between the three groups is expected to have any relevance in the treatment of infectious diseases with cefetamet pivoxil.
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PMID:Pharmacokinetics of cefetamet pivoxil and interaction with cisapride and N-acetylcysteine. 1186

When a patient with acetaminophen overdose arrives in the emergency room more than 14 hours after ingestion, the value of N-acetylcysteine is unproven and patient mortality is at least 10%. Anecdotal case reports have indicated benefit of extracorporeal detoxification of these late-arriving patients with acetaminophen overdose. We identified 10 patients with serious acetaminophen overdose, 8 that arrived in the emergency room 16 to 44 hours after acetaminophen overdose with plasma levels predicting severe hepatic toxicity, and 2 that arrived in the emergency room 8 to 12 hours after overdose but with exceedingly high levels. All patients developed severe hepatitis (mean peak alanine aminotransferase, 4,052; mean peak protime, 25 seconds). At 16 to 68 hours after overdose, the patients were treated for 4 to 6 hours with the Liver Dialysis System (Hemocleanse Inc, W. Lafayette, IN), a single-access hemodiabsorption system indicated for treatment of serious drug overdose and for treatment of hepatic encephalopathy. Acetaminophen levels fell an average of 73% during treatment. Treatment was repeated 24 or 48 hours later if acetaminophen was still measurable in plasma. All 10 patients recovered intrinsic liver function and general health, with liver enzymes starting to normalize 24 hours after treatment, and were discharged 3 to 7 days after overdose. No patient required liver transplant. Because market introduction of Liver Dialysis, there have been 40 more patients with acetaminophen-induced hepatotoxicity treated with Liver Dialysis. All have recovered liver function without long-term sequelae. Though most of these patients with already established hepatic toxicity from acetaminophen would recover without extracorporeal blood therapy, treatment with the Liver Dialysis System should assure recovery from acute hepatic failure, and may shorten the clinical course of the illness.
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PMID:Treatment of acetaminophen-induced hepatitis and fulminant hepatic failure with extracorporeal sorbent-based devices. 1192 6

Obtaining effective analgesia with a minimal erosive effect on gastric mucosal tissue has increased the consumption of acetaminophen (paracetamol), especially among the elderly. However, the hepatotoxic effects of acetaminophen have also increased. We aimed to compare the effects of 4-methylpyrazole (4-MP), N-acetylcysteine (NAC) and their combined use on the hepatotoxicity of acetaminophen in a rat model. Male Wistar Albino rats were divided into six groups. Groups 1-5 received 2,000 mg/kg acetaminophen by gavage while the control group was group 6. Group 2 animals were given NAC (loading dose 140 mg/kg followed by seven doses at 4 h intervals); group 3 received 50 mg/kg 4-MP; group 4 received 200mg/kg 4-MP; and group 5 received NAC as in group 2 plus 200 mg/kg 4-MP. Blood samples were taken for measurements of serum AST and ALT levels. The livers of the rats were removed for microscopic examination and grading of hepatic necrosis. AST and ALT levels in groups 2-5 were lower than that of group 1 (p < 0.001), although no significant difference was noted between groups 2-5 (p > 0.05). Higher levels of ALT were found in group 5 than in group 2 (p < 0.05), and higher levels of AST were found in group 5 than in group 3 (p < 0.01). Median necrosis scores were 3.36 for rats receiving acetaminophen alone (p < 0.001, compared with groups 2-6), 1.45-1.81 for groups 2-5 (p > 0.05, compared with each other), and 0.18 for control rats (p < 0.001, compared with groups 1-5). In conclusion, the administration of 4-MP and/or NAC after 4 h of administering toxic dose of acetaminophen, inhibits hepatotoxicity in rats. There was no difference between the 4-MP and NAC-treated groups as reflected by comparable levels of serum transaminases and the degree of hepatic necrosis. Combining of 4-MP and NAC offers no benefit.
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PMID:Comparison of the therapeutic efficacy of 4-methylpyrazole and N-acetylcysteine on acetaminophen (paracetamol) hepatotoxicity in rats. 1201 14

Administration of acetaminophen (ACP, 400 mg/kg, i.p.) to fasted, male Swiss-Webster mice caused a rapid 90% decrease in total hepatic glutathione (GSH) and a 58% decrease in mitochondrial GSH by 2 h post ACP. This was followed by a time-dependent decrease (72%) in hepatic AdoMet synthetase activity and rise in plasma ALT levels (>10000 U/l) at 24 h post ACP treatment. AdoMet synthetase activity was maintained at 82, 78 and 60% of controls, respectively, by the cysteine prodrugs PTCA, CySSME and NAC. Total hepatic and mitochondrial GSH levels were also protected from severe ACP-induced depletion by CySSME and MTCA. These results suggest that the maintenance of GSH homeostasis by cysteine prodrugs can protect mouse hepatic AdoMet synthetase, a sulfhydryl enzyme whose integrity is dependent on GSH, as well as the liver itself from the consequences of oxidative stress elicited by toxic metabolites of xenobiotics.
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PMID:Acetaminophen-induced suppression of hepatic AdoMet synthetase activity is attenuated by prodrugs of L-cysteine. 1208 14


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