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)

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

1. The roles of cytochrome P450 monooxygenases (P450) and glutathione (GSH) in styrene hepatotoxicity were investigated in mice by pretreating with either phenobarbital (PB; P450 inducer), SKF 525A (P450 inhibitor), N-acetylcysteine (NAC; GSH precursor), or saline (vehicle control) prior to a 6-h exposure to either 500 ppm styrene on air. 2. Styrene caused hepatocellular degeneration or necrosis in all groups; these changes were more extensive and severe in mice pretreated with PB. Styrene significantly increased relative liver weights and serum ALT and SDH levels only in mice pretreated with PB. NAC did not prevent GSH depletion or hepatotoxicity. 3. In the fat of SKF 525A-pretreated mice a slight but statistically significant increase in styrene levels was observed, suggesting that metabolism was decreased; the SO/styrene ratio in the fat of PB-pretreated mice showed a slight, but statistically significant, increase indicating a slight increase in styrene metabolism. Neither SKF 525A nor PB caused changes in microsomal enzyme activity in vitro. 4. These results suggest that styrene may be activated by a pathway not totally dependent upon P450 enzyme activity, or more likely that PB and SKF 525A are not specific for the P450 enzymes involved in activation and detoxification of styrene.
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PMID:Effects of various pretreatments on the hepatotoxicity of inhaled styrene in the B6C3F1 mouse. 914 79

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

Azathioprine (AZA) is an important drug used in the therapy of autoimmune system disorders. It induces hepatotoxicity that restricts its use. The rationale behind this study was the proven efficacy of N-acetylcysteine (NAC; a replenisher of sulfhydryls) and reports on the antioxidant potential of aminoguanidine (AG; an iNOS inhibitor), that might be useful to protect against the toxic implications of AZA. AG (100 mg/kg; i.p.) or NAC (100 mg/kg; i.p.) were administered to the Wistar male rats for 7 days and after that AZA (15 mg/kg, i.p.) was given as a single dose. This caused an increase in the activity of hepatic aminotransferases (AST and ALT) in the serum 24 h after AZA treatment. AZA (7.5 or 15 mg/kg, i.p.) also caused an increase in rat liver lipid peroxides and a lowering of reduced glutathione (GSH) contents. In the other part of experiment, protective effects of AG and NAC were observed on AZA induced hepatotoxicity. NAC significantly protected against the toxic effects produced by AZA. Pretreatment with NAC prevented any change in the activities of both the aminotransferases after AZA. This pretreatment also resulted in a significant decline in the contents of lipid peroxides and a significant elevation in GSH level was evident after AZA treatment. In the group with AG pretreatment the activities of AST and ALT did not increase significantly after AZA when compared to control. However, the lipid peroxides and GSH levels did not have any significant difference when compared to AZA group. These observations also indicate that the improvement in the GSH levels by NAC is the most significant protective mechanism rather than any other mechanistic profile. The protective effect of AG against the enzyme leakage seems to be through the liver cell membrane permeability restoration and is independent of any effects on liver GSH contents.
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PMID:A comparison of hepatoprotective activities of aminoguanidine and N-acetylcysteine in rat against the toxic damage induced by azathioprine. 1272 94

Oxidative stress and especially its connection with many diseases has been discussed much recently. Among markers of oxidative stress there appear new and quite specific ones called advanced oxidation protein products (AOPPs). We tried to influence the level of AOPPs by an antioxidant therapy with N-acetylcysteine. Fourteen individuals with many cardiovascular risk factors were examined. All these patients were administered acetylcysteine (NAC) 600 mg/day orally during 20 days. Before starting the therapy we determined AOPP, albumin cobalt binding (ACB), glucose, creatinine, urea, ALT, AST, cholesterol, LDL, HDL and triglycerides values in peripheral venous blood in all individuals. After finishing our intervention we determined AOPP, ACB and glucose level again. Our results show a statistically significant decrease in AOPP levels after 20-day N-acetylcysteine therapy (medians, initially 82.2, at study end 74.3 umol/l, p = 0.039). We demonstrate a significant decrease in AOPP levels after 20-day N-acetylcysteine therapy in dose 600 mg/day.
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PMID:The antioxidant acetylcysteine reduces oxidative stress by decreasing level of AOPPs. 1574 60

Steatotic livers are highly susceptible to I/R (ischaemia/reperfusion) injury and, therefore, the aim of the present study was to evaluate the in vivo effect of NAC (N-acetylcysteine) on hepatic function in the early and initial late phase of warm liver I/R injury in steatotic rabbits. Twelve New Zealand White rabbits were fed a high-cholesterol (2%) diet. The control group (n=6) underwent lobar liver ischaemia for 1 h, followed by 6 h of reperfusion. In the treated group receiving NAC (n=6), an intravenous infusion of NAC was administered prior to and during the 6 h reperfusion period. Systemic and hepatic haemodynamics were monitored continuously. ALT (alanine aminotransferase) activity and bile production were measured. NMR spectroscopy was used to analyse bile composition. Oxidation of DHR (dihydrorhodamine) to RH (rhodamine) was used as a marker of production of reactive oxygen and nitrogen species. Moderate centrilobular hepatic steatosis was demonstrated by histology. The results showed that NAC administration significantly improved portal flow, hepatic microcirculation, bile composition and bile flow after 5 h of reperfusion. NAC administration was also associated with less hepatocellular injury, as indicated by ALT serum activity, and decreased the oxidation of DHR to RH. In conclusion, NAC administration decreased the extent of I/R injury in the steatotic liver, particularly during the late phase of reperfusion.
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PMID:N-Acetylcysteine ameliorates the late phase of liver ischaemia/reperfusion injury in the rabbit with hepatic steatosis. 1598 89

3-Butene-1,2-diol (BDD), an allylic alcohol and major metabolite of 1,3-butadiene, has previously been shown to cause hepatotoxicity and hypoglycemia in male Sprague-Dawley rats, but the mechanisms of toxicity were unclear. In this study, rats were administered BDD (250 mg/kg) or saline, ip, and serum insulin levels, hepatic lactate levels, and hepatic cellular and mitochondrial GSH, GSSG, ATP, and ADP levels were measured 1 or 4 h after treatment. The results show that serum insulin levels were not causing the hypoglycemia and that the hypoglycemia was not caused by an enhancement of the metabolism of pyruvate to lactate because hepatic lactate levels were either similar (1 h) or lower (4 h) than controls. However, both hepatic cellular and mitochondrial GSH and GSSG levels were severely depleted 1 and 4 h after treatment and the mitochondrial ATP/ADP ratio was also lowered 4 h after treatment relative to controls. Because these results suggested a role for hepatic cellular and mitochondrial GSH in BDD toxicity, additional rats were administered N-acetyl-l-cysteine (NAC; 200 mg/kg) 15 min after BDD administration. NAC treatment partially prevented depletion of hepatic cellular and mitochondrial GSH and preserved the mitochondrial ATP/ADP ratio. NAC also prevented the severe depletion of serum glucose concentration and the elevation of serum alanine aminotransferase activity after BDD treatment without affecting the plasma concentration of BDD. Thus, depletion of hepatic cellular and mitochondrial GSH followed by the decrease in the mitochondrial ATP/ADP ratio was likely contributing to the mechanisms of hepatotoxicity and hypoglycemia in the rat.
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PMID:Protection of rats against 3-butene-1,2-diol-induced hepatotoxicity and hypoglycemia by N-acetyl-l-cysteine. 1612 19

This study examined effects of S-allyl cysteine (SAC) on carbon tetrachloride (CCl4)-induced interstitial pulmonary fibrosis in Wistar rats. CCl4 (0.5 ml/kg) was intraperitoneally injected into rats twice a week for 8 weeks, and SAC (50, 100, or 200 mg/kg), N-acetyl cysteine (NAC, 200 or 600 mg/kg), or L-cysteine (CYS, 600 mg/kg) were orally administrated to rats everyday for 8 weeks. SAC significantly reduced the increases of transforming growth factor beta, lipid peroxides, AST, and ALT in plasma, induced by CCl4. Although CCl4 is mainly metabolized by hepatic cytochrome P450, CCl4 induced systemic inflammation and some organ fibrosis. SAC dose-dependently and significantly attenuated CCl4-induced systemic inflammation and fibrosis of lung. SAC also inhibited the decrease of thiol levels, the increase of inducible nitric oxide synthase expression, the infiltration of leukocytes, and the generation of reactive oxygen species in lungs. Although NAC and CYS attenuated CCl4-induced pulmonary inflammation and fibrosis, the order of preventive potency was SAC > NAC > CYS according to their applied doses. These results indicate that SAC is more effective than other cysteine compounds in reducing CCl4-induced lung injury, and might be useful in prevention of interstitial pulmonary fibrosis.
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PMID:S-allyl cysteine attenuated CCl4-induced oxidative stress and pulmonary fibrosis in rats. 1661 85

Efficacy of thiol chelators viz. N-acetyl cysteine and D-penicillamine (NAC and DPA) along with nutritional supplements viz. zinc acetate, sodium selenite and magnesium sulphate (Zn, Se and Mg) in the treatment of mercury intoxication was investigated in rats. This is of particular interest since high bonding affinity between mercuric ion and the thiol group exits. The mutual antagonism of mercury and selenium is one of the strongest examples of the interaction in the trace element field. Adult rats of Sprague-Dawley strain were administered a bolus dose of dimethyl mercury (10 mg/kg) orally. A significant rise in the aspartate aminotransferase, alanine aminotransferase, serum alkaline phosphatase, lactate dehydrogenase, gamma glutamyltranspeptidase, bilirubin and creatinine were observed. Single mercury exposure also resulted in a significant increase in lipid peroxides with a concomitant decrease in reduced glutathione level in liver, kidney and brain. A decrease in the enzymatic activities of acetyl cholinesterase in different regions of the brain was observed. These parameters were restored considerably with chelating agents along with nutritional supplementation, but NAC+Se and DPA+Mg offered significant protection in comparison with other combinations.
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PMID:Effect of monothiol along with antioxidant against mercury-induced oxidative stress in rat. 1825 9

This study was aimed to investigate the molecular mechanisms underlying prevention of hepatic fibrosis by S-nitroso-N-acetylcysteine (SNAC), a nitric oxide donor that inhibits lipid peroxidation. Secondary biliary cirrhosis was induced by 4 weeks of common bile duct ligation (CBDL). Both sham-operated and CBDL animals received SNAC (6.0 micromol/kg/day) starting 2 weeks after surgery. SNAC treatment reduced the increase in blood enzyme activities (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase), induced by CBDL. Histological changes were attenuated and there was a significant decrease in the area of liver fibrosis and in the activation of stellate cells measured by alpha-smooth muscle actin (alpha-SMA) immunostaining. The increase in TBARS concentration and hydroperoxide-induced chemiluminescence were also reduced by SNAC treatment. SNAC down-regulated expression of collagen 1 alpha, alpha-SMA, tumor necrosis factor-alpha, tumor growth factor-beta, metalloproteinase-2, metalloproteinase inhibitor 1, platelet-derived growth factor (PDGF), and PDGF receptor in CBDL rats. These effects were accompanied by inhibited activation of extracellular signal-regulated kinases, Jun amino-terminal kinases, p38 and Akt. Antifibrotic effects were more efficient than those of the free thiol NAC administered at a dose of 60 mumol/kg. In conclusion, results obtained indicate that SNAC, beyond its antioxidant capacity, exerts antifibrotic effects in rats with secondary biliary cirrhosis by down-regulating increased expression of genes and modulating intracellular signaling pathways that contribute to the accumulation of matrix proteins. Thus, SNAC may be an interesting candidate for the treatment of human fibrosis and cirrhosis.
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PMID:S-nitroso-N-acetylcysteine attenuates liver fibrosis in cirrhotic rats. 2006 61


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