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)

The protective effects of polysaccharide peptide (PSP), isolated from Coriolus versicolor COV-1, on paracetamol-induced hepatotoxicity was investigated in this study. The effect of PSP on hepatic glutathione status was also studied. PSP (300 mg/kg, i.p.) caused a 40% depletion of hepatic reduced glutathione (GSH) with a concomitant 50% increase in oxidized glutathione (GSSG), thus producing a 3-fold increase in the GSSG/GSH ratio. The PSP-induced GSH depletion itself had no hepatotoxic effects. PSP protected against paracetamol-induced hepatotoxicity by decreasing the paracetamol-induced elevation of serum glutamic-pyruvic transaminase (SGPT) activity from 511 +/- 71 U/ml to 187 +/- 58 U/ml (controls without paracetamol 105 +/- 4 U/ml) and serum glutamic-oxaloacetic transaminase (SGOT) activity from 462 +/- 63 to 152 +/- 48 U/ml (controls without paracetamol 54 +/- 6 U/ml). PSP did not reverse the depletion of total glutathione (GSH+GSSG) by the toxic dose of paracetamol. The GSSG/GSH ratio, which is a measure of oxidative stress, was significantly (p < 0.05) decreased when PSP was coadministered with paracetamol. PSP dose-dependently decreased the covalent binding of [14C]-paracetamol to microsomal proteins in vitro. When PSP was given to rats subchronically for 7 days (300 mg/kg/day, i.p.), the subsequent microsomes obtained also showed a 25% decrease in covalent binding to [14C]-paracetamol, suggesting that PSP interacted with the microsomal proteins rather than the chemically reactive metabolite of paracetamol. The changes in the binding affinity and capacity of the microsomal proteins by PSP may be related to its ability to alter the redox potential as indicated by the effects of PSP on the GSSG/GSH status.
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PMID:Effect of polysaccharide peptide (PSP) on glutathione and protection against paracetamol-induced hepatotoxicity in the rat. 772 71

The in vivo effects of ascorbic acid on the reoxygenated liver tissue were examined, with regard to the following effects: (i) the effects of scavenging radicals and/or reducing peroxidative reactions, and (ii) the effects of the chelation with low-molecular-weight iron and increasing its reactivity (radical production). Ascorbic acid is one of the water-soluble vitamins known to have various physiological effects involving both chelating and reducing properties at once. Lipid peroxidation of the reoxygenated liver tissue estimated by the production of TBARS (thiobarbituric acid-reactive substance) and LPO (lipid hydroperoxides) was suppressed effectively by the preischemic intraperitoneal administration of ascorbic acid. Ascorbic acid also showed this anti-oxidant effect in a dose-dependent manner. The analysis of the levels of ascorbic acid and glutathione of the liver tissue revealed that ascorbic acid works as an anti-oxidant probably by being oxydized finally to dehydroascorbic acid just after the reoxygenation. The latter was reduced to ascorbic acid again, coupled with the conversion of GSH to GSSG in the postischemic time course. The predominant effect of ascorbic acid on the reoxygenated liver tissue seems to be caused by the scavenging radicals and/or reducing peroxidative reactions, rather than by chelating iron and increasing its reactivity (radical production). Cellular integrity (estimated by the release of GOT, GPT, and LDH) and the energy state of the postischemic liver tissue (estimated by the tissue ATP level) were also well preserved by the administration of ascorbic acid.
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PMID:The in vivo cytoprotection of ascorbic acid against ischemia/reoxygenation injury of rat liver. 773 75

Plasma levels of glutathione disulfide (GSSG) as an indicator of a vascular oxidant stress, tumor necrosis factor-alpha (TNF-alpha) formation, and liver injury (alanine aminotransferase activity, histology) were monitored in male Fischer rats after 30 min of hepatic ischemia followed by up to 4 hr of reperfusion. The injection of 1 mg/kg Salmonella enteritidis endotoxin at 30 min of reflow potentiated the postischemic oxidant stress and liver injury. TNF-alpha levels increased from 10 +/- 7 pg/ml (baseline) to 3,553 +/- 738 pg/ml after ischemia-reperfusion followed by endotoxin, or to 3,670 +/- 508 pg/ml after endotoxin alone. Depletion of serum complement before ischemia attenuated the endotoxin-mediated increase of reactive oxygen formation by 70% but did not affect TNF-alpha levels. Complement activation with cobra venom factor (CVF) during reperfusion had an effect similar to that of endotoxin on the oxidant stress and liver injury. CVF did not increase TNF-alpha formation during reperfusion. Kupffer cells and neutrophils isolated from the postischemic liver 2.5 hr after endotoxin injection generated 600% and 400% more superoxide, respectively, than cells isolated from control livers. The results demonstrate a substantial priming of hepatic phagocytes for reactive oxygen production but not TNF-alpha formation, even after short periods of hepatic ischemia, and the vulnerability of the postischemic liver to severe endotoxin-induced injury. Activated complement seems to be mainly responsible for the effects. These results may explain the high risk for hepatic failure after extensive liver resection and hypovolemic shock.
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PMID:Priming of phagocytes for reactive oxygen production during hepatic ischemia-reperfusion potentiates the susceptibility for endotoxin-induced liver injury. 798 73

The changes in the concentrations of reduced (GSH) and oxidized glutathione (GSSG) in the plasma as well as in the liver were investigated in rats with endotoxin hepatitis. Hepatitis was induced by intraperitoneal co-administration of small doses of Escherichia coli endotoxin and D-galactosamine. In the liver, the concentration of GSH decreased and that of GSSG increased 12 hr later. In the plasma taken from the right atrium, the concentration of both GSH and GSSG increased. The GSH/GSSG ratio in the plasma decreased, as it did in the liver. The net sinusoidal efflux of GSH and GSSG from the liver was calculated by subtracting their concentrations in plasma of the infrahepatic, suprarenal inferior vena cava from those of the suprahepatic inferior vena cava. The efflux started to increase as early as 2-4 hr after the injection of the toxins. In contrast, a leakage of alanine aminotransferase, an elongation of prothrombin time, an inhibition of starvation ketosis, and an increase in serum concentration of total bilirubin were detected as late as 6-8 hr after the injection. We conclude that endotoxin/D-galactosamine hepatitis induced an increase in plasma concentrations of GSH as well as GSSG by increasing the efflux of these peptides from the liver, and that changes in plasma glutathione status might be useful and sensitive markers for liver damage.
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PMID:Increased sinusoidal efflux of reduced and oxidized glutathione in rats with endotoxin/D-galactosamine hepatitis. 802 75

To elucidate the significance of the changes in plasma glutathione concentrations associated with carbon tetrachloride (CCl4)-induced liver damage, the changes in the concentrations of reduced (GSH) and oxidized glutathione (GSSG) in plasma as well as in the liver were investigated in rats. In the liver, the concentration of GSH decreased, and that of GSSG increased 24 hr after the intraperitoneal administration of CCl4. In the right atrial plasma, the concentration of both GSH and GSSG increased. The GSH/GSSG ratio in the plasma decreased as did that in the liver. The net sinusoidal efflux of GSH and GSSG from the liver was calculated by subtracting their concentrations in plasma of the infrahepatic inferior vena cava from those of the suprahepatic inferior vena cava. The net efflux of GSH and GSSG started to increase as early as 3-6 hr after CCl4 administration, and reached a plateau 6 and 24 hr after CCl4 administration, respectively. On the other hand, an elongation of prothrombin time and leakage of alanine aminotransferase reached a maximum 24 and 48 hr after CCl4 administration, respectively. Vacuolization in the centri-lobular region and inflammatory infiltration started 3 and 6 hr after CCl4 administration, respectively, and progressed for 48 hr. These results suggest that CCl4 induced an increase in plasma concentrations of GSH as well as GSSG by increasing their efflux from the liver, and that the changes in plasma glutathione status might be a useful and sensitive marker for CCl4-induced liver damage.
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PMID:Carbon tetrachloride increases sinusoidal efflux of reduced and oxidized glutathione in rats. 811 11

Chronic liver damage induced by thioacetamide (TAM) was accompanied by changes in the expression of genes related to growth (beta-actin) and function (albumin and haptoglobin) of the liver. Their messenger RNA (mRNA) levels increased during the first days after TAM administration, but 4 to 7 days after prolonged treatment with this drug, liver gene expression was considerable decreased. TAM-induced changes in albumin and beta-actin mRNA levels were prevented by cotreatment with S-adenosyl-L-methionine (SAM). We have investigated the possible involvement of glutathione in the protective mechanism of SAM. Firstly, we found that TAM treatment in the rat induced changes in liver glutathione disulfide (GSSG) levels, with a concomitant increase in the glutathione reductase enzymatic activity, these changes being abolished when animals were cotreated with TAM and SAM. Secondly, when rats were pretreated with buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, before thioacetamide administration, the beneficial effect of SAM on liver gene expression was completely abolished. These results were confirmed by assaying the alanine transaminase serum activity, a parameter of liver injury. TAM-treated animals had increases in this serum enzyme, this effect being partially blocked by SAM. However, in BSO-pretreated rats, the protective effect of SAM was impaired. Taking together all these results, we propose a glutathione-dependent mechanism in the SAM protection against TAM hepatotoxicity in the rat.
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PMID:Changes in rat liver gene expression induced by thioacetamide: protective role of S-adenosyl-L-methionine by a glutathione-dependent mechanism. 861 42

The purpose of this study was to investigate the protective effects of the calcium channel blocker verapamil on warm ischemia-reperfusion injury to the liver using a rat model. Ischemia of the left and median lobes was created by total inflow occlusion for 60 min followed by 24 hr of reperfusion. Hepatocell injury was assessed by the release of liver enzymes [alanine aminotransferase (ALT) and lactic dehydrogenase (LDH)], reduced (GSH) and oxygenated (GSSG) plasma glutathione and total biliary glutathione. Hepatocyte function was quantitated by measuring bile flow. Rats were randomized to one of two groups: pretreatment with iv verapamil (0.3 mg/kg) or iv normal saline (controls). Verapamil significantly increased bile flow and GSH efflux while decreasing plasma ALT and LDH compared to those in controls 24 hr after liver ischemia-reperfusion (LIR). A significant correlation existed between bile flow and biliary GSH efflux at 1 but not 24 hr after LIR, suggesting that early LIR injury is mediated predominantly by generation of oxygen free radicals. Liver enzyme elevation and bile flow were inversely correlated at 24 but not 1 hr after injury. We conclude that verapamil significantly protects the liver against warm LIR injury. The minimal protective effect of verapamil on early liver ischemia-reperfusion demonstrates that verapamil does not prevent the early generation of oxygen radicals upon reperfusion. However, the significant restoration of biliary GSH efflux and hepatocyte protection at 24 hr suggests involvement of calcium ions in late hepatocyte injury. Verapamil's protective effects may be related to attenuating pathophysiologic events occurring beyond 1 hr of reperfusion. Future studies investigating the protective effects of verapamil on warm LIR injury should be carried out for at least 24 hr postreperfusion.
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PMID:Protective effects of the calcium channel blocker verapamil on hepatic function following warm ischemia. 881 26

The role of nitric oxide (NO) on liver oxidative stress and tissue injury in rats subjected to tourniquet shock was investigated. This shock model differs from others in that injury is a consequence of remote organ damage. Liver oxidative stress becomes evident after hind limb reperfusion, as evidenced by the loss of total tissue thiols; by increases in tissue oxidized glutathione (GSSG), lipid peroxidation (LPO), plasma aminotransferases (alanine aminotransferase (ALT) and (aspartate aminotransferase (AST)), and plasma nitrites; and by a 36% loss in total superoxide dismutase (SOD) activity. Portal blood flow is reduced by 54.1% after 2 h of hind limb reperfusion. Inhibition of NO synthesis with Nomega-nitro-L-arginine methyl ester or L-arginine methyl ester increased mean arterial blood pressure; further reduced portal blood flow; and aggravated liver injury as assessed by further loss in total thiols, increased LPO and GSSG content, and further increases in plasma ALT and AST. Total plasma nitrites were lower than in control animals, and total tissue SOD activity decreased by more than 80%. Treatment with the NO donor sodium nitroprusside reverted the decrease in portal blood flow and also reverted tissue thiol loss, LPO, and GSSG increases, as well as the loss of ALT and AST to plasma and of SOD activity to levels comparable to untreated control shock animals. As expected, plasma nitrites were greater than in tourniquet control animals. These data support the hypothesis that endogenous NO formation protects the rat liver from the consequences of oxidative stress elicited by hind limb reperfusion in rats subjected to tourniquet shock.
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PMID:Inhibition of nitric oxide synthesis aggravates hepatic oxidative stress and enhances superoxide dismutase inactivation in rats subjected to tourniquet shock. 961 80

Effects of a single dose of betaine on the chloroform-induced hepatotoxicity were examined in adult male ICR mice. Administration of betaine (1000 mg/kg, ip) 1 to 7 hr prior to a chloroform challenge (0.25 ml/kg, ip) resulted in remarkable enhancement of hepatotoxicity as indicated by increases in serum sorbitol dehydrogenase (SDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. The potentiation of hepatotoxicity was most significant when mice were treated with betaine 4 hr earlier than chloroform. However, a 24 hr prior administration of betaine protected the animals from induction of the chloroform hepatotoxicity. Thus, its effect appeared to be highly dependent on the time lapse from the betaine pretreatment to the challenge of mice with chloroform. Betaine treated either 4 or 24 hr prior to sacrifice did not alter the hepatic contents of cytochrome P-450, cytochrome b5, or NADPH cytochrome P-450 reductase activity. Accordingly the hepatic microsomal p-nitroanisole O-demethylase, aminopyrine N-demethylase, or p-nitrophenol hydroxylase activities were not influenced by the betaine pretreatment. Betaine was shown not to affect any of the enzyme activities associated with glutathione (GSH) conjugation reaction, such as glutathione S-transferases (GSTs), glutathione disulfide (GSSG) reductase and GSH peroxidase irrespective of the time of its administration. When betaine was administered to mice 2-6 hr prior to sacrifice, hepatic GSH level, but not plasma GSH, was decreased significantly. Enhancement of the chloroform hepatotoxicity by betaine correlated well with the reduction in hepatic GSH levels. Both hepatic and plasma GSH levels were elevated in mice 24 hr following the betaine treatment. The results suggest that betaine affects induction of the chloroform hepatotoxicity by modulating the availability of hepatic GSH, which appears to be associated with its role in the transsulfuration pathway in the liver.
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PMID:Effects of singly administered betaine on hepatotoxicity of chloroform in mice. 973 16

In the model of liver damage induced by acetaminophen of mice, injection of interleukin-1 beta (IL-1 beta, i.p. 50,000 U/kg) 1, 6 or 12 h before the administration of acetaminophen could reduce the leakages of GPT and GOT induced by acetaminophen, with the 12 h pretreatment being the most effective. Treatment with IL-1 beta 1 h after administration of acetaminophen had no effect. Treatment with IL-1 beta of different doses (10,000, 30,000 or 50,000 U/kg) 12 h before the administration of acetaminophen could reduce the leakages of transaminases in a dose dependent manner and decrease the mortality of mice. The protective effect of IL-1 beta on the liver could be abolished by IL-1 beta receptor antagonist. Further experiments showed that IL-1 beta could increase the content of reduced glutathione (GSH) in normal liver and reverse the decline of GSH and the increase of GSSG induced by acetaminophen. IL-1 beta could also reduce malondiadehyde (MDA) content enhanced by acetaminophen. The above results indicate that the preventive effect of IL-1 beta against liver damage due to acetaminophen may be mediated through IL-1 beta receptor by increasing glutathione synthesis and decreasing lipid peroxidation of the liver.
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PMID:[Protective effect of interleukin-1 beta on acetaminophen induced liver damage in mice]. 981 50


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