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)

Pretreatment of rats with large doses of vitamin A (VA) potentiates the hepatotoxicity of CCl4. Because our previous studies indicate that VA treatment does not enhance CCl4 metabolism but does enhance CCl4-induced lipid peroxidation and activates liver Kupffer cells to release increased amounts of oxygen-centered free radicals, the current studies were designed to determine if VA treatment potentiates CCl4-induced liver injury through increased release of reactive oxygen species. Plasma clearance of colloidal carbon, an index of Kupffer cell phagocytic activity, was enhanced two- to threefold in rats treated for 7 days with VA (retinol, 250,000 IU/kg per day). Accordingly, VA treatment alone caused Kupffer cell activation. To determine if these activated Kupffer cells could potentiate hepatic injury through release of reactive oxygen species upon CCl4 challenge, polyethylene glycol coupled-superoxide dismutase (PEG-SOD, 10,000 IU/kg) or -catalase (PEG-CAT, 40,000 IU/kg) was given iv 2 hr after CCl4 (0.15 ml/kg, ip) to control or VA-pretreated rats to quench any released reactive oxygen. PEG-SOD and PEG-CAT effectively blocked VA potentiation of CCl4 liver injury as assessed at 24 hr by change in plasma ALT. Methylpalmitate (MP, 2 g/kg), an inhibitor of Kupffer cell phagocytosis and related oxygen burst, also blocked the potentiation of liver injury when given iv 24 hr before CCl4 to VA-pretreated rats. At the doses used, PEG-SOD or PEG-CAT did not influence CCl4 toxicity in control rats (at 0.15 or 2 ml CCl4/kg). Importantly, SOD, CAT, and MP blocked the enhanced lipid peroxidation induced by CCl4 in VA-pretreated rats. From these findings we conclude that the potentiation of CCl4 liver injury by VA pretreatment is mediated, at least in part, by active oxygen species released from Kupffer cells and possibly other macrophages that are activated by VA. Supporting this conclusion is the failure of VA pretreatment to increase the release of LDH from suspension of hepatocytes incubated with CCl4.
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PMID:Vitamin A potentiation of carbon tetrachloride hepatotoxicity: role of liver macrophages and active oxygen species. 848 Mar 39

Superoxide radical (O2-) is a free radical that may be involved in various toxic processes. Cu-Zn superoxide dismutase catalyzes the dismutation of the superoxide free radical and protects cells from oxidative damage. A rat bioassay validated for the identification of the toxic effects of azomethine H revealed increased serum activities of amylase, alanine transaminase, and alkaline phosphatase. The lipoperoxide and bilirubin concentrations were also increased in animals that received azomethine H (1 g/kg) from ascorbic or hydrochloric acid solutions. Azomethine H increased Cu-Zn superoxide dismutase activity. This elevation of Cu-Zn superoxide dismutase activity was highest on the 7th day and was at levels comparable with those of control rats from day 60 onwards. Superoxide is an important intermediate in the action and toxicity of azomethine H.
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PMID:Reactive oxygen generation by azomethine H: a new antimalarial drug. 856 88

Hepatoprotective effect of Tamra bhasma has been studied on cumene hydroperoxide (CHP) induced peroxidation, reduced glutathione content and superoxide dismutase (SOD)-in rat liver homogenate. The drug was orally given for 8 days which showed significant reduction in the level of malondialdehyde (MDA) production at different concentrations of cumene hydroperoxide in vitro. Glutathione content was maintained upto seventy minutes and SOD activity was enhanced to 166%. These animals did not show any rise in serum GOT and GPT. On similar doses no histological changes were observed in liver. The results suggested that Tamra bhasma is a strong antioxidant drug and could be used in the management of lipid peroxidation with no detectable adverse effect.
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PMID:Role of Tamra bhasma, an Ayurvedic preparation, in the management of lipid peroxidation in liver of albino rats. 869 11

The present studies were performed to test the hypothesis that Kupffer and endothelial cells are activated after recovery from an acute alcohol binge, which is accompanied by formation of oxygen-derived radicals. These radicals have been implicated in the pathogenesis of alcohol-mediated tissue injury in a number of organs. Male Sprague-Dawley rats received an intravenous injection of 20% ethanol in saline (1.75 g/kg), followed by an intravenous infusion (250 to 300 mg/kg/hr) for 12 hr. At the end of 12-hr infusion, ethanol was replaced by saline, and the infusion was continued for a further 6 hr. This was referred to as the recovery period. The 6-hr recovery period was selected because superoxide anion generation by the perfused liver peaked at this time point. Superoxide anion formation by the perfused liver was measured by the superoxide dismutase-inhibitable reduction of ferricytochrome c. Kupffer and endothelial cells were isolated for the determination of in vivo glucose uptake and in vitro superoxide anion release. Results show that a significant (p < 0.05) amount of superoxide (1.54 nmol/min/g) was generated by the perfused liver at 6 hr recovery after 12 hr of ethanol infusion. Serum ALT activity was also elevated in this treatment group. Time-matched control-saline infused animals or ethanol-treated animals without a recovery period released < 0.2 nmol/min/g of superoxide. The postrecovery superoxide production and an accompanying increase in the in vivo glucose uptake were also observed in isolated Kupffer and endothelial cells. Depletion of Kupffer cells by gadolinium chloride before ethanol treatment and recovery was associated with significant attenuation of free radical formation by the perfused liver and reduction of serum ALT. These studies demonstrate that recovery from an acute alcohol binge has a stimulating effect on hepatic sinusoidal superoxide production, and it may also affect liver function.
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PMID:Postbinge effects of acute alcohol intoxication on hepatic free radical formation. 872 45

The antimalarial properties of azomethine H represent the basis for its use as a chemotherapeutic agent. This work was carried out in order to verify the biological side effects of azomethine H and to clarify the contribution of reactive oxygen species (ROS) in this process. It was shown that azomethine H increased serum activities of amylase, alanine transaminase (ALT) and the TBARS concentrations, in rats. No changes were observed in glutathione peroxidase and catalase activities. The drug-induced tissue damage might be due to superoxide radicals (O2.-), since Cu-Zn superoxide dismutase activities were increased by azomethine H treatment. This study allows tentative conclusions to be drawn regarding which reactive oxygen metabolites play a role in azomethine H activity. We concluded that (O2.-) maybe produced as a mediator of azomethine H action.
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PMID:Free radical production by azomethine H: effects on pancreatic and hepatic tissues. 916 36

When activated, inflammatory cells such as polymorphonuclear leukocytes (PMNs) can damage isolated hepatocytes in vitro. These studies were performed to determine if flutamide activates PMNs. Flutamide (Eulexin) is an orally active, nonsteroidal antiandrogen that can cause liver injury associated with inflammation. Activation of PMNs was assessed from the production of superoxide anion and the release of myeloperoxidase in the presence or absence of flutamide and phorbol myristate acetate (PMA) or f-methionyl-leucyl-phenylalanine (fmlp). In addition, hepatocytes were cocultured with PMNs stimulated with PMA or fmlp in the presence or absence of flutamide, and cytotoxicity to hepatocytes was evaluated from the release of alanine aminotransferase into the medium. Flutamide alone did not stimulate the generation of superoxide anion by PMNs but potentiated its production in response to PMA. At lower concentrations of flutamide (i.e. 25 microM), there was a tendency toward increased release of myeloperoxidase, whereas at higher concentrations (i.e. 75-100 microM) flutamide inhibited degranulation in response to fmlp. In coculture with hepatocytes, PMNs exposed to either flutamide, fmlp, or PMA alone caused a significant increase in release of alanine aminotransferase. Hepatocellular toxicity caused by PMNs incubated with flutamide and PMA was additive and was not affected by the addition of superoxide dismutase and catalase. Flutamide had no significant effect on fmlp-induced injury in cocultures. These data indicate that flutamide alters the activation of PMNs by subsequent stimuli in vitro. In addition, in the presence of flutamide, minor PMN-mediated injury to isolated hepatocytes was observed.
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PMID:Alteration by flutamide of neutrophil response to stimulation. Implications for tissue injury. 917 23

The association between an in vivo oxidative stress condition of the liver and hepatic porphyria during HCB intoxication is postulated. After 30 days of treatment, HCB (25 mg/kg b.w.) promotes an induction of microsomal cytochrome P450 system, increase in microsomal superoxide anion generation accompanied by increased levels of liver lipid peroxidation, as measured by the production of thiobarbituric acid reactants and by spontaneous visible chemiluminescence. Concomitantly, liver antioxidant defenses are slightly modified, with decreased activity of glutathione peroxidase, superoxide dismutase and glucose-6-phosphate dehydrogenase contributing to an oxidative stress condition of the liver. These liver biochemical alterations are closely related to increased levels of urinary coproporphyrin, plasma AST and ALT activities and to the onset of liver morphological lesions.
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PMID:Pro- and anti-oxidant parameters in rat liver after short-term exposure to hexachlorobenzene. 919 4

Prevention of cellular damage after warm ischemia is of major importance in liver transplantation. In this study, we determined the extent to which lipid peroxides contribute to the pathogenesis of hepatic cell damage induced by transient warm ischemia with subsequent reperfusion. In addition, the function and immunohistochemical features of glutathione peroxidase, a potent physiological lipid peroxide scavenger of the liver, was assessed. Reperfusion following 15 or 30 minutes of warm ischemia resulted in a significant elevation in serum and liver lipid peroxidase (LPO) levels. In addition, necrosis of the hepatic periportal area accompanied with remarkable rises in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were observed. In contrast, 30 min of ischemia without reperfusion caused minimal hepatocellular damage. The adverse changes after ischemia/reperfusion were minimized by pretreatment with superoxide dismutase (SOD). These results indicate that increased lipid peroxidation by production of radicals after reperfusion caused the liver cell damage. After ischemia/reperfusion, liver glutathione peroxidase (GSH-PO) activity was significantly decreased and its location altered in the damaged liver. These findings suggest that GSH-PO contributes significantly to the protection against hepatic reperfusion injuries.
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PMID:Alterations in glutathione peroxidase activity following reperfusion injury to rat liver. 960 29

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

Using the cytochrome c method, superoxide anion that is released into the hepatic sinusoid was measured after a lipopolysaccharide challenge in a liver perfusion system. Moreover, damages of epithelial cells of the hepatic sinusoid were estimated with scanning electron microscopic analysis and levels of purine nucleoside phosphorylase/GPT ratio. Lipopolysaccharide administration increased the conversion of oxidized cytochrome c into reduced cytochrome c in the perfusate, indicating that superoxide anion was formed in the hepatic sinusoid. This change was associated with increase in levels of portal tumor necrosis factor-alpha and attenuated by the simultaneous administration of superoxide dismutase. Scanning electron microscope analysis revealed that diameters of sinusoidal fenestrae increased in rats treated with lipopolysaccharide, compared with controls. Moreover, levels of purine nucleoside phosphorylase/GPT ratio was significantly increased in the liver perfusate in lipopolysaccharide-treated rats, compared with controls. Superoxide anion in hepatic sinusoid may be one of the pathogenic factors behind damages of epithelial cells of the hepatic sinusoid caused by lipopolysaccharide.
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PMID:Formation of superoxide anion in the hepatic sinusoid after lipopolysaccharide challenge. 962 90


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