ascorbic-acid and Liver-Failure--Acute

This study was designed to investigate the influence of 2-methyl-6-phenylethynyl pyridine hydrochloride (MPEP), an antagonist of metabotropic glutamate receptor subtype 5, in lipopolysaccharide (LPS) and d-galactosamine (D-GalN)-induced fulminant hepatic failure in mice. Mice were given an intraperitoneal injection of 50 microg kg(-1) LPS and 500 mg kg(-1) D-GalN. MPEP (1, 5 and 25 mg kg(-1)) was administered intraperitoneally 1 h before LPS/D-GalN injection. Twenty-four hours after administration of LPS/D-GalN, plasma was collected and used for biochemical assays. Mice were euthanized and histological analysis and toxicological parameters were carried out in the liver. MPEP, at all doses tested, protected against the increase in aspartate and alanine aminotransferase activities induced by LPS/D-GalN exposure. Ascorbic acid levels were not altered in all experimental groups. Glutathione S-transferase activity was increased by administration of LPS/D-GalN and MPEP did not modify the enzyme activity in mice. MPEP, at the doses of 5 and 25 mg kg(-1), was effective in protecting against the decrease in catalase activity caused by LPS/D-GalN administration in mice. The histological data showed that sections of liver from LPS/D-GalN-exposed mice presented extensive injuries. MPEP, at all doses tested, reduced the scores of liver damage and markedly ameliorated the degree of liver damage. The hepatoprotective effect of MPEP on fulminant hepatic failure induced by LPS and D-GalN in mice was demonstrated.

Topics: Alanine Transaminase; Animals; Ascorbic Acid; Aspartate Aminotransferases; Catalase; Chemical and Drug Induced Liver Injury; Excitatory Amino Acid Antagonists; Galactosamine; Glutathione Transferase; Injections, Intraperitoneal; Lipid Peroxidation; Lipopolysaccharides; Liver Failure, Acute; Mice; Protective Agents; Pyridines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Survival Analysis

The aim of this study was to investigate the hepatoprotective effect of 3-alkynyl selenophene (compound a), a selenophene compound, on acute liver injury induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS) in rats. The animals received compound a (25 and 50 mg/kg; per oral, p.o.) in the first day of treatment. In the second day, the rats received D-GalN (500 mg/kg; intraperitoneal, i.p.) and LPS (50 microg/kg; intraperitoneal, i.p.). Twenty-four hours after D-GalN/LPS administration animals were euthanized to the biochemical and histological analysis. Compound a (25 and 50 mg/kg; p.o.) protected against the increase in aspartate aminotransferase (AST) activity induced by D-GalN/LPS. Compound a at 50 mg/kg protected against the increase in alanine aminotransferase (ALT) activity induced by D-GalN/LPS. The inhibition of delta-aminolevulinic dehydratase (delta-ALA-D) activity and the decrease of ascorbic acid levels caused by D-GalN/LPS were protected by compound a (25 and 50 mg/kg). Glutathione S-transferase (GST) and catalase activities were not altered in all groups. The histological data showed that sections of liver from D-GalN/LPS-treated rats presented massive hemorrhage, the presence of inflammatory cells and necrosis. Compound a attenuated D-GalN/LPS-induced hepatic histopathological alterations. Based on the results, we demonstrated the hepatoprotective effect of compound a on acute liver injury induced by D-GalN/LPS.

Topics: Alanine Transaminase; Animals; Antioxidants; Ascorbic Acid; Aspartate Aminotransferases; Catalase; Chemical and Drug Induced Liver Injury; Galactosamine; Glutathione Transferase; Humans; Lipopolysaccharides; Liver; Liver Failure, Acute; Male; Molecular Structure; Organoselenium Compounds; Porphobilinogen Synthase; Rats; Rats, Wistar

Ceramide is a biologically active lipid causing apoptosis in a variety of cells. In this study, we examined the effect of CCl4 on the ceramide metabolism and indicators of oxidative stress. After 12 h of oral administration of CCl4 (4 ml/kg body weight as a 1:1 mixture of CCl4 and mineral oil) to rats, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were increased. Antioxidants such as vitamins C and E were decreased in the liver and kidney. In addition, the ratio of GSH/GSSG in the liver, plasma, kidney, and brain decreased at 2h. The total ceramide in the liver significantly increased as early as 2h after CCl4 administration. After 24 and 36 h, the total ceramide in plasma and the kidney was also augmented. In the brain, the total ceramide dramatically increased at 36 h. These results suggested that the increased ceramide in plasma was transferred to the kidney and the brain. The activity of neutral sphingomyelinase (SMase), which was reported to be enhanced by the decrease of GSH, was significantly increased after CCl4 treatment in the liver, kidney, and brain. However, acid SMase activities were not increased in the liver and kidney. Thus, the activation of neutral SMase via oxidative stress induced the increase of ceramide during CCl4 intoxication in not only the liver but also other tissues. These results suggested that the excess accumulation of ceramide causes damage in other organs including the kidney and brain during fulminant hepatic failure.

Topics: Alanine Transaminase; Animals; Ascorbic Acid; Aspartate Aminotransferases; Blood Urea Nitrogen; Brain; Carbon Tetrachloride; Ceramides; Disease Models, Animal; Glutathione; Glutathione Disulfide; Kidney; Liver; Liver Failure, Acute; Male; Oxidative Stress; Rats; Rats, Wistar; Sphingomyelin Phosphodiesterase; Time Factors; Up-Regulation; Vitamin E

Organoselenium compounds display important antioxidant activity and many biological activities interesting from pharmacological point of view. The aim of this study was to evaluate the hepatoprotective effect of p-methoxyl-diphenyl diselenide, a disubstituted diaryl diselenide, on acute liver injury induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS) in mice. The animals received p-methoxyl-diphenyl diselenide (10, 50 and 100 mg/kg; per oral, p.o.) and 1 h after d-GalN (500 mg/kg) and LPS (50 microg/kg) were administered by intraperitoneal route (i.p.). Twenty-four hours after LPS/d-GalN exposure the animals were euthanized to the biochemical and histological analysis. Pretreatment with p-methoxyl-diphenyl diselenide (50 and 100 mg/kg; p.o.) protected against the increase in aspartate aminotransferase (AST) activity induced by LPS/d-GalN exposure in mice. p-Methoxyl-diphenyl diselenide at the doses of 50 and 100 mg/kg protected against the increase in alanine aminotransferase (ALT) activity induced by LPS/D-GalN exposure. In this study, no alteration in ascorbic acid levels was observed in livers of mice exposed to LPS/D-GalN. Glutathione-S-transferase (GST) activity was stimulated by LPS/D-GalN exposure and p-methoxyl-diphenyl diselenide, at all doses, protected against this alteration. p-Methoxyl-diphenyl diselenide was effective in ameliorating inhibition of catalase activity induced by LPS/d-GalN exposure. Histological data showed that sections of livers from LPS/D-GalN-treated mice presented massive hemorrhage, inflammatory cells and necrosis. p-Methoxyl-diphenyl diselenide significantly attenuated LPS/D-GalN-induced hepatic histopathological alterations. Based on the results, we suggest the hepatoprotective effect of p-methoxyl-diphenyl diselenide on acute liver injury induced by LPS/d-GalN exposure in mice.

Topics: Administration, Oral; Alanine Transaminase; Animals; Antioxidants; Ascorbic Acid; Aspartate Aminotransferases; Benzene Derivatives; Catalase; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Galactosamine; Glutathione Transferase; Injections, Intraperitoneal; Lipopolysaccharides; Liver Failure, Acute; Male; Mice; Organoselenium Compounds

The protective effects of 18beta-glycyrrhetinic acid (GA), the aglycone of glycyrrhizin (GL) derived from licorice, on carbon tetrachloride-induced hepatotoxicity and the possible mechanisms involved in this protection were investigated in mice. Pretreatment with GA prior to the administration of carbon tetrachloride significantly prevented an increase in serum alanine, aspartate aminotransferase activity and hepatic lipid peroxidation in a dose-dependent manner. In addition, pretreatment with GA also significantly prevented the depletion of glutathione (GSH) content in the livers of carbon tetrachloride-intoxicated mice. However, reduced hepatic GSH levels and glutathione-S-transferase activities were unaffected by treatment with GA alone. Carbon tetrachloride-induced hepatotoxicity was also prevented, as indicated by a liver histopathologic study. The effects of GA on the cytochrome P450 (P450) 2E1, the major isozyme involved in carbon tetrachloride bioactivation, were also investigated. Treatment of mice with GA resulted in a significant decrease of the P450 2E1-dependent hydroxylation of p-nitrophenol and aniline in a dose-dependent manner. Consistent with these observations, the P450 2E1 expressions were also decreased, as determined by immunoblot analysis. GA also showed antioxidant effects upon FeCl(2)-ascorbate-induced lipid peroxidation in mice liver homogenate and upon superoxide radical scavenging activity. These results show that protective effects of GA against the carbon tetrachloride-induced hepatotoxicity may be due to its ability to block the bioactivation of carbon tetrachloride, primarily by inhibiting the expression and activity of P450 2E1, and its free radical scavenging effects.

Topics: Administration, Topical; Alanine; Animals; Anti-Inflammatory Agents; Ascorbic Acid; Aspartate Aminotransferases; Carbon Tetrachloride; Chlorides; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP2E1 Inhibitors; Ferric Compounds; Free Radical Scavengers; Glutathione; Glycyrrhetinic Acid; Glycyrrhiza; Glycyrrhizic Acid; Lipid Peroxidation; Liver Failure, Acute; Male; Mice; Mice, Inbred ICR; Phytotherapy; Plant Extracts; Superoxides