6-methyl-2-(phenylethynyl)pyridine and Chemical-and-Drug-Induced-Liver-Injury

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

mGlu5 metabotropic glutamate receptor antagonists protect rat hepatocytes against hypoxic death. Here, we have examined whether mGlu5 receptor antagonists are protective against liver damage induced by oxidative stress.. Toxicity of isolated hepatocytes was induced by tert-butylhydroperoxide (t-BuOOH) after pretreatment with the mGlu5 receptor antagonists, MPEP, SIB-1757 and SIB-1893. The effect of these drugs was also examined in mice challenged with toxic doses of acetaminophen.. Addition of tBuOOH (0.5 mM) to isolated hepatocytes induced cell death (70+/-5% at 3 h). Addition of MPEP or SIB-1893 to hepatocytes reduced both the production of reactive oxygen species (ROS) and cell toxicity induced by t-BuOOH (tBuOOH=70+/-5%; tBuOOH+MPEP=57+/-6%; tBuOOH+SIB-1893=40+/-4%). In mice, a single injection of acetaminophen (300 mg/kg, i.p.) induced centrilobular liver necrosis, which was detectable after 24 h. MPEP (20 mg/kg, i.p.) substantially reduced liver necrosis and the production of ROS, although it did not affect the conversion of acetaminophen into the toxic metabolite, N-acetylbenzoquinoneimine. MPEP, SIB-1893 and SIB-1757 (all at 20 mg/kg, i.p.) also reduced the increased expression and activity of liver iNOS induced by acetaminophen.. We conclude that pharmacological blockade of mGlu5 receptors might represent a novel target for the treatment of drug-induced liver damage.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Chemical and Drug Induced Liver Injury; Excitatory Amino Acid Antagonists; Hepatocytes; Male; Mice; Oxidative Stress; Phenazopyridine; Pyridines; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; tert-Butylhydroperoxide