Selective blockade of mGlu5 metabotropic glutamate receptors is protective against acetaminophen hepatotoxicity in mice

Storto, Marianna and Ngomba, Richard T. and Battaglia, Giuseppe and Freitas, Isabel and Griffini, Patrizia and Richelmi, Plinio and Nicoletti, Ferdinando and Vairetti, Mariapia (2003) Selective blockade of mGlu5 metabotropic glutamate receptors is protective against acetaminophen hepatotoxicity in mice. Journal of Hepatology, 38 (2). pp. 179-187. ISSN 0168-8278

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Background/Aims: 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.

Methods: 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.

Results: 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.

Conclusions: We conclude that pharmacological blockade of mGlu5 receptors might represent a novel target for the treatment of drug-induced liver damage.

Keywords:2 methyl 6 (2 phenylvinyl)pyridine, 2 methyl 6 (phenylethynyl)pyridine, 6 methyl 2 phenylazo 3 pyridinol, metabotropic receptor, metabotropic receptor antagonist, paracetamol, reactive oxygen metabolite, tert butyl hydroperoxide, animal cell, animal experiment, animal model, animal tissue, article, cell death, controlled study, drug effect, enzyme activity, liver cell, liver injury, liver necrosis, liver toxicity, male, nonhuman, oxidative stress, priority journal, rat, receptor blocking, Acetaminophen, Analgesics, Non-Narcotic, Animals, Excitatory Amino Acid Antagonists, Hepatitis, Toxic, Hepatocytes, Mice, Phenazopyridine, Pyridines, Rats, Rats, Wistar, Receptors, Metabotropic Glutamate, tert-Butylhydroperoxide
Subjects:B Subjects allied to Medicine > B210 Pharmacology
B Subjects allied to Medicine > B140 Neuroscience
Divisions:College of Science > School of Pharmacy
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ID Code:22168
Deposited On:24 Feb 2016 14:41

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