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

J Hepatol. 2003 Feb;38(2):179-87. doi: 10.1016/s0168-8278(02)00384-7.


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.

MeSH terms

  • Acetaminophen / toxicity*
  • Analgesics, Non-Narcotic / toxicity*
  • Animals
  • Chemical and Drug Induced Liver Injury / drug therapy*
  • Chemical and Drug Induced Liver Injury / metabolism
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Male
  • Mice
  • Oxidative Stress / drug effects
  • Phenazopyridine / pharmacology
  • Pyridines / pharmacology*
  • Rats
  • Rats, Wistar
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • tert-Butylhydroperoxide


  • Analgesics, Non-Narcotic
  • Excitatory Amino Acid Antagonists
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • SIB 1757
  • SIB 1893
  • Acetaminophen
  • 6-methyl-2-(phenylethynyl)pyridine
  • tert-Butylhydroperoxide
  • Phenazopyridine