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Ticlopidine-induced hepatotoxicity in a GSH-depleted rat model.

Abstract
We investigated hepatotoxicity induced by ticlopidine (TIC) in glutathione (GSH)-depleted rats by pre-treatment of a well-known GSH synthesis inhibitor, L-buthionine-S,R-sulfoxinine (BSO). Although sole administration of either TIC or BSO showed no signs of hepatotoxicity, combined administration of TIC with BSO induced hepatotoxicity, which was characterized by centrilobular necrosis of the hepatocytes and an elevation of plasma alanine aminotransferase activity. Administration of radio-labeled TIC in combination with BSO resulted in significantly higher covalent binding to rat liver proteins than that observed after sole dosing of radio-labeled TIC. Pre-treatment of 1-aminobenzotriazole, a non-specific inhibitor of P450s, completely suppressed both hepatotoxicity and the increased hepatic covalent binding caused by TIC co-treatment with BSO. The results obtained in this animal model suggest that GSH depletion and covalent binding may be involved in hepatotoxicity induced by TIC. These observations may help to understand the risk factors and the mechanism of hepatotoxicity of TIC in humans.
AuthorsShinji Shimizu, Ryo Atsumi, Tsunenori Nakazawa, Takashi Izumi, Kenichi Sudo, Osamu Okazaki, Hideo Saji
JournalArchives of toxicology (Arch Toxicol) Vol. 85 Issue 4 Pg. 347-53 (Apr 2011) ISSN: 1432-0738 [Electronic] Germany
PMID20871981 (Publication Type: Journal Article)
Chemical References
  • Enzyme Inhibitors
  • Platelet Aggregation Inhibitors
  • Triazoles
  • 1-aminobenzotriazole
  • Buthionine Sulfoximine
  • Glutathione
  • Ticlopidine
Topics
  • Animals
  • Buthionine Sulfoximine (pharmacology)
  • Chemical and Drug Induced Liver Injury (etiology, metabolism)
  • Disease Models, Animal
  • Drug Synergism
  • Drug Therapy, Combination
  • Enzyme Inhibitors (pharmacology)
  • Glutathione (antagonists & inhibitors, deficiency)
  • Platelet Aggregation Inhibitors (pharmacokinetics, toxicity)
  • Protein Binding
  • Rats
  • Ticlopidine (pharmacokinetics, toxicity)
  • Triazoles (pharmacology)

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