title: 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.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Research and Development Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. shimizu.shinji.d3@daiichisankyo.co.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Shimizu
authors.forename: Ryo
authors.initials: R
authors.lastname: Atsumi
authors.forename: Tsunenori
authors.initials: T
authors.lastname: Nakazawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sudo
authors.forename: Osamu
authors.initials: O
authors.lastname: Okazaki
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
mesh_terms: D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000172:deficiency*; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D011485:Protein Binding; D051381:Rats; D013988:Ticlopidine / Q000493:pharmacokinetics / Q000633:toxicity*; D014230:Triazoles / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D010975:Platelet Aggregation Inhibitors; D014230:Triazoles; C033020:1-aminobenzotriazole; D019328:Buthionine Sulfoximine; D005978:Glutathione; D013988:Ticlopidine