title: Metabolism-dependent hepatotoxicity of amodiaquine in glutathione-depleted mice.
abstract: We investigated the hepatotoxicity induced by AQ using a glutathione (GSH)-depleted mice model. Although sole administration of either AQ or L-buthionine-S,R-sulfoxinine (BSO), a well-known GSH synthesis inhibitor, produced no significant hepatotoxicity, combined administration of AQ with BSO induced hepatotoxicity characterized by centrilobular necrosis of the hepatocytes and an elevation of plasma alanine aminotransferase activity. Pretreatment of aminobenzotriazole, a nonspecific inhibitor for P450s, completely suppressed the above hepatotoxicity caused by AQ co-treatment with BSO. Administration of radiolabeled AQ in combination with BSO exhibited significantly higher covalent binding to mice liver proteins than that observed after sole dosing of radiolabeled AQ. The results obtained in this GSH-depleted animal model suggest that the reactive metabolite of AQ formed by hepatic P450 binds to liver proteins, and then finally leads to hepatotoxicity. These observations may help to understand the risk factors and the mechanism for idiosyncratic hepatotoxicity of AQ in humans.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Research and Development Division, Daiichi Sankyo Co, Ltd, 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: Kenichi
authors.initials: K
authors.lastname: Itokawa
authors.forename: Masaru
authors.initials: M
authors.lastname: Iwasaki
authors.forename: Takanori
authors.initials: T
authors.lastname: Aoki
authors.forename: Chiho
authors.initials: C
authors.lastname: Ono
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
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000655:Amodiaquine / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D004195:Disease Models, Animal; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000172:deficiency*; D007928:Lethal Dose 50; D008107:Liver Diseases / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D000655:Amodiaquine; D019328:Buthionine Sulfoximine; D000410:Alanine Transaminase; D005978:Glutathione