Metabolism-dependent hepatotoxicity of amodiaquine in glutathione-depleted mice.
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.
Shimizu
Shinji
S
Drug Metabolism and Pharmacokinetics Research Laboratories, Research and Development Division, Daiichi Sankyo Co, Ltd, Tokyo 140-8710, Japan. shimizu.shinji.d3@daiichisankyo.co.jp
Atsumi
Ryo
R
Itokawa
Kenichi
K
Iwasaki
Masaru
M
Aoki
Takanori
T
Ono
Chiho
C
Izumi
Takashi
T
Sudo
Kenichi
K
Okazaki
Osamu
O
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
D000962:Antimalarials; D004791:Enzyme Inhibitors; D000655:Amodiaquine; D019328:Buthionine Sulfoximine; D000410:Alanine Transaminase; D005978:Glutathione