Metabolism-dependent hepatotoxicity of amodiaquine in glutathione-depleted mice

被引：57

作者：

Shimizu, Shinji ^{[1
]}

Atsumi, Ryo ^{[1
]}

Itokawa, Kenichi ^{[1
]}

Iwasaki, Masaru ^{[1
]}

Aoki, Takanori ^{[1
]}

Ono, Chiho ^{[1
]}

Izumi, Takashi ^{[1
]}

Sudo, Kenichi ^{[1
]}

Okazaki, Osamu ^{[1
]}

机构：

[1] Daiichi Sankyo Co Ltd, Drug Metab & Pharmacokinet Res Labs, Div Res & Dev, Shinagawa Ku, Tokyo 1408710, Japan

来源：

ARCHIVES OF TOXICOLOGY | 2009年 / 83卷 / 07期

关键词：

Amodiaquine; Glutathione; L-Buthionine-S; R-sulfoxinine; Covalent binding; Idiosyncratic; Hepatotoxicity; ADVERSE DRUG-REACTIONS; BUTHIONINE SULFOXIMINE; BIOACTIVATION; HOMOCYSTEINE; TISSUE; RATS;

D O I：

10.1007/s00204-009-0436-9

中图分类号：

R99 [毒物学（毒理学）];

学科分类号：

100405 ;

摘要：

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.

引用

页码：701 / 707

页数：7

共 29 条

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