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.
journal_name
Arch Toxicoljournal_title
Archives of toxicologyauthors
Shimizu S,Atsumi R,Itokawa K,Iwasaki M,Aoki T,Ono C,Izumi T,Sudo K,Okazaki Odoi
10.1007/s00204-009-0436-9subject
Has Abstractpub_date
2009-07-01 00:00:00pages
701-7issue
7eissn
0340-5761issn
1432-0738journal_volume
83pub_type
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