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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.
AuthorsShinji Shimizu, Ryo Atsumi, Kenichi Itokawa, Masaru Iwasaki, Takanori Aoki, Chiho Ono, Takashi Izumi, Kenichi Sudo, Osamu Okazaki
JournalArchives of toxicology (Arch Toxicol) Vol. 83 Issue 7 Pg. 701-7 (Jul 2009) ISSN: 1432-0738 [Electronic] Germany
PMID19479240 (Publication Type: Journal Article)
Chemical References
  • Antimalarials
  • Enzyme Inhibitors
  • Amodiaquine
  • Buthionine Sulfoximine
  • Alanine Transaminase
  • Glutathione
Topics
  • Alanine Transaminase (blood)
  • Amodiaquine (pharmacology)
  • Animals
  • Antimalarials (pharmacology)
  • Buthionine Sulfoximine (pharmacology)
  • Chemical and Drug Induced Liver Injury (etiology, metabolism)
  • Disease Models, Animal
  • Drug Interactions
  • Enzyme Inhibitors (pharmacology)
  • Glutathione (antagonists & inhibitors, deficiency)
  • Lethal Dose 50
  • Liver Diseases (pathology)
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Biological

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