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Metabolism-dependent hepatotoxicity of amodiaquine in glutathione-depleted mice

  • Organ Toxicity and Mechanisms
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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.

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Abbreviations

AQ:

Amodiaquine

GSH:

Glutathione

BSO:

l-Buthionine-S,R-sulfoxinine

ALT:

Alanine aminotransferase

ABT:

Aminobenzotriazole

LD50:

50% Lethal dose

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Acknowledgments

We would like to thank Minoru Inoue and Keiko Okato for preparing the samples for the liver histopathological evaluation. We are also very grateful to Hiroshi Sato for his assistance with the histology.

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Correspondence to Shinji Shimizu.

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Shimizu, S., Atsumi, R., Itokawa, K. et al. Metabolism-dependent hepatotoxicity of amodiaquine in glutathione-depleted mice. Arch Toxicol 83, 701–707 (2009). https://doi.org/10.1007/s00204-009-0436-9

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  • DOI: https://doi.org/10.1007/s00204-009-0436-9

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