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Ticlopidine-induced hepatotoxicity in a GSH-depleted rat model

  • Organ Toxicity and Mechanisms
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Abstract

We investigated hepatotoxicity induced by ticlopidine (TIC) in glutathione (GSH)-depleted rats by pre-treatment of a well-known GSH synthesis inhibitor, l-buthionine-S,R-sulfoxinine (BSO). Although sole administration of either TIC or BSO showed no signs of hepatotoxicity, combined administration of TIC with BSO induced hepatotoxicity, which was characterized by centrilobular necrosis of the hepatocytes and an elevation of plasma alanine aminotransferase activity. Administration of radio-labeled TIC in combination with BSO resulted in significantly higher covalent binding to rat liver proteins than that observed after sole dosing of radio-labeled TIC. Pre-treatment of 1-Aminobenzotriazole, a non-specific inhibitor of P450s, completely suppressed both hepatotoxicity and the increased hepatic covalent binding caused by TIC co-treatment with BSO. The results obtained in this animal model suggest that GSH depletion and covalent binding may be involved in hepatotoxicity induced by TIC. These observations may help to understand the risk factors and the mechanism of hepatotoxicity of TIC in humans.

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Acknowledgments

We would like to thank Minoru Inoue and Yutaka Iigo for their excellent assistance with the histopathological evaluations. We are also very grateful to Takatoshi Nishiya for his helpful comments.

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Authors and Affiliations

  1. Drug Metabolism and Pharmacokinetics Research Laboratories, Research and Development Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan

    Shinji Shimizu, Ryo Atsumi, Tsunenori Nakazawa, Takashi Izumi, Kenichi Sudo & Osamu Okazaki

  2. Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Hideo Saji

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  1. Shinji Shimizu
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  2. Ryo Atsumi
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  3. Tsunenori Nakazawa
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  4. Takashi Izumi
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  6. Osamu Okazaki
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Correspondence to Shinji Shimizu.

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Shimizu, S., Atsumi, R., Nakazawa, T. et al. Ticlopidine-induced hepatotoxicity in a GSH-depleted rat model. Arch Toxicol 85, 347–353 (2011). https://doi.org/10.1007/s00204-010-0594-9

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  • DOI: https://doi.org/10.1007/s00204-010-0594-9

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