Ticlopidine-induced hepatotoxicity in a GSH-depleted rat model |
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Authors: | Shinji Shimizu Ryo Atsumi Tsunenori Nakazawa Takashi Izumi Kenichi Sudo Osamu Okazaki Hideo Saji |
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Institution: | (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;(2) Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan |
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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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