caa a22 4500 445853654 CHVBK 20180317145421.0 cr unu---uuuuu 170323e20110401xx s 000 0 eng 10.1007/s00204-010-0594-9 doi (NATIONALLICENCE)springer-10.1007/s00204-010-0594-9 Ticlopidine-induced hepatotoxicity in a GSH-depleted rat model [Elektronische Daten] [Shinji Shimizu, Ryo Atsumi, Tsunenori Nakazawa, Takashi Izumi, Kenichi Sudo, Osamu Okazaki, Hideo Saji] 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. Springer-Verlag, 2010 Ticlopidine nationallicence Iidiosyncratic nationallicence Hepatotoxicity nationallicence Glutathione nationallicence Reactive metabolite nationallicence Covalent binding nationallicence Shimizu Shinji Drug Metabolism and Pharmacokinetics Research Laboratories, Research and Development Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, 140-8710, Shinagawa-ku, Tokyo, Japan aut Atsumi Ryo Drug Metabolism and Pharmacokinetics Research Laboratories, Research and Development Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, 140-8710, Shinagawa-ku, Tokyo, Japan aut Nakazawa Tsunenori Drug Metabolism and Pharmacokinetics Research Laboratories, Research and Development Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, 140-8710, Shinagawa-ku, Tokyo, Japan aut Izumi Takashi Drug Metabolism and Pharmacokinetics Research Laboratories, Research and Development Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, 140-8710, Shinagawa-ku, Tokyo, Japan aut Sudo Kenichi Drug Metabolism and Pharmacokinetics Research Laboratories, Research and Development Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, 140-8710, Shinagawa-ku, Tokyo, Japan aut Okazaki Osamu Drug Metabolism and Pharmacokinetics Research Laboratories, Research and Development Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, 140-8710, Shinagawa-ku, Tokyo, Japan aut Saji Hideo Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, 606-8501, Sakyo-ku, Kyoto, Japan aut Archives of Toxicology Springer-Verlag 85/4(2011-04-01), 347-353 0340-5761 85:4<347 2011 85 204 https://doi.org/10.1007/s00204-010-0594-9 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00204-010-0594-9 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Shimizu Shinji Drug Metabolism and Pharmacokinetics Research Laboratories, Research and Development Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, 140-8710, Shinagawa-ku, Tokyo, Japan aut NATIONALLICENCE 700 1- Atsumi Ryo Drug Metabolism and Pharmacokinetics Research Laboratories, Research and Development Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, 140-8710, Shinagawa-ku, Tokyo, Japan aut NATIONALLICENCE 700 1- Nakazawa Tsunenori Drug Metabolism and Pharmacokinetics Research Laboratories, Research and Development Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, 140-8710, Shinagawa-ku, Tokyo, Japan aut NATIONALLICENCE 700 1- Izumi Takashi Drug Metabolism and Pharmacokinetics Research Laboratories, Research and Development Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, 140-8710, Shinagawa-ku, Tokyo, Japan aut NATIONALLICENCE 700 1- Sudo Kenichi Drug Metabolism and Pharmacokinetics Research Laboratories, Research and Development Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, 140-8710, Shinagawa-ku, Tokyo, Japan aut NATIONALLICENCE 700 1- Okazaki Osamu Drug Metabolism and Pharmacokinetics Research Laboratories, Research and Development Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, 140-8710, Shinagawa-ku, Tokyo, Japan aut NATIONALLICENCE 700 1- Saji Hideo Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, 606-8501, Sakyo-ku, Kyoto, Japan aut NATIONALLICENCE 773 0- Archives of Toxicology Springer-Verlag 85/4(2011-04-01), 347-353 0340-5761 85:4<347 2011 85 204 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer