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Research ArticleArticle

Carbamazepine-Induced Liver Injury Requires CYP3A-Mediated Metabolism and Glutathione Depletion in Rats

Azumi Iida, Eita Sasaki, Azusa Yano, Koichi Tsuneyama, Tatsuki Fukami, Miki Nakajima and Tsuyoshi Yokoi
Drug Metabolism and Disposition July 2015, 43 (7) 958-968; DOI: https://doi.org/10.1124/dmd.115.063370
Azumi Iida
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (A.I., E.S., A.Y., T.F., M.N., T.Y.); Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan (K.T.); and Department of Drug Safety Science, Nagoya University Graduate School of Medicine, Nagoya, Japan (T.Y.)
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Eita Sasaki
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (A.I., E.S., A.Y., T.F., M.N., T.Y.); Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan (K.T.); and Department of Drug Safety Science, Nagoya University Graduate School of Medicine, Nagoya, Japan (T.Y.)
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Azusa Yano
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (A.I., E.S., A.Y., T.F., M.N., T.Y.); Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan (K.T.); and Department of Drug Safety Science, Nagoya University Graduate School of Medicine, Nagoya, Japan (T.Y.)
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Koichi Tsuneyama
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (A.I., E.S., A.Y., T.F., M.N., T.Y.); Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan (K.T.); and Department of Drug Safety Science, Nagoya University Graduate School of Medicine, Nagoya, Japan (T.Y.)
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Tatsuki Fukami
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (A.I., E.S., A.Y., T.F., M.N., T.Y.); Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan (K.T.); and Department of Drug Safety Science, Nagoya University Graduate School of Medicine, Nagoya, Japan (T.Y.)
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Miki Nakajima
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (A.I., E.S., A.Y., T.F., M.N., T.Y.); Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan (K.T.); and Department of Drug Safety Science, Nagoya University Graduate School of Medicine, Nagoya, Japan (T.Y.)
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Tsuyoshi Yokoi
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (A.I., E.S., A.Y., T.F., M.N., T.Y.); Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan (K.T.); and Department of Drug Safety Science, Nagoya University Graduate School of Medicine, Nagoya, Japan (T.Y.)
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Abstract

Carbamazepine (CBZ) is widely used as an antiepileptic agent and causes rare but severe liver injury in humans. It has been generally recognized that reactive metabolites formed via the metabolic activation reaction contribute to the onset of liver injuries by several drugs. However, the role of CBZ metabolism in the development of liver injury is not fully understood. In this study, we developed a novel rat model of CBZ-induced liver injury and attempted to elucidate the associated mechanisms by focusing on the metabolism of CBZ. The repeated administration of CBZ for 5 days in combination with l-buthionine sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, resulted in increases in the plasma alanine aminotransferase (ALT) levels and centrilobular necrosis in the liver that were observed in various degrees. The CBZ and 2-hydroxy-CBZ concentrations in the plasma after the last CBZ administration were lower in the rats with high plasma ALT levels compared with those with normal plasma ALT levels, showing the possibility that the further metabolism of CBZ and/or 2-hydroxy-CBZ is associated with the liver injury. Although a single administration of CBZ did not affect the plasma ALT levels, even when cotreated with BSO, pretreatment with dexamethasone, a CYP3A inducer, increased the plasma ALT levels. In addition, the rats cotreated with troleandomycin or ketoconazole, CYP3A inhibitors, suppressed the increased plasma ALT levels. In conclusion, reactive metabolite(s) of CBZ produced by CYP3A under the GSH-depleted condition might be involved in the development of liver injury in rats.

Footnotes

    • Received January 16, 2015.
    • Accepted April 13, 2015.
  • This work was supported by Health and Labor Sciences Research Grants from the Ministry of Health, Labor and Welfare of Japan [H23-BIO-G001].

  • dx.doi.org/10.1124/dmd.115.063370.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (7)
Drug Metabolism and Disposition
Vol. 43, Issue 7
1 Jul 2015
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Research ArticleArticle

Hepatotoxicity by Carbamazepine Requires Metabolism in Rats

Azumi Iida, Eita Sasaki, Azusa Yano, Koichi Tsuneyama, Tatsuki Fukami, Miki Nakajima and Tsuyoshi Yokoi
Drug Metabolism and Disposition July 1, 2015, 43 (7) 958-968; DOI: https://doi.org/10.1124/dmd.115.063370

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Research ArticleArticle

Hepatotoxicity by Carbamazepine Requires Metabolism in Rats

Azumi Iida, Eita Sasaki, Azusa Yano, Koichi Tsuneyama, Tatsuki Fukami, Miki Nakajima and Tsuyoshi Yokoi
Drug Metabolism and Disposition July 1, 2015, 43 (7) 958-968; DOI: https://doi.org/10.1124/dmd.115.063370
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