title: Carbamazepine-Induced Liver Injury Requires CYP3A-Mediated Metabolism and Glutathione Depletion in Rats.
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.
authors: 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.).
authors: Azumi
authors: A
authors: Iida
authors: 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.).
authors: Eita
authors: E
authors: Sasaki
authors: 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.).
authors: Azusa
authors: A
authors: Yano
authors: 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.).
authors: Koichi
authors: K
authors: Tsuneyama
authors: 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.).
authors: Tatsuki
authors: T
authors: Fukami
authors: 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.).
authors: Miki
authors: M
authors: Nakajima
authors: 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.) tyokoi@med.nagoya-u.ac.jp.
authors: Tsuyoshi
authors: T
authors: Yokoi
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002220:Carbamazepine / Q000378:metabolism* / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006900:Hydroxylation; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D011916:Rats, Inbred F344; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D002220:Carbamazepine; D019328:Buthionine Sulfoximine; D014217:Troleandomycin; D051544:Cytochrome P-450 CYP3A; D000410:Alanine Transaminase; D005978:Glutathione; D007654:Ketoconazole