title: Pathogenetic analyses of carbamazepine-induced liver injury in F344 rats focused on immune- and inflammation-related factors.
abstract: Drug-induced liver injury is one of the major reasons for a drug to be withdrawn postmarketing. Carbamazepine (CBZ), an anticonvulsant agent, has been reported rarely to cause liver failure in humans. We recently generated a rat model of CBZ-induced liver injury using F344 rats for five consecutive days of CBZ administration combined with a glutathione (GSH) depletor, L-buthionine S,R-sulfoximine, treatment. The involvement of metabolic activation was demonstrated in developing CBZ-induced liver injury, and a difference in metabolic activation reactions between mice and rats was indicated. In this study, we analyzed the pathogenetic mechanism of CBZ-induced liver injury, primarily focusing on immune- and inflammation-related factors using the rat model for CBZ-induced liver injury. After the last CBZ administration, plasma alanine aminotransfearase (ALT) levels were drastically increased. In the histopathological evaluation, time-dependent hepatocellular degeneration and necrosis were observed in the centrilobular region. Different from mice, although hepatic mRNA expression levels of inflammation-related genes were increased, T-helper cell-related genes were not predominantly changed in rats. The number of ED1- and ED2-positive macrophages was increased in injured centrilobular areas in the liver with CBZ-induced liver injury. Treatment with a Kupffer cell depletor, gadolinium chloride, prevented the elevation of plasma ALT levels and an increase in the hepatic mRNA expression levels of inflammation-related genes. Hepatic adenosine triphosphate (ATP) contents were significantly decreased 24 h after CBZ administration. Therefore, the Kupffer cells-mediated inflammation was predominant in the development of the CBZ-induced liver injury in rats.
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan. Electronic address: esasaki@stu.kanazawa-u.ac.jp.
authors.forename: Eita
authors.initials: E
authors.lastname: Sasaki
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan. Electronic address: pandasan@stu.kanazawa-u.ac.jp.
authors.forename: Azumi
authors.initials: A
authors.lastname: Iida
authors.affiliation: Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: shingo61@med.nagoya-u.ac.jp.
authors.forename: Shingo
authors.initials: S
authors.lastname: Oda
authors.affiliation: Department of Molecular and Environmental Pathology, Institute of Health Biosciences, Tokushima University, Tokushima 770-8503, Japan. Electronic address: tsuneyama.koichi@tokushima-u.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan. Electronic address: tatsuki@p.kanazawa-u.ac.jp.
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Fukami
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan. Electronic address: nmiki@p.kanazawa-u.ac.jp.
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan; Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: tyokoi@med.nagoya-u.ac.jp.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D002220:Carbamazepine / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000473:pathology*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D007728:Kupffer Cells / Q000187:drug effects / Q000473:pathology*; D008297:Male; D016133:Polymerase Chain Reaction; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D000927:Anticonvulsants; D002220:Carbamazepine
keywords: Carbamazepine; Drug-induced liver injury; Inflammation; Kupffer cell; Preclinical testing; Rat