Pathogenetic analyses of carbamazepine-induced liver injury in F344 rats focused on immune- and inflammation-related factors

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• 作者：Eita Sasaki<sup>asup><sup> ; sup><sup>esasaki@stu.kanazawa-u.ac.jp" class="auth_mail" title="E-mail the corresponding authorsup> ; Azumi Iida<sup>asup><sup> ; sup><sup>pandasan@stu.kanazawa-u.ac.jp" class="auth_mail" title="E-mail the corresponding authorsup> ; Shingo Oda<sup>csup><sup> ; sup><sup>shingo61@med.nagoya-u.ac.jp" class="auth_mail" title="E-mail the corresponding authorsup> ; Koichi Tsuneyama<sup>bsup><sup> ; sup><sup>tsuneyama.koichi@tokushima-u.ac.jp" class="auth_mail" title="E-mail the corresponding authorsup> ; Tatsuki Fukami<sup>asup><sup> ; sup><sup>tatsuki@p.kanazawa-u.ac.jp" class="auth_mail" title="E-mail the corresponding authorsup> ; Miki Nakajima<sup>asup><sup> ; sup><sup>nmiki@p.kanazawa-u.ac.jp" class="auth_mail" title="E-mail the corresponding authorsup> ; Tsuyoshi Yokoi<sup>asup><sup> ; sup><sup>csup><sup> ; sup><sup>tyokoi@med.nagoya-u.ac.jp" class="auth_mail" title="E-mail the corresponding authorsup>
• 关键词：ALT ; alanine aminotransferase ; APAP ; acetaminophen ; ATP ; adenosine triphosphate ; BSO ; l-buthionine S ; R-sulfoximine ; CBZ ; carbamazepine ; CD ; cluster of differentiation ; CV ; centrilobular vein ; CYP ; cytochrome P450 ; DAMPs ; damage-associated molecular patterns ; ELISA ; enzyme-linked immunosorbent assay ; FoxP3 ; forkhead box P3 ; GATA-3 ; GATA-binding domain-3 ; GSH ; glutathione ; Ho-1 ; heme oxygenase-1 ; Ig ; immunoglobulin ; IL ; interleukin ; MCP-1 ; monocyte chemoattaractant protein-1 ; MIP-2 ; macrophage inf
• 刊名：Experimental and Toxicologic Pathology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：68
• 期：1
• 页码：27-38
• 全文大小：3695 K

文摘

Drug-induced liver injury is one of the major reasons for a drug to be withdrawn postmarketing.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, <span class="smallcaps">lspan>-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.