Takai Shohei, Oda Shingo, Tsuneyama Koichi, Fukami Tatsuki, Nakajima Miki, Yokoi Tsuyoshi
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
J Appl Toxicol. 2016 Jan;36(1):35-47. doi: 10.1002/jat.3141. Epub 2015 Apr 20.
Drug-induced liver injury (DILI) is the most frequent cause of post-marketing warnings and withdrawals. Amiodarone (AMD), an antiarrhythmic, presents a risk of liver injury in humans, and its metabolites, formed by cytochrome P450 3A4, are likely more toxic to hepatocytes than AMD is. However, it remains to be clarified whether the metabolic activation of AMD is involved in liver injury in vivo. In this study, to elucidate the underlying mechanisms of AMD-induced liver injury, mice were administered AMD [1000 mg kg(-1), per os (p.o.)] after pretreatment with dexamethasone [DEX, 60 mg kg(-1), intraperitoneal (i.p.)], which induces P450 expression, once daily for 3 days. The plasma alanine aminotransferase (ALT) levels were significantly increased by AMD administration in the DEX-pretreated mice, and the liver concentrations of desethylamiodarone (DEA), a major metabolite of AMD, were correlated with the changes in the plasma ALT levels. Cytochrome c release into the hepatic cytosol and triglyceride levels in the plasma were increased in DEX plus AMD-administered mice. Furthermore, the ratio of reduced glutathione to oxidized glutathione disulfide in the liver significantly decreased in the DEX plus AMD-administered mice. The increase of ALT levels was suppressed by treatment with gadolinium chloride (GdCl3 ), which is an inhibitor of Kupffer cell function. From these results, it is suggested that AMD and/or DEA contribute to the pathogenesis of AMD-induced liver injury by producing mitochondrial and oxidative stress and Kupffer cell activation. This study proposes the mechanisms of AMD-induced liver injury using an in vivo mouse model.
药物性肝损伤（DILI）是上市后药品警告和撤市的最常见原因。抗心律失常药物胺碘酮（AMD）对人类存在肝损伤风险，其由细胞色素P450 3A4形成的代谢产物对肝细胞的毒性可能比AMD本身更大。然而，AMD的代谢活化是否参与体内肝损伤仍有待阐明。在本研究中，为了阐明AMD诱导肝损伤的潜在机制，在用地塞米松[DEX，60 mg kg(-1)，腹腔注射（i.p.）]预处理以诱导P450表达后，给小鼠口服AMD[1000 mg kg(-1)]，每天一次，持续3天。在DEX预处理的小鼠中，AMD给药后血浆丙氨酸氨基转移酶（ALT）水平显著升高，AMD的主要代谢产物去乙基胺碘酮（DEA）的肝脏浓度与血浆ALT水平的变化相关。在给予DEX加AMD的小鼠中，细胞色素c释放到肝细胞溶质中以及血浆甘油三酯水平升高。此外，在给予DEX加AMD的小鼠中，肝脏中还原型谷胱甘肽与氧化型谷胱甘肽二硫化物的比率显著降低。用氯化钆（GdCl3）治疗可抑制ALT水平的升高，氯化钆是一种库普弗细胞功能抑制剂。从这些结果表明，AMD和/或DEA通过产生线粒体和氧化应激以及库普弗细胞活化，促进了AMD诱导的肝损伤的发病机制。本研究使用体内小鼠模型提出了AMD诱导肝损伤的机制。
