Amiodarone exposure during modest inflammation induces idiosyncrasy-like liver injury in rats: role of tumor necrosis factor-alpha.
Amiodarone exposure during modest inflammation induces idiosyncrasy-like liver injury in rats: role of tumor necrosis factor-alpha.
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DOI：
10.1093/toxsci/kfr266
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发表时间：
2012-01
期刊：
影响因子：
--
通讯作者：
Ganey PE
中科院分区：
文献类型：
--
作者：
Lu J;Jones AD;Harkema JR;Roth RA;Ganey PE
胺碘酮(amodarone[2-butyl-3-(3′，5′-diiodo-4’α-diethylaminoethoxybenzoyl)-benzofuran]，AMD)是一种III类抗心律失常药物，已知在人类患者中会引起特殊的肝毒性反应。关于特殊药物不良反应的病因学的一个假设是，同时存在的炎症应激导致药物毒性阈值降低。为了在动物模型中探索这一假说，雄性SpragueDawley大鼠被用非肝毒性剂量的AMD或其载体以及生理盐水或脂多糖(LPS)诱导低水平炎症。血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(ALT)、碱性磷酸酶(ALP)和γ-谷氨酰转移酶(GGT)活性升高，血清总胆汁酸浓度升高，肝细胞中段坏死。AMD和内毒素之间的时间间隔是关键的：AMD在内毒素引起肝损伤前16h注射，而AMD在内毒素引起肝损伤前2-12h注射则不能引起这种反应。AMD/LPS联合治疗后ALT活性升高与AMD和LPS均呈明显的剂量-反应关系。脂多糖联合暴露不影响AMD的代谢和肝脏蓄积。血清肿瘤坏死因子-α(TNF-α)浓度明显升高，而AMD则略有延长。在Hepac1c7细胞中，加入肿瘤坏死因子可增强AMD及其主要代谢物单-N-脱乙基胺碘酮的细胞毒性。依那西普体内抑制肿瘤坏死因子信号转导可减轻AMD/LPS诱导的大鼠肝损伤。综上所述，AMD在轻度炎症期间的治疗导致了大鼠严重的肝毒性，而在这种特殊的AMD诱导的肝损伤的动物模型中，肿瘤坏死因子参与了肝损伤的诱导。
Amiodarone [2-butyl-3-(3′,5′-diiodo-4’α-diethylaminoethoxybenzoyl)-benzofuran] (AMD), a class III antiarrhythmic drug, is known to cause idiosyncratic hepatotoxic reactions in human patients. One hypothesis for the etiology of idiosyncratic adverse drug reactions is that a concurrent inflammatory stress results in decreased threshold for drug toxicity. To explore this hypothesis in an animal model, male Sprague-Dawley rats were treated with nonhepatotoxic doses of AMD or its vehicle and with saline vehicle or lipopolysaccharide (LPS) to induce low-level inflammation. Elevated alanine aminotransferase (ALT), aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase activities as well as increased total bile acid concentrations in serum and midzonal hepatocellular necrosis were observed only in AMD/LPS-cotreated rats. The time interval between AMD and LPS administration was critical: AMD injected 16 h before LPS led to liver injury, whereas AMD injected 2–12 h before LPS failed to cause this response. The increase in ALT activity in AMD/LPS cotreatment showed a clear dose-response relationship with AMD as well as LPS. The metabolism and hepatic accumulation of AMD were not affected by LPS coexposure. Serum concentration of tumor necrosis factor-alpha (TNF) was significantly increased by LPS and was slightly prolonged by AMD. In Hepac1c7 cells, addition of TNF potentiated the cytotoxicity of both AMD and its primary metabolite, mono-N-desethylamiodarone. In vivo inhibition of TNF signaling by etanercept attenuated the AMD/LPS-induced liver injury in rats. In summary, AMD treatment during modest inflammation induced severe hepatotoxicity in rats, and TNF contributed to the induction of liver injury in this animal model of idiosyncratic AMD-induced liver injury.
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