Amiodarone, Unlike Dronedarone, Activates Inflammasomes via Its Reactive Metabolites: Implications for Amiodarone Adverse Reactions,Chemical Research in Toxicology

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Amiodarone, Unlike Dronedarone, Activates Inflammasomes via Its Reactive Metabolites: Implications for Amiodarone Adverse Reactions
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2021-06-18 , DOI: 10.1021/acs.chemrestox.1c00127
Ryuji Kato ₁ , Yoshio Ijiri ₁ , Tetsuya Hayashi ₁

Affiliation

Amiodarone is a benzofuran derivative used to treat arrhythmias, but its use is limited by adverse reactions. There is evidence that some of the severe adverse reactions such as liver injury and interstitial lung disease are immune-mediated; however, details of the mechanism have not been elucidated. We tested the ability of amiodarone to induce the release of danger-associated molecular patterns (DAMPs) that activate inflammasomes. Human hepatocarcinoma functional liver cell-4 (FLC-4) cells were used for drug bioactivation, and the detection of inflammasome activation was performed with the human macrophage cell line, THP-1 cells. Amiodarone is known to be oxidized to reactive quinone metabolites. The supernatant from the incubation of amiodarone with FLC-4 cells for 7 days increased caspase-1 activity and production of IL-1ß by THP-1 cells. In the supernatant of FLC-4 cells with amiodarone, the heat shock protein (HSP) 40 was significantly increased. Addition of a cytochrome P450 inhibitor to the FLC-4 cells prevented the release of HSP40 from the FLC-4 cells and activation of THP-1 inflammasomes by the FLC-4 supernatant. These results suggested that the reactive quinone metabolites of amiodarone can cause the release of DAMPs from hepatocytes which can activate inflammasomes. Dronedarone, a safer analog of amiodarone, did not activate inflammasomes. Inflammasome activation may be an important step in the activation of the immune system by amiodarone, which in some patients, can cause immune-related adverse events. In addition, our data suggest that drugs that block the effects or the formation of IL-1β would provide better treatment of amiodarone-induced immune-related adverse reactions.

中文翻译：

胺碘酮与决奈达隆不同，通过其反应性代谢物激活炎症小体：对胺碘酮不良反应的影响

胺碘酮是一种苯并呋喃衍生物，用于治疗心律失常，但其使用受到不良反应的限制。有证据表明一些严重的不良反应如肝损伤和间质性肺病是免疫介导的；然而，该机制的细节尚未阐明。我们测试了胺碘酮诱导释放激活炎症小体的危险相关分子模式 (DAMP) 的能力。使用人肝癌功能性肝细胞4（FLC-4）细胞进行药物生物活化，并用人巨噬细胞系THP-1细胞进行炎症小体活化的检测。已知胺碘酮被氧化成反应性醌代谢物。胺碘酮与 FLC-4 细胞孵育 7 天的上清液增加了 caspase-1 的活性和 THP-1 细胞产生的 IL-1ß。在含有胺碘酮的 FLC-4 细胞上清液中，热休克蛋白 (HSP) 40 显着增加。向 FLC-4 细胞添加细胞色素 P450 抑制剂阻止了 FLC-4 细胞释放 HSP40 和 FLC-4 上清液对 THP-1 炎性体的激活。这些结果表明胺碘酮的反应性醌代谢物可引起肝细胞释放 DAMP，从而激活炎症小体。决奈达隆是一种更安全的胺碘酮类似物，不会激活炎症小体。炎症小体激活可能是胺碘酮激活免疫系统的重要步骤，在某些患者中，这会导致免疫相关的不良事件。此外，

更新日期：2021-08-16

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