Amiodarone, Unlike Dronedarone, Activates Inflammasomes via Its Reactive Metabolites: Implications for Amiodarone Adverse Reactions

Abstract

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.

Clozapine Induces an Acute Proinflammatory Response That Is Attenuated by Inhibition of Inflammasome Signaling: Implications for Idiosyncratic Drug-Induced Agranulocytosis

“…To investigate whether clozapine can activate inflammasomes in vitro , similar to other drugs associated with IDRs ( Imano et al , 2021 ; Kato and Uetrecht 2017 ; Kato et al , 2019 , 2020 , 2021 ; Weston and Uetrecht, 2014 ), THP-1 monocytes, and PMA-differentiated macrophages were treated with clozapine and the structural analogues olanzapine and fluperlapine. First, to confirm that a clozapine reactive metabolite was generated, covalent binding to THP-1 cells was assessed by Western blotting.…”

“…Investigations conducted by our group and collaborators have demonstrated that inflammasome activation occurs in vitro with numerous IDR-associated drugs and/or their metabolites but does not occur with structurally similar drugs that are not associated with IDRs ( Imano et al , 2021 ; Kato and Uetrecht 2017 ; Kato et al , 2019 , 2020 , 2021 ; Weston and Uetrecht, 2014 ). Olanzapine and fluperlapine have structures similar to clozapine, where the former forms an analogous reactive nitrenium ion but is not associated with IDIAG ( Gardner et al , 1998b ), and the latter forms a reactive quinone imine but is not approved for clinical use due to concerns of potential IDR cases during development ( Lai et al , 2000 ).…”

“…Recombinant human caspase-1 (0.125–2 U; Sigma-Aldrich, Oakville, ON) was used as a positive control, and treated sample activity was normalized to control. Caspase-1 activity in differentiated THP-1 cells was measured using a Caspase-Glo 1 Inflammasome Assay (Promega Corporation, Madison, Wisconsin), as described previously ( Kato et al , 2021 ).…”

Amiodaron-Induced Thyrotoxicosis

“…Для АиТ характерно ухудшение течения сердечно-сосудистой патологии -усугубление нарушений ритма сердца, ишемии миокарда, учащение приступов стенокардии, появление или нарастание признаков сердечной недостаточности [14,16].…”

“…Вопрос о целесообразности продолжения лечения амиодароном при развитии АиТ до сих пор остается дискутабельным. Нередко контроль аритмии без амиодарона затруднен, несмотря на появление новых антиаритмических препаратов со сходным эффектом, но не содержащих молекул йода (дронедарон/dronedarone) [14].…”