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Trovafloxacin is a quinolone antibiotic drug with broad-spectrum activity, which was withdrawn from a global market relatively soon after approval because of serious liver injury. The characteristics of trovafloxacin-induced liver injury are consistent with an idiosyncratic reaction; however, the details of the mechanism have not been elucidated. We examined whether trovafloxacin induces the release of damage-associated molecular patterns (DAMPs) that activate inflammasomes. We also tested ciprofloxacin, levofloxacin, gatifloxacin, and grepafloxacin for their ability to activate inflammasomes. Drug bioactivation was performed with human hepatocarcinoma functional liver cell-4 (FLC-4) cells, and THP-1 cells (human monocyte cell line) were used for the detection of inflammasome activation. The supernatant from the incubation of trovafloxacin 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 that had been incubated with trovafloxacin, 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 inflammasome activation in THP-1 cells by the FLC-4 supernatant. These results suggest that reactive metabolites of trovafloxacin can cause the release of DAMPs from hepatocytes that can activate inflammasomes. Inflammasome activation may be an important step in the activation of the immune system by trovafloxacin, which, in some patients, can cause immune-related liver injury., (© 2024 John Wiley & Sons Ltd.)

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.

Vascular endothelial growth factor (VEGF) promotes tumor angiogenesis through stimulating the proliferation and survival of endothelial cells. The severe adverse events caused by VEGF inhibitors might include immune-related ones; however, details of the mechanism have not been elucidated. We tested whether axitinib, pazopanib, sorafenib, and sunitinib, which are tyrosine kinase inhibitors (TKIs) of VEGF receptor used for the therapy of renal cell carcinoma can activate inflammasomes in differentiated THP-1 cells, a human macrophage cell line. We also performed similar studies with semaxanib. In this study, semaxanib and sorafenib activated the inflammasome of differentiated THP-1 cells. Although pazopanib increased the production of IL-1β, inflammasomes were not activated because caspase-1 was not activated in differentiated THP-1 cells. Our results support the hypothesis that activation of inflammasomes contributes to the idiosyncratic reactions associated with semaxanib and sorafenib. Although pazopanib did not activate inflammasomes, it did cause increased IL-1β production, which may facilitate the induction of idiosyncratic reactions., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have been approved for non-small cell lung cancer. Although EGFR TKIs are less toxic than traditional cytotoxic therapies, they cause many severe idiosyncratic drug reactions. Reactive metabolites can cause cellular damage with the release of danger-associated molecular patterns (DAMPs), which is thought to be involved in immune activation. Inflammasomes can be activated by DAMPs, and this may be a common mechanism by which DAMPs initiate an immune response. We tested the ability of afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib to induce the release of DAMPs that activate inflammasomes. Human hepatocarcinoma functional liver cell-4 (FLC-4) cells were used for bioactivation of drugs, and the detection of inflammasome activation was performed with the human macrophage cell line, THP-1 cells. Gefitinib is known to be oxidized to a reactive iminoquinone metabolite. We found that the supernatant from the incubation of gefitinib with FLC-4 cells for 7 days led to increased caspase-1 activity and production of IL-1ß by THP-1 cells. In the supernatant of FLC-4 cells with gefitinib, the heat shock protein (HSP) 40, 70 and 90 were significantly increased. In addition, activated THP-1 cells secreted high mobility group box 1 (HMGB1) protein. These results support the hypothesis that the reactive iminoquinone metabolite can cause the release of DAMPs from hepatocytes, which in turn, can activate inflammasomes. Inflammasome activation may be an important step in the activation of the immune system by gefitinib, which in some patients, can cause immune-related adverse events.

Although the pathophysiology of carbamazepine-induced idiosyncratic or hypersensitivity reactions is unclear, they are presumed to be immune mediated, involving a complex interaction between drug metabolism and activation of the immune system. Cell stress can be caused by reactive metabolites, and this has the potential to release damage-associated molecular patterns (DAMPs), which are responsible for activation of the immune system. Idiosyncratic drug reactions occur mainly in the liver because of its role in drug metabolism and reactive metabolite formation. DAMPs can activate inflammasomes, which may be a common mechanism by which DAMPs lead to an immune response. In the present study, we investigated whether carbamazepine induces the release of DAMPs by using human hepatocarcinoma functional liver cell-4 (FLC-4) cells for bioactivation of carbamazepine. THP-1 cells, a human macrophage cell line, were used for detecting inflammasome activation. We found that increased caspase-1 activity and production of interleukin-1 β by THP-1 cells were caused by the supernatant from the incubation of carbamazepine with FLC-4 cells. In the supernatant, heat shock protein 60 was significantly increased. In addition, 2-hydroxyiminostilbene, which is a metabolite of carbamazepine, activated inflammasomes. These results suggest that the reactive iminoquinone metabolite can directly activate inflammasomes or that stressed hepatocytes cause the release of DAMPs, which are responsible for inflammasome activation. The activation of inflammasomes may be an important step in the immune system activation by carbamazepine, which can lead to hypersensitivity reactions in some patients. SIGNIFICANCE STATEMENT: A metabolite of carbamazepine, 2-hydroxyiminostilbene itself, and the damage-associated molecular patterns released from hepatocytes incubated with carbamazepine activated inflammasomes. The activation of inflammasomes may be an important step in the immune system activation by carbamazepine, which can lead to hypersensitivity reactions in some patients., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Flutamide is a non-steroidal anti-androgen agent, which is mainly used for the treatment of prostate cancer. Flutamide is known to cause severe adverse events, which includes idiosyncratic liver injury. However, details of the mechanism of these adverse reactions have not been elucidated. We investigated whether flutamide induces the release of damage-associated molecular patterns (DAMPs) that activate inflammasomes. We also tested bicalutamide, enzalutamide, apalutamide, and darolutamide for their ability to activate inflammasomes in differentiated THP-1 cells. The supernatant from the incubation of flutamide and bicalutamide with human hepatocarcinoma functional liver cell-4 (FLC-4) cells increased caspase-1 activity and production of IL-1ß by differentiated THP-1 cells. In the supernatant of FLC-4 cells with flutamide and bicalutamide, the heat shock protein (HSP) 40 or 60 was significantly increased. Addition of a carboxylesterase or a CYP inhibitor to the FLC-4 cells prevented release of HSPs from the FLC-4 cells. These results suggested that the reactive metabolites of flutamide and bicalutamide can cause the release of DAMPs from hepatocytes and activate inflammasomes. Inflammasome activation may be an important step in the activation of the immune system by flutamide or bicalutamide, which in some patients, can cause immune-related adverse events. • Reactive metabolites of flutamide and bicalutamide can cause the release of DAMPs from hepatocytes. • The production of DAMPs activates inflammasomes thereby resulting in an immune response. • The activation of inflammasome reaction may be an important step in the immune system activation. • Bicalutamide is racemic, and both enantiomers activate inflammasomes to the same extent. [ABSTRACT FROM AUTHOR]