Mechanism of non-steroidal anti-androgen-induced liver injury: Reactive metabolites of flutamide and bicalutamide activate inflammasomes

• Published in: Toxicology in vitro 2023-08, Vol.90, p.105606-105606, Article 105606
• Main Authors: Kato, Ryuji, Yamada, Tomoyuki, Noda, Takumi, Tanaka, Saori, Kohda, Yuka, Ijiri, Yoshio
• Format: Article
• Language: English
• Subjects: Androgen Antagonists - toxicity; Anilides - pharmacology; Bicalutamide; Chemical and Drug Induced Liver Injury, Chronic; Damage-associated molecular patterns; Flutamide; Flutamide - toxicity; Humans; Inflammasomes; Inflammasomes - metabolism; Male; Nitriles - toxicity; Prostatic Neoplasms; Reactive metabolite
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2023.105606

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.