Elucidation of the pathogenesis of trovafloxacin induced liver injury

<p>Trova (trova) was withdrawn from a global market because trova induced serious liver injury. However, the detail is unclear. On the other hand, we have reported that the drug or its reactive metabolite causes the idiosyncratic drug-induced serious adverse effects by activating the immune cells. In this study, we evaluated whether trova or its reactive metabolites lead to inflammasome activation with the human hepatocarcinoma functional liver cell-4 (FLC-4) cells and the human macrophage cell line (THP-1 cell) to test trova or its reactive metabolite activate immune cells. FLC4-cells were cultured with 3.0-30 µM trova for 7 days. The supernatant from the FLC-4 cells was added to THP-1 cells, which was incubated for 24 hr. These supernatant and cells were used for measurement of IL-1β production and caspase-1 activity. 1-aminobenzotriazole (ABT, 1 mM) was used to inhibit cytochromes P450 activities, and Ac-YVAD-cmk (YVAD, 1 µM) was used to inhibit caspase-1 activity. Trova did not increase the production of IL-1β or caspase-1 activity of THP-1 cells directly. However, the supernatant from an incubation of FLC-4 cells with trova increased the IL-1β production and caspse-1 activity of THP-1 cells. In addition, the production of IL-1β and caspase-1 activation were inhibited by adding the ABT or YVAD. These results support that the reactive metabolite of trova can activate inflammasomes, which can cause immune-related adverse events.</p>