Reactive Metabolites Cause Idiosyncratic Drug-Induced Liver Injury via Inflammasome Activation in Antigen-Presenting Cells.

Abstract

Although the pathophysiology of idiosyncratic drug-induced liver injury (IDILI) is unclear, it is presumed to be immune-mediated, involving complex interactions between drug metabolism and activation of the immune system. The following four reactive metabolite production patterns are considered: (1) parent compounds into reactive metabolites within neutrophils or antigen-presenting cells (APCs), (2) reactive metabolites produced by cytochrome P450 (CYP), (3) nonreactive metabolites produced by CYP into reactive metabolites within APCs, and (4) reactive metabolites produced by non-CYPs. Reactive metabolites indirectly activate inflammasomes in APCs, leading to IDILIs. These metabolites can cause cell damage, resulting in the release of damage-associated molecular patterns (DAMPs), which subsequently activate APCs. Given the diversity of DAMPs, comprehensive analyses are warranted to identify additional candidates. If validates, these DAMPs could be used as early biomarkers and predictive markers of IDILIs onset.