Idiosyncratic drug hepatotoxicity revisited: new insights from mechanistic toxicology

Drug-induced hepatotoxicity is a serious problem and has repeatedly led to the withdrawal of a drug after successful launching. Although reactive metabolites (which are predictable) are often involved, genetic or acquired host factors (which are unpredictable) can increase the penetrance and expressivity of the potential hepatotoxicity in a small subset of patients. The molecular mechanisms underlying liver injury are largely unknown. Evidence suggests, however, that there are four major modes of action: covalent modification of target proteins and oxidoreductive stress; immune-mediated reactions; interference with hepatobiliary export; and mitochondrial injury. A better prediction will include new animal models, new biomarkers, and genomics/transcriptomics analysis.