Mechanisms of drug-induced liver injury

Idiosyncratic drug-induced liver injury (iDILI) is a relatively rare condition, but can have serious consequences for the individual patient, public health, regulatory agencies and the pharmaceutical industry. Despite increased awareness of iDILI, its underlying mechanism is still not fully understood. This review summarizes the current understanding of the molecular mechanism behind iDILI.Genetic variations in drug metabolizing genes are in line with proposed mechanisms based on acetaminophen hepatotoxicity, whereby reactive metabolites covalently bind to cellular proteins and disturb the redox balance. In addition, immune-mediated effects have been reported for flucloxacillin hepatotoxicity, demonstrating both haptenization and direct binding between the drug and immune receptors.Idiosyncratic DILI development is believed to be orchestrated by multiple events, such as reactive metabolite formations, oxidative stress and signalling pathway inductions, with the mitochondria taking centre stage. Evidence also points towards the immune system (innate and adaptive responses) as important components in iDILI. Interindividual differences in one or more of these events, due to genetic variations and environmental factors, are likely to contribute to the idiosyncratic nature of this condition and subsequently distinguish between patient susceptibility and tolerance.