Mechanisms of drug induced liver injury.

Drug induced liver injury (DILI) is a serious and potentially life-threatening condition resulting from an adverse drug reaction. Both the clinical manifestations and pathological mechanisms of DILI vary depending on drug characteristics, dose, duration of exposure as well as host specific factors. Disease onset can occur within days or months after the introduction of a drug. This has challenged identification of disease specific biomarkers and resulted in delayed and even erroneous diagnosis of patients. Apart from discontinuation of current pharmacotherapy, options for DILI patients are scarce and the condition can sometimes continue or worsen after drugs are discontinued or result in irreversible liver damage such as cirrhosis. This illustrates the need to uncover relevant pathological pathways that will pave the road for targeted interventions. In an effort to accommodate these needs, novel insights from preclinical and cellular disease modeling have allowed coupling of specific drugs to potential mechanisms of toxicity. This review outlines three signaling pathways of DILI: organelle stress, cholestasis, and immune responses, discusses their interplay with oxidative stress, and provides examples of drugs specifically targeting one or more steps in these pathways. A systematic approach identifying specific mechanisms of DILI could allow for the assembly of large databases, in turn enabling advanced computational modelling to provide accurate predictions of the DILI potential of both known drugs and future drug candidates.