Abstract

Severity of drug-induced liver injury (DILI) ranges from mild, asymptomatic and transient elevations in liver function tests to irreversible liver damage, often needing transplantation. Traditionally, DILI is classified mechanistically as high-frequency intrinsic DILI, commonly dose dependent or DILI that rarely occurs and is idiosyncratic in nature. This latter form is not dose dependent and has a pattern of histopahological manifestation that is not always uniform. Currently, a third type of DILI called indirect hepatotoxicity has been described which is associated with the pharmacological action of the drug. Historically, DILI was primarily linked to drug metabolism events; however, the impact of transporter-mediated rates of drug uptake and excretion in has gained greater prominence in DILI research. This review provides a comprehensive view of the major findings from studies examinining the contribution of hepatic ATP-binding cassette (ABC) transporters as key contributors to DILI and how changes in their expression and function influence the development, severity and overall toxicity outcome.

Significance Statement Drug-induced liver injury (DILI) continues to be a focal point in drug development research. ABC transporters have emerged as important determinants of drug detoxification, disposition and safety. This review article provides a comprehensive analysis of the literature addressing: (a) the role of hepatic ABC transporters on DILI, (b) the influence of genetic mutations in ABC transporters on DILI, and (c) new areas of research emphasis, such as the influence of the gut microbiota and epigenetic regulation on ABC transporters.