Drug metabolizing enzymes and transporters, and their roles for the development of drug-induced liver injury

Drug-induced liver injury (DILI) poses a significant challenge to drug development and human healthcare. The complex mechanisms underlying DILI make it challenging to accurately predict its occurrence, often leading to substantial financial losses from failed drug development projects and drug withdrawals. Growing evidence suggests that drug-metabolizing enzymes and transporters (DMETs) play a critical role in the development of DILI. In this review, we explore findings about the contributions of DMETs to DILI, with a focus on the studies examining genetic polymorphisms and their interactions with drugs. Additionally, we highlight the roles of DMETs in the development of predictive models for assessing DILI potential and in uncovering the mechanisms involved in DILI. As new approach methods (NAMs) for assessing and predicting drug toxicity gain more prominence, it is imperative to better understand the adverse outcome pathways (AOPs) that underpin these methods. DMETs largely play a pivotal role in the molecular initiating events of DILI-related AOPs. Further research is needed to characterize DILI-related AOP networks and enhance the predictive performance of NAMs for assessing DILI risk.