Drug-Induced Liver Injury and TNFα Signaling: From In Vivo Understanding to In Vitro Testing Approaches

Abstract

Abstract

For new candidate drugs, the liability toward idiosyncratic drug-induced liver injury (DILI) remains difficult to predict from preclinical in vitro and in vivo studies. The DILI-inducing potential of a drug is generally only detected in the clinical testing phase or once on the market. In the last decades, research on the interaction of host factors and drug-dependent processes has produced valuable insights into the mechanisms of idiosyncratic DILI. Continued development of screening methods and prediction models has led to improved prediction of DILI. However, the immune component involved in many drug-induced toxicities is notoriously difficult to characterize. In this review, we will discuss the interaction of innate inflammatory signaling, thereby focusing on tumor necrosis factor alpha-signaling and drug-induced processes leading to hepatotoxicity. In general, there is a clear interaction between liver-resident innate immune cells and hepatocytes during the onset of DILI. At a mechanistic, intracellular level, this involves interaction of drug-induced general adaptive stress response activation and cytokine-mediated signaling, and this interaction provides a basis for hepatocyte cytotoxicity. Understanding of these complex mechanistic interactions in human idiosyncratic DILI will allow development of tailored in vitro screening approaches.