Acetaminophen-induced Liver Injury: from Animal Models to Humans

Abstract

Drug-induced liver injury is an important clinical problem and a challenge for drug development. Whereas progress in understanding rare and unpredictable (idiosyncratic) drug hepatotoxicity is severely hampered by the lack of relevant animal models, enormous insight has been gained in the area of predictable hepatotoxins, in particular acetaminophen-induced liver injury, from a broad range of experimental models. Importantly, mechanisms of toxicity obtained with certain experimental systems, such as in vivo mouse models, primary mouse hepatocytes, and metabolically competent cell lines, are being confirmed in translational studies in patients and in primary human hepatocytes. Despite this progress, suboptimal models are still being used and experimental data can be confusing, leading to controversial conclusions. Therefore, this review attempts to discuss mechanisms of drug hepatotoxicity using the most studied drug acetaminophen as an example. We compare the various experimental models that are used to investigate mechanisms of acetaminophen hepatotoxicity, discuss controversial topics in the mechanisms, and assess how these experimental findings can be translated to the clinic. The success with acetaminophen in demonstrating the clinical relevance of experimental findings could serve as an example for the study of other drug toxicities.

Keywords: Drug hepatotoxicity; Necrosis; Sterile inflammation; Translational studies.

Fig. 1. Experimental models to study acetaminophen (APAP) hepatotoxicity.

The most common models used to study APAP hepatotoxicity are mice, rats, primary mouse and human hepatocytes (PMH and PHH, respectively), and hepatoma cell lines. However, the mechanisms of injury and mode of cell death differ. In mouse models and in humans, APAP-induced liver injury involves mitochondrial damage, oxidative stress, c-jun N-terminal kinase (JNK) activation, and nuclear DNA fragmentation. The mode of cell death in these models is oncotic necrosis. However, rats develop little or no oxidative stress and thus no injury, while hepatoma cells may develop injury but through different mechanisms than mouse or human hepatocytes. In the latter case, the mode of cell death is almost always apoptosis. The results suggest that mice and PHH are the best available models for the study of APAP toxicity.