Abstract
Drug-Induced Liver Injury (DILI) represents a major problem in drug development. The clinical signature of DILI is broad (acute or chronic; hepatocellular, cholestatic or mixed) and the detection in clinical trials is mainly based on routine lab findings. Cases meeting Hy's law criteria identifies a potentially serious problem. The mechanisms of the pathogenesis of DILI remain a challenging issue. Although exposure to reactive drug metabolites is usually a prerequisite, downstream stress responses, cell death mechanisms and the immune system have emerged as critical determinants of DILI. In the case of "direct" toxicity, acetaminophen (APAP) has received the most attention and highlights the importance of signal transduction, programmed necrosis, and the role of mitochondrial dysfunction. Knowledge gained from recent studies of APAP from our laboratory has implicated sustained JNK activation in a type of programmed necrosis. Interaction of P-JNK with a protein in the outer membrane called Sab is required for sustained JNK activation. Inhibition of JNK or silencing the expression of Sab prevents APAP induced necrosis in vitro and in vivo without altering APAP metabolism (GSH depletion). Further these two approaches prevent massive apoptosis in the TNF/galactosamine model underscoring the general importance of JNK activation and interaction with mitochondrial Sab in hepatotoxicity. The hypothesis consistent with both models is that mitochondria made vulnerable by APAP or TNF produce enhanced ROS production when JNK interacts with Sab. ROS then lead to sustained JNK activation and ultimately cell death. In the case of idiosyncratic DILI, several examples of striking HLA associations point to the important role of the adaptive immune system in mediating injury. Recent genetic studies have shown increased risk with certain HLA markers in studies of flucloxacillin, ticlopidine, ximelagatran, lumiracoxib, amoxicillin and clavulanic acid, and lapatanib. However, GWAS studies conducted by the U.S. Drug-Induced Liver Injury Network of a large population of cases of DILI from various causes have not shown strong or reproducible associations. These findings leave us with two issues concerning idiosyncratic DILI: (1) In those with HLA risk factors, only a small percentage of cases actually develop DILI; what else determines the development of DILI in these cases? (2) concerning drugs with negative GWAS data, are genetic factors still involved (rare variants or multiple common polymorphisms)? In conclusion, considerable progress in predicting and understanding the mechanisms of DILI have been made recently, but there remains much to be learned.
