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.
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds elicit a broad spectrum of species-specific effects. Hepatic steatosis is a classic response following exposure to TCDD characterized by increases in lipid accumulation, hepatocellular vacuolization, inflammation, and serum free fatty acids. Many of these effects resemble characteristics of metabolic syndrome (MetS), a multi-factorial disease that includes dyslipidemia, obesity, and can progress into non-alcoholic fatty liver disease (NAFLD) and , and diabetes. We have systematically integrated omic data from genome-wide chromatin immunoprecipitation (ChIPchip), microarray and metabolomic studies with complementary histopathology, and comparative analysis of in vivo and in vitro human, mice and rat models, as well as bioinformatic approaches to further elucidate the mechanisms involved in aryl hydrocarbon receptor (AhR)-mediated hepatic steatosis in female C57BL/6 mice. Our results suggest that TCDD induces hepatic steatosis due to alterations in lipid transport and metabolism that increase fat uptake and inhibit beta oxidation. Lipidomic and gene expression analyses also suggests that there is increased uptake of dietary fatty acids and regulation of fatty acid metabolism that alters saturated, mono-, and poly-unsaturated fatty acid ratios resulting in hepatoxicity. The integration of ChIP-chip data with the genomewide computational identification of dioxin response elements (DREs) is consistent with AhR-AhR nuclear translocator (ARNT)- mediated regulation for many of these responses. However, ~50% of AhR enriched regions in our ChIP-chip data did not contain a DRE. Bioinformatic analyses with supporting microarray data suggest that the AhR interacts with DNA to regulate gene expression by dimerizing with other transcription factors to alter lipid metabolism and transport. Collectively, these results not only further elucidate the mechanisms involved in TCDD-induced steatosis, but also suggest that TCDD and related compounds may contribute to the development of MetS and its associated diseases by increasing hepatic fat accumulation.