Translational Mechanistic Biomarkers of Drug-Induced Liver Injury

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SELECTBIO

The identification and screening for idiosyncratic hepatotoxicity remains a major challenge for clinicians and in drug development as well as being a leading cause of drug withdrawal from the market. Translational, mechanistic biomarkers are required in order assist in the identification patients at risk and screening of chemical liability. Paracetamol hepatotoxicity represents a major cause of acute liver failure and serves as a paradigm to elucidate mechanisms of Drug-Induced Liver Injury (DILI) for the identification of predisposing factors and the development of therapeutic interventions. Paracetamol is an excellent tool for translational drug safety investigations as there are broadly similar mechanisms of initiation of hepatotoxicity across animal models and man. The role of apoptosis and the innate immune response during paracetamol-mediated hepatotoxicity remains controversial. This presentation will focus on two mechanism-based serum markers, high mobility group box-1 (HMGB-1) and keratin-18 (K18), in helping to further understand the biology occurring during drug induced hepatotoxicity in the mouse. Translation of these biomarkers to humans has been performed in paracetamol overdose patients.