Drug-induced liver injury (DILI) is a reason many drugs fail in preclinical and early phase clinical testing. Even marketed drugs have such liabilities.  The commonly used, OTC drug, acetaminophen (APAP) is a major cause of DILI.  APAP-induced toxicity causes oxidative stress, ROS production, glutathione depletion, mitochondria dysfunction, disruption of energy metabolism, and altered immune response.  Biofluid and tissue samples from preclinical APAP toxicity studies were analyzed by genomics, proteomics and metabolomics technologies to discover omics biomarkers of liver injury and recovery.  Some of the metabolomics biomarkers were found in the preclinical studies are being evaluated in blood and urine samples from children that were accidentally overdosed with APAP.  Omics evaluations of samples from a preclinical study of APAP toxicity identified changes related to fatty acid beta-oxidation metabolism and bile acids transportation.  Evaluation of these biomarkers in clinical samples showed elevations of bile acid metabolites occurred at the early stages of liver injury in association with elevations of APAP-protein adducts.  Importantly, bile acid metabolites and APAP-protein adducts were increased prior to the elevation of ALT, a standard clinical test for liver injury. The data suggest that bile acid metabolites and APAP-protein adducts are very sensitive indicators of liver toxicity due to APAP overdose.  These data can be used to stratify patients for potential clinical intervention, thus allowing a personalized medicine approach.  To explore the universality of these biomarkers, efforts are underway to evaluate other drugs in animals and in humans including those of an idiosyncratic nature.

Metabolic profiling of rodents and children with acetaminophen overdose

247th National Meeting (2014)

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