Metabolomics and miRNA biomarkers of paracetamol overdose in rodents and children

Abstract

The commonly used drug, paracetamol, also known as acetaminophen (APAP), is a major cause of liver injury in adults and children. 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. Some of the metabolomics and miRNA biomarkers that were found in the preclinical studies have been evaluated in blood and urine samples from children that were overdosed with APAP. Metabolomics evaluations of samples from a preclinical study of APAP toxicity identified changes related to fatty acid beta-oxidation metabolism and bile acids transportation. In a subset of clinical samples, miRNAs were evaluated and urinary miR-375 was significantly increased in children with APAP overdose. Evaluation of these biomarkers in clinical samples showed that elevations of acylcarnitines, bile acids and miRNAs occurred in association with elevations of APAP-protein adducts and liver injury. The data suggest that bile acid metabolites, urinary miRNA-375 and APAPprotein adducts are very sensitive non-invasive indicators of liver toxicity due to APAP overdose.