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Drug-induced hepatotoxicity is one of the major reasons for drug failure and recall and hence it is of major concern to the FDA and consumers. An overdose of acetaminophen (APAP), a widely used over-the counter analgesic and antipyretic drug, can lead to acute liver failure associated with hepatic centrilobular necrosis.The metabolomics profiles, which primarily represent downstream changes in transcription and proteomic changes, have been adopted to investigate the mechanism of APAP-induced toxicity and to discover novel biomarkers of hepatotoxicity.In previous studies, NMR spectroscopy and ultra-performance liquid chromatography/mass spectrometry (UPLC/MS)-based metabolomics were employed to study urinary metabolic perturbations induced by APAP administration and the drugâs metabolites profile . These results showed the depletion of antioxidants (e.g., ferulic acid), trigonelline, S-adenosyl-methionine (SAMe), and energy-related metabolites caused by APAP administration.The multiple metabolomics profiling technologies in biofluids provided comprehensive insights into the metabolome changes and their corresponding pathways are altered by APAP, while the tissue transcriptomics data supported the pathway analysis. Novel liver injury metabolite biomarkers were also discovered through the correlation analysis between metabolites and hepatic necrosis scores and blood ALT levels.liver injury biomarkers involved in energy metabolism pathway (medium chain dicarboxylic acids and Î±-ketoglutarate) and bile acid pathway (taurocholic acid and taurodeoxycholic acid) and arginine metabolites (arginine and 2-oxoarginine) were also discovered. This was a limited study in which the toxic dose of acetaminophen caused moderate necrosis and ALT increases in two rats and therefore further studies and needed to evaluate these potential metabolic biomarkers of liver injury. (Sun J, Ando Y, Ahlbory-Dieker D, Schnackenberg LK, Yang X, Systems Biology Investigation to Discover Metabolic Biomarkers of Acetaminophen-Induced Hepatic Injury Using Integrated Transcriptomics and Metabolomics)
Last date updated on July, 2014