Quantitative Chemical Proteomic Profiling of the in Vivo Targets of Reactive Drug Metabolites.

ABSTRACT: Idiosyncratic liver toxicity represents an important problem in drug research and pharmacotherapy. Reactive drug metabolites that modify proteins are thought to be a principal factor in drug-induced liver injury. Here, we describe a quantitative chemical proteomic method to identify the targets of reactive drug metabolites in vivo. Treating mice with clickable analogues of four representative hepatotoxic drugs, we demonstrate extensive covalent binding that is confined primarily to the liver. Each drug exhibited a distinct target profile that, in certain cases, showed strong enrichment for specific metabolic pathways (e.g., lipid/sterol pathways for troglitazone). Site-specific proteomics revealed that acetaminophen reacts with high stoichiometry with several conserved, functional (seleno)

SUBMITTER: Whitby LR 

PROVIDER: S-EPMC5626524 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature