title: Metabolic activation and drug-induced liver injury: in vitro approaches for the safety risk assessment of new drugs.
abstract: Drug-induced liver injury (DILI) is a significant leading cause of hepatic dysfunction, drug failure during clinical trials and post-market withdrawal of approved drugs. Many cases of DILI are unexpected reactions of an idiosyncratic nature that occur in a small group of susceptible individuals. Intensive research efforts have been made to understand better the idiosyncratic DILI and to identify potential risk factors. Metabolic bioactivation of drugs to form reactive metabolites is considered an initiation mechanism for idiosyncratic DILI. Reactive species may interact irreversibly with cell macromolecules (covalent binding, oxidative damage), and alter their structure and activity. This review focuses on proposed in vitro screening strategies to predict and reduce idiosyncratic hepatotoxicity associated with drug bioactivation. Compound incubation with metabolically competent biological systems (liver-derived cells, subcellular fractions), in combination with methods to reveal the formation of reactive intermediates (e.g., formation of adducts with liver proteins, metabolite trapping or enzyme inhibition assays), are approaches commonly used to screen the reactivity of new molecules in early drug development. Several cell-based assays have also been proposed for the safety risk assessment of bioactivable compounds. Copyright © 2015 John Wiley & Sons, Ltd.
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain.|CIBEREHD, FIS, Spain.
authors.forename: M José
authors.initials: MJ
authors.lastname: Gómez-Lechón
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Tolosa
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain.|CIBEREHD, FIS, Spain.|Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Spain.
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Donato
mesh_terms: D065767:Activation, Metabolic; D000818:Animals; D018929:Cell Culture Techniques / Q000639:trends; D002460:Cell Line; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology; D018920:Coculture Techniques / Q000639:trends; D004353:Drug Evaluation, Preclinical / Q000639:trends; D015507:Drugs, Investigational / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D066298:In Vitro Techniques / Q000639:trends; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D044085:Microfluidics / Q000379:methods / Q000639:trends; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008954:Models, Biological; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D054457:Tissue Scaffolds / Q000639:trends
chemical_list: D015507:Drugs, Investigational; D011994:Recombinant Proteins
keywords: DILI; bioactivation; covalent binding; engineered cells; hepatocytes; hepatotoxicity; iPSCs; idiosyncrasy; microsomes; reactive metabolites