title: Development of novel tools for the in vitro investigation of drug-induced liver injury.
abstract: BACKGROUND
  Due to its complex mechanisms and unpredictable occurrence, drug-induced liver injury (DILI) complicates drug identification and classification. Since species-specific differences in metabolism and pharmacokinetics exist, data obtained from animal studies may not be sufficient to predict DILI in humans.
  
  
  METHODS
  Over the last few decades, numerous in vitro models have been developed to replace animal testing. The advantages and disadvantages of commonly used liver-derived in vitro models (e.g., cell lines, hepatocyte models, liver slices, three-dimensional (3D) hepatospheres, etc.) are discussed. Toxicogenomics-based methodologies (genomics, epigenomics, transcriptomics, proteomics and metabolomics) and next-generation sequencing have also been used to enhance the reliability of DILI prediction. This review presents an overview of the currently used alternative toxicological models and of the most advanced approaches in the field of DILI research.
  
  
  CONCLUSIONS
  It seems unlikely that a single in vitro system will be able to mimic the complex interactions in the human liver. Three-dimensional multicellular systems may bridge the gap between conventional 2D models and in vivo clinical studies in humans and provide a reliable basis for hepatic toxicity assay development. Next-generation sequencing technologies, in comparison to microarray-based technologies, may overcome the current limitations and are promising for the development of predictive models in the near future.
authors.affiliation: a 1 Maastricht University, GROW School for Oncology and Developmental Biology, Department of Toxicogenomics , Maastricht, The Netherlands +31 43 3881090 ; +31 43 3884146 ; j.jiang@maastrichtuniversity.nl.
authors.forename: Jian
authors.initials: J
authors.lastname: Jiang
authors.affiliation: b 2 Maastricht University, GROW School for Oncology and Developmental Biology, Department of Toxicogenomics , Maastricht, The Netherlands.
authors.forename: Jarno E J
authors.initials: JE
authors.lastname: Wolters
authors.affiliation: b 2 Maastricht University, GROW School for Oncology and Developmental Biology, Department of Toxicogenomics , Maastricht, The Netherlands.
authors.forename: Simone G
authors.initials: SG
authors.lastname: van Breda
authors.affiliation: b 2 Maastricht University, GROW School for Oncology and Developmental Biology, Department of Toxicogenomics , Maastricht, The Netherlands.
authors.forename: Jos C
authors.initials: JC
authors.lastname: Kleinjans
authors.affiliation: b 2 Maastricht University, GROW School for Oncology and Developmental Biology, Department of Toxicogenomics , Maastricht, The Netherlands.
authors.forename: Theo M
authors.initials: TM
authors.lastname: de Kok
mesh_terms: D000826:Animal Testing Alternatives; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D006801:Humans; D008954:Models, Biological; D013045:Species Specificity; D043922:Toxicogenetics / Q000379:methods; D014116:Toxicology / Q000379:methods*
keywords: -omics technologies; 3D culture; drug-induced liver injury; multicellular hepatospheres; primary hepatocytes; sequencing technologies; toxicogenomics