title: Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro.
abstract: In order to improve attrition rates of candidate-drugs there is a need for a better understanding of the mechanisms underlying drug-induced hepatotoxicity. We aim to further unravel the toxicological response of hepatocytes to a prototypical cholestatic compound by integrating transcriptomic and metabonomic profiling of HepG2 cells exposed to Cyclosporin A. Cyclosporin A exposure induced intracellular cholesterol accumulation and diminished intracellular bile acid levels. Performing pathway analyses of significant mRNAs and metabolites separately and integrated, resulted in more relevant pathways for the latter. Integrated analyses showed pathways involved in cell cycle and cellular metabolism to be significantly changed. Moreover, pathways involved in protein processing of the endoplasmic reticulum, bile acid biosynthesis and cholesterol metabolism were significantly affected. Our findings indicate that an integrated approach combining metabonomics and transcriptomics data derived from representative in vitro models, with bioinformatics can improve our understanding of the mechanisms of action underlying drug-induced hepatotoxicity. Furthermore, we showed that integrating multiple omics and thereby analyzing genes, microRNAs and metabolites of the opposed model for drug-induced cholestasis can give valuable information about mechanisms of drug-induced cholestasis in vitro and therefore could be used in toxicity screening of new drug candidates at an early stage of drug discovery.
authors.affiliation: Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands; Netherlands Toxicogenomics Centre, Maastricht, The Netherlands. Electronic address: w.vandenhof@maastrichtuniversity.nl.
authors.forename: Wim F P M
authors.initials: WF
authors.lastname: Van den Hof
authors.affiliation: RIKILT, Institute of Food Safety, Wageningen University and Research Centre, Wageningen, The Netherlands; Netherlands Toxicogenomics Centre, Maastricht, The Netherlands. Electronic address: aruizaracama@gmail.com.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Ruiz-Aracama
authors.affiliation: Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands; Netherlands Toxicogenomics Centre, Maastricht, The Netherlands. Electronic address: a.vansummeren@maastrichtuniversity.nl.
authors.forename: Anke
authors.initials: A
authors.lastname: Van Summeren
authors.affiliation: Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands; Netherlands Toxicogenomics Centre, Maastricht, The Netherlands. Electronic address: danyel.jennen@maastrichtuniversity.nl.
authors.forename: Danyel G J
authors.initials: DG
authors.lastname: Jennen
authors.affiliation: Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands; Netherlands Toxicogenomics Centre, Maastricht, The Netherlands. Electronic address: s.gaj@maastrichtuniversity.nl.
authors.forename: Stan
authors.initials: S
authors.lastname: Gaj
authors.affiliation: Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands; Netherlands Toxicogenomics Centre, Maastricht, The Netherlands. Electronic address: m.coonen@maastrichtuniversity.nl.
authors.forename: Maarten L J
authors.initials: ML
authors.lastname: Coonen
authors.affiliation: Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands. Electronic address: k.brauers@maastrichtuniversity.nl.
authors.forename: Karen
authors.initials: K
authors.lastname: Brauers
authors.affiliation: Department of Clinical Chemistry, Maastricht University Medical Center, Maastricht, The Netherlands; Netherlands Toxicogenomics Centre, Maastricht, The Netherlands. Electronic address: will.wodzig@mumc.nl.
authors.forename: Will K W H
authors.initials: WK
authors.lastname: Wodzig
authors.affiliation: Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands; Netherlands Toxicogenomics Centre, Maastricht, The Netherlands. Electronic address: jhm.vandelft@gmail.com.
authors.forename: Joost H M
authors.initials: JH
authors.lastname: van Delft
authors.affiliation: Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands; Netherlands Toxicogenomics Centre, Maastricht, The Netherlands. Electronic address: j.kleinjans@maastrichtuniversity.nl.
authors.forename: Jos C S
authors.initials: JC
authors.lastname: Kleinjans
mesh_terms: D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D016572:Cyclosporine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D056945:Hep G2 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D066298:In Vitro Techniques; D055432:Metabolomics; D035683:MicroRNAs / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D059467:Transcriptome
chemical_list: D007166:Immunosuppressive Agents; D035683:MicroRNAs; D012333:RNA, Messenger; D016572:Cyclosporine
keywords: Cholestasis; Cyclosporin A; Hepatotoxicity; Metabonomics; MicroRNA; Transcriptomics