Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Record number 496037
Title Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro
Author(s) Hof, W.F.P.M. Van den; Ruiz Aracama, Ainhoa; Summeren, Anke Van; Jennen, D.G.J.; Gaj, Stan; Coonen, M.L.J.; Brauers, Karen; Wodzig, W.K.W.H.; Delft, J.H.M. van; Kleinjans, J.C.S.
Source Toxicology in Vitro 29 (2015)3. - ISSN 0887-2333 - p. 489 - 501.
DOI http://dx.doi.org/10.1016/j.tiv.2014.12.016
Department(s) RIKILT - BU Toxicology Bioassays & Novel Foods
Publication type Refereed Article in a scientific journal
Publication year 2015
Keyword(s) Cholestasis - Cyclosporin A - Hepatotoxicity - Metabonomics - MicroRNA - Transcriptomics
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.

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