Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro

W.F.P.M. van den Hof, A. Ruiz-Aracama, A. Anke Summeren van, D.G. Jennen, S. Gaj, Maarten Coonen, K. Brauers, W.K. Wodzig, J.H. van Delft, J.C. Kleinjans

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)489-501
Number of pages13
JournalToxicology in Vitro
Volume29
Issue number3
DOIs
Publication statusPublished - Apr 2015

Keywords

  • Hepatotoxicity
  • Transcriptomics
  • Metabonomics
  • Cyclosporin A
  • MicroRNA
  • Cholestasis
  • DRUG-INDUCED HEPATOTOXICITY
  • SALT EXPORT PUMP
  • HEPG2 CELLS
  • GENE-EXPRESSION
  • NUCLEAR RECEPTORS
  • HUMAN HEPATOCYTES
  • TOXICITY
  • LIVER
  • METABONOMICS
  • CHOLESTEROL

Cite this

van den Hof, W. F. P. M., Ruiz-Aracama, A., Anke Summeren van, A., Jennen, D. G., Gaj, S., Coonen, M., Brauers, K., Wodzig, W. K., van Delft, J. H., & Kleinjans, J. C. (2015). Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicology in Vitro, 29(3), 489-501. https://doi.org/10.1016/j.tiv.2014.12.016