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Arch Toxicol. 2018 Jun;92(6):1939-1952. doi: 10.1007/s00204-018-2214-z. Epub 2018 May 14.

Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures.

Author information

1
Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
2
Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany.
3
Institute of Neurophysiology and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
4
Department of Chemistry, College of Physical Sciences, University of Aberdeen, Aberdeen, Scotland, UK.
5
Medizinische Fakultät, Medizinische Proteom-Center (MPC), Ruhr-Universität Bochum, Bochum, Germany.
6
Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
7
Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, UK.
8
Leibniz Research Centre for Working Environment and Human Factors at the Technical University of Dortmund, Dortmund, Germany.
9
Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit Leuven, Leuven, Belgium.
10
BioNotus GCV, Niel, Belgium.
11
Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium. mvinken@vub.ac.be.

Abstract

Bosentan is well known to induce cholestatic liver toxicity in humans. The present study was set up to characterize the hepatotoxic effects of this drug at the transcriptomic, proteomic, and metabolomic levels. For this purpose, human hepatoma-derived HepaRG cells were exposed to a number of concentrations of bosentan during different periods of time. Bosentan was found to functionally and transcriptionally suppress the bile salt export pump as well as to alter bile acid levels. Pathway analysis of both transcriptomics and proteomics data identified cholestasis as a major toxicological event. Transcriptomics results further showed several gene changes related to the activation of the nuclear farnesoid X receptor. Induction of oxidative stress and inflammation were also observed. Metabolomics analysis indicated changes in the abundance of specific endogenous metabolites related to mitochondrial impairment. The outcome of this study may assist in the further optimization of adverse outcome pathway constructs that mechanistically describe the processes involved in cholestatic liver injury.

KEYWORDS:

Adverse outcome pathway.; BSEP; Bosentan; Cholestasis; HepaRG; Metabolomics; Proteomics; Transcriptomics

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