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

Archives of Toxicology
Robim M RodriguesMathieu Vinken

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.

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Citations

Nov 22, 2018·Archives of Toxicology·Amruta Damle-Vartak
Nov 24, 2018·Archives of Toxicology·Tarek EllethyMohamed M M Hashem
Mar 11, 2020·Archives of Toxicology·Eva GijbelsMathieu Vinken
Aug 28, 2020·Archives of Toxicology·Miren Garcia-CortesRaúl J Andrade
Aug 30, 2018·Archives of Toxicology·Matthias CuykxAdrian Covaci
Nov 18, 2018·Archives of Toxicology·Patrick Nell
Aug 20, 2019·Archives of Toxicology·Hermann M Bolt
Mar 13, 2021·Biomarkers in Medicine·Alanah PietersMathieu Vinken
Apr 6, 2021·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Eva GijbelsMathieu Vinken
Jun 3, 2021·International Journal of Molecular Sciences·Andrés TabernillaMathieu Vinken
Aug 6, 2021·The Journal of Pharmacology and Experimental Therapeutics·Marlies OortsPieter Annaert

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Methods Mentioned

BETA
fluorescence microscopy
chips
reversed phase chromatography
nuclear magnetic resonance
NMR
PCA

Software Mentioned

Ingenuity Pathways Analysis ( IPA )
Mascot
Affymetrix Transcriptome Analysis Console ( TAC )
Masterplex Readerfit
AOP
Robust Multiarray Analysis ( RMA
Affymetrix GCOS
Ingenuity Pathway Analysis
Matlab
Partek Genomics Suite

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