Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures
File(s)
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2018-06-01
Date Acceptance
2018-04-26
Citation
Archives of Toxicology, 2018, 92 (6), pp.1939-1952
ISSN
0340-5761
Publisher
Springer Verlag
Start Page
1939
End Page
1952
Journal / Book Title
Archives of Toxicology
Volume
92
Issue
6
Copyright Statement
© Springer-Verlag GmbH Germany, part of Springer Nature 2018. The final publication is available at Springer via https://link.springer.com/article/10.1007%2Fs00204-018-2214-z
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/29761207
PII: 10.1007/s00204-018-2214-z
Subjects
Adverse outcome pathway.
BSEP
Bosentan
Cholestasis
HepaRG
Metabolomics
Proteomics
Transcriptomics
Publication Status
Published
Coverage Spatial
Germany
Date Publish Online
2018-05-14