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.
Pharmacology, Toxicology and Pharmaceutical Science
15
24%
Biochemistry, Genetics and Molecular Biology
6
10%
Medicine and Dentistry
5
8%
Agricultural and Biological Sciences
3
5%
Materials Science
2
3%
Other
6
10%
Unknown
25
40%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 16 May 2018.
All research outputs
#20,742,744
of 23,344,526 outputs
Outputs from Archives of Toxicology
#2,395
of 2,669 outputs
Outputs of similar age
#288,348
of 327,646 outputs
Outputs of similar age from Archives of Toxicology
#27
of 30 outputs
Altmetric has tracked 23,344,526 research outputs across all sources so far. This one is in the 1st percentile – i.e., 1% of other outputs scored the same or lower than it.
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