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

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


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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 11 / metabolism*
  • Bile Acids and Salts / metabolism
  • Bosentan / toxicity*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Gene Expression Profiling
  • Humans
  • Liver / drug effects*
  • Liver / metabolism
  • Metabolomics
  • Oxidative Stress / drug effects*
  • Oxidative Stress / genetics
  • Proteomics
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Transcriptome / drug effects*


  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • Bile Acids and Salts
  • Receptors, Cytoplasmic and Nuclear
  • farnesoid X-activated receptor
  • Bosentan