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

Area of Science:

• Hepatology and Toxicology
• Molecular Biology
• Drug-Induced Liver Injury

Background:

• Bosentan is known to cause cholestatic liver toxicity in humans.
• Understanding the molecular mechanisms of bosentan-induced liver injury is crucial for patient safety.

Purpose of the Study:

• To characterize the transcriptomic, proteomic, and metabolomic effects of bosentan in human liver cells.
• To elucidate the mechanisms underlying bosentan-induced cholestatic liver toxicity.

Main Methods:

• Exposure of human hepatoma-derived HepaRG cells to various concentrations of bosentan.
• Transcriptomic, proteomic, and metabolomic analyses to assess cellular responses.
• Pathway analysis to identify key toxicological events.

Main Results:

• Bosentan suppressed the bile salt export pump (BSEP) and altered bile acid levels.
• Transcriptomic and proteomic data identified cholestasis as a primary toxicological event.
• Observed induction of oxidative stress, inflammation, and mitochondrial impairment.

Conclusions:

• Bosentan induces cholestatic liver injury through multiple molecular pathways.
• Findings contribute to understanding adverse outcome pathways for drug-induced liver injury.
• The study provides a multi-omics characterization of bosentan hepatotoxicity.