TY  - JOUR
AU  - Rodrigues, Robim M
AU  - Kollipara, Laxmikanth
AU  - Chaudhari, Umesh
AU  - Sachinidis, Agapios
AU  - Zahedi, René P
AU  - Sickmann, Albert
AU  - Kopp-Schneider, Annette
AU  - Jiang, Xiaoqi
AU  - Keun, Hector
AU  - Hengstler, Jan
AU  - Oorts, Marlies
AU  - Annaert, Pieter
AU  - Hoeben, Eef
AU  - Gijbels, Eva
AU  - De Kock, Joery
AU  - Vanhaecke, Tamara
AU  - Rogiers, Vera
AU  - Vinken, Mathieu
TI  - Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures.
JO  - Archives of toxicology
VL  - 92
IS  - 6
SN  - 1432-0738
CY  - Berlin
PB  - Springer
M1  - DKFZ-2018-01230
SP  - 1939 - 1952
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:29761207
DO  - DOI:10.1007/s00204-018-2214-z
UR  - https://inrepo02.dkfz.de/record/136792
ER  -