Universität zu Köln

Rodrigues, Robim M., Kollipara, Laxmikanth, Chaudhari, Umesh ORCID: 0000-0002-7743-4371, Sachinidis, Agapios, Zahedi, Rene P., Sickmann, Albert ORCID: 0000-0002-2388-5265, Kopp-Schneider, Annette, Jiang, Xiaoqi, Keun, Hector, Hengstler, Jan, Oorts, Marlies, Annaert, Pieter, Hoeben, Eef, Gijbels, Eva ORCID: 0000-0002-7366-0769, De Kock, Joery ORCID: 0000-0002-4078-4896, Vanhaecke, Tamara ORCID: 0000-0002-6685-7299, Rogiers, Vera ORCID: 0000-0003-0635-7740 and Vinken, Mathieu ORCID: 0000-0001-5115-8893 (2018). Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch. Toxicol., 92 (6). S. 1939 - 1953. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1432-0738

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Rodrigues, Robim M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kollipara, Laxmikanth UNSPECIFIED UNSPECIFIED UNSPECIFIED Chaudhari, Umesh UNSPECIFIED orcid.org/0000-0002-7743-4371 UNSPECIFIED Sachinidis, Agapios UNSPECIFIED UNSPECIFIED UNSPECIFIED Zahedi, Rene P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sickmann, Albert UNSPECIFIED orcid.org/0000-0002-2388-5265 UNSPECIFIED Kopp-Schneider, Annette UNSPECIFIED UNSPECIFIED UNSPECIFIED Jiang, Xiaoqi UNSPECIFIED UNSPECIFIED UNSPECIFIED Keun, Hector UNSPECIFIED UNSPECIFIED UNSPECIFIED Hengstler, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Oorts, Marlies UNSPECIFIED UNSPECIFIED UNSPECIFIED Annaert, Pieter UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoeben, Eef UNSPECIFIED UNSPECIFIED UNSPECIFIED Gijbels, Eva UNSPECIFIED orcid.org/0000-0002-7366-0769 UNSPECIFIED De Kock, Joery UNSPECIFIED orcid.org/0000-0002-4078-4896 UNSPECIFIED Vanhaecke, Tamara UNSPECIFIED orcid.org/0000-0002-6685-7299 UNSPECIFIED Rogiers, Vera UNSPECIFIED orcid.org/0000-0003-0635-7740 UNSPECIFIED Vinken, Mathieu UNSPECIFIED orcid.org/0000-0001-5115-8893 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-183211
DOI:	10.1007/s00204-018-2214-z
Journal or Publication Title:	Arch. Toxicol.
Volume:	92
Number:	6
Page Range:	S. 1939 - 1953
Date:	2018
Publisher:	SPRINGER HEIDELBERG
Place of Publication:	HEIDELBERG
ISSN:	1432-0738
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SALT EXPORT PUMP; DRUG-INDUCED CHOLESTASIS; FARNESOID-X-RECEPTOR; SAMPLE PREPARATION; LIVER-INJURY; BILE-ACIDS; MECHANISMS; IDENTIFICATION; HEPATOCYTES; INHIBITION Multiple languages Toxicology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/18321