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000136792 0247_ $$2doi$$a10.1007/s00204-018-2214-z
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000136792 0247_ $$2ISSN$$a0003-9446
000136792 0247_ $$2ISSN$$a0340-5761
000136792 0247_ $$2ISSN$$a1432-0738
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000136792 037__ $$aDKFZ-2018-01230
000136792 041__ $$aeng
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000136792 1001_ $$aRodrigues, Robim M$$b0
000136792 245__ $$aOmics-based responses induced by bosentan in human hepatoma HepaRG cell cultures.
000136792 260__ $$aBerlin$$bSpringer$$c2018
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000136792 520__ $$aBosentan is well known to induce cholestatic liver toxicity in humans. The present study was set up to characterize the hepatotoxic effects of this drug at the transcriptomic, proteomic, and metabolomic levels. For this purpose, human hepatoma-derived HepaRG cells were exposed to a number of concentrations of bosentan during different periods of time. Bosentan was found to functionally and transcriptionally suppress the bile salt export pump as well as to alter bile acid levels. Pathway analysis of both transcriptomics and proteomics data identified cholestasis as a major toxicological event. Transcriptomics results further showed several gene changes related to the activation of the nuclear farnesoid X receptor. Induction of oxidative stress and inflammation were also observed. Metabolomics analysis indicated changes in the abundance of specific endogenous metabolites related to mitochondrial impairment. The outcome of this study may assist in the further optimization of adverse outcome pathway constructs that mechanistically describe the processes involved in cholestatic liver injury.
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000136792 7001_ $$aKollipara, Laxmikanth$$b1
000136792 7001_ $$aChaudhari, Umesh$$b2
000136792 7001_ $$aSachinidis, Agapios$$b3
000136792 7001_ $$aZahedi, René P$$b4
000136792 7001_ $$aSickmann, Albert$$b5
000136792 7001_ $$0P:(DE-He78)bb6a7a70f976eb8df1769944bf913596$$aKopp-Schneider, Annette$$b6$$udkfz
000136792 7001_ $$0P:(DE-He78)079436c5442874052d541943e53145ef$$aJiang, Xiaoqi$$b7$$udkfz
000136792 7001_ $$aKeun, Hector$$b8
000136792 7001_ $$aHengstler, Jan$$b9
000136792 7001_ $$aOorts, Marlies$$b10
000136792 7001_ $$aAnnaert, Pieter$$b11
000136792 7001_ $$aHoeben, Eef$$b12
000136792 7001_ $$aGijbels, Eva$$b13
000136792 7001_ $$aDe Kock, Joery$$b14
000136792 7001_ $$aVanhaecke, Tamara$$b15
000136792 7001_ $$aRogiers, Vera$$b16
000136792 7001_ $$aVinken, Mathieu$$b17
000136792 773__ $$0PERI:(DE-600)1458459-1$$a10.1007/s00204-018-2214-z$$gVol. 92, no. 6, p. 1939 - 1952$$n6$$p1939 - 1952$$tArchives of toxicology$$v92$$x1432-0738$$y2018
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