Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany.
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.
波生坦已被证实可引起人体胆汁淤积性肝毒性。本研究旨在从转录组学、蛋白质组学和代谢组学层面来描述该药物的肝毒性作用。为此，本研究将人肝癌衍生的 HepaRG 细胞暴露于不同浓度的波生坦中不同时间。研究发现波生坦可在功能和转录水平上抑制胆盐输出泵，并改变胆汁酸水平。转录组学和蛋白质组学数据分析的途径分析确定胆汁淤积是一个主要的毒理学事件。转录组学结果进一步显示了与核法尼醇 X 受体激活相关的几个基因变化。还观察到氧化应激和炎症的诱导。代谢组学分析表明与线粒体损伤相关的特定内源性代谢物丰度发生变化。本研究的结果可能有助于进一步优化不良结局途径构建，从而以机械的方式描述参与胆汁淤积性肝损伤的过程。
