Effects of Pharmaceuticals on the Expression of Genes Involved in Detoxification in a Carp Primary Hepatocyte Model
Effects of Pharmaceuticals on the Expression of Genes Involved in Detoxification in a Carp Primary Hepatocyte Model
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DOI：
10.1021/es3005305
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发表时间：
2012-06-05
影响因子：
11.4
通讯作者：
Tyler, Charles R.
中科院分区：
文献类型：
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作者：
Corcoran, Jenna;Lange, Anke;Tyler, Charles R.
许多表层淡水中的鱼类通过废水处理厂的污水排放接触到一系列药物。在哺乳动物中，PXR在调节一系列参与药物生物转化的基因中起着关键作用，但有关鱼类中这一反应途径的作用的信息有限。在这里，我们研究了鲤鱼（鲤鱼）原代肝细胞暴露于人PXR激动剂利福平（RIF）对参与I相（cyp2k，cyp3a）和II相（GST α，GST π）药物代谢和药物转运蛋白mdr1和mrp2的靶基因表达的影响。RIF可诱导所有靶基因的表达，PXR拮抗剂酮康唑（KET）可抑制cyp2k和cyp3a的反应。原代鲤鱼肝细胞暴露于药物布洛芬（IBU），克霉唑（CTZ），氯贝酸（CFA）和普萘洛尔（PRP），发现IBU和CFA的反应，但没有CTZ或PRP。这与哺乳动物相反，其中CTZ是有效的PXR激动剂。总的来说，我们的数据表明，潜在的PXR参与调节选定的基因参与药物代谢的鱼类，但建议一些分歧的调节途径与哺乳动物。鲤鱼原代肝细胞模型是筛选药物代谢相关靶基因的有效系统。
Fish in many surface freshwaters are exposed to a range of pharmaceuticals via wastewater treatment works effluent discharges. In mammals the pregnane X receptor (PXR) plays a key role in the regulation of a suite of genes involved in drug biotransformation, but information on the role of this response pathway in fish is limited. Here we investigated the effects of exposure of carp (Cyprinus carpio) primary hepatocytes to the human PXR agonist rifampicin (RIF) on expression of target genes involved in phase I (cyp2k, cyp3a) and phase II (gst alpha, gst pi) drug metabolism and drug transporters mdr1 and mrp2. RIF induced expression of all target genes measured and the PXR antagonist ketoconazole (KET) inhibited responses of cyp2k and cyp3a. Exposure of the primary carp hepatocytes to the pharmaceuticals ibuprofen (IBU), clotrimazole (CTZ), clofibric acid (CFA) and propranolol (PRP), found responses to IBU and CFA, but not CTZ or PRP. This is in contrast with mammals, where CTZ is a potent PXR-agonist. Collectively our data indicate potential PXR involvement in regulating selected genes involved in drug metabolism in fish, but suggest some divergence in the regulation pathways with those in mammals. The carp primary hepatocyte model serves as a useful system for screening for responses in these target genes involved in drug metabolism.