Hepatoprotective role of PXR activation and MRP3 in cholic acid-induced cholestasis
Hepatoprotective role of PXR activation and MRP3 in cholic acid-induced cholestasis
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DOI：
10.1038/sj.bjp.0707235
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发表时间：
2007-06-01
影响因子：
7.3
通讯作者：
Piquette-Miller, M.
中科院分区：
文献类型：
--
作者：
Teng, S.;Piquette-Miller, M.
背景和目的：研究表明，激活胆甾烷X受体（PXR）可预防胆汁淤积性肝毒性。由于PXR改变了许多肝脏胆汁酸转运蛋白的表达，我们试图描述它们在肝脏保护中的潜在作用。实验方法：野生型（PXR+/+）和PXR-敲除（PXR-/-）小鼠喂食含或不含PXR激活剂PCN的1%胆汁酸（CA）饲料。肝脏功能进行了评估沿着相应的变化在肝脏基因expression.Key结果：CA管理引起显着的肝毒性PXR+/+小鼠，并与诱导几个FXR和PXR调节基因，编码胆汁酸转运和代谢蛋白。与CA单独给药相比，给予CA喂养的PXR+/+小鼠PCN可显著降低肝毒性，并与诱导MRP 3 mRNA以及CYP 3A 11 mRNA和功能活性相关。出乎意料的是，PXR-/-小鼠表达显著更高的基础和CA诱导的MRP 2、MRP 3、OST α、OST β、OATP 2和CYP 3A 11水平，对CA肝毒性的敏感性显著低于PXR +/+小鼠。PXR-/-小鼠对CA诱导的肝毒性的抗性可能是由于胆汁酸转运蛋白（特别是MRP 3）的基础表达和诱导表达较高所致。这些发现强调了MRP 3转运和代谢作为胆汁淤积性肝损伤的主要保护途径的重要性。英国药理学杂志（2007）。
Background and purpose: Activation of the pregnane X receptor ( PXR) has been shown to protect against cholestatic hepatotoxicity. As PXR alters the expression of numerous hepatic bile acid transporters, we sought to delineate their potential role in hepatoprotection.Experimental approach: Wild- type ( PXR+/+) and PXR- null ( PXR-/-) mice were fed a 1% cholic acid ( CA) diet with or without the PXR activator, PCN. Liver function was assessed along with the corresponding changes in hepatic gene expression.Key results: CA administration caused significant hepatotoxicity in PXR+/+ mice and was associated with induction of several FXR and PXR regulated genes, which encode for bile acid transport and metabolizing proteins. Compared to CA alone, coadministration of PCN to CA- fed PXR+/+ mice significantly decreased hepatotoxicity and was associated with induction of MRP3 mRNA as well as CYP3A11 mRNA and functional activity. Unexpectedly, PXR-/- mice, which expressed significantly higher basal and CA- induced levels of MRP2, MRP3, OST alpha, OST beta, OATP2 and CYP3A11, were dramatically less sensitive to CA hepatotoxicity than PXR+/+ mice.Conclusions: Protection of PXR+/+ mice against CA induced hepatotoxicity by PCN is associated with the induction of MRP3 and CYP3A11 expression. Resistance against CA- induced hepatotoxicity in PXR-/- mice may result from higher basal and induced expression of bile acid transporters, particularly MRP3. These findings emphasize the importance of transport by MRP3 and metabolism as major protective pathways against cholestatic liver injury. British Journal of Pharmacology ( 2007).