LOSS of Mrp1 alters detoxification enzyme expression in a tissue- and hormonal-status-specific manner.
LOSS of Mrp1 alters detoxification enzyme expression in a tissue- and hormonal-status-specific manner.
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Mrp1 的缺失会以组织和激素状态特异性的方式改变解毒酶的表达。
DOI：
10.1002/jat.2727
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Bain,LisaJ
中科院分区：
文献类型：
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作者：
Sivils,JeffreyC;Ancrum,TiffanyM;Bain,LisaJ
多药耐药相关蛋白1 （MRP1/ABCC1）是ABCC转运蛋白亚家族的一员，介导药物、外源药物和类固醇激素的外排，典型的是谷胱甘肽、葡萄糖醛酸盐或硫酸盐缀合物。由于一种转运蛋白的缺失可以通过增加其他转运蛋白和偶联酶的表达来补偿，因此我们试图检测完整或阉割的mrp1−/−雄性小鼠肝外组织（包括肾脏、肺和小肠）I、II和III期酶表达的代偿性变化。在肾脏中，几个p450的表达，磺胺转移酶1a1 (Sult)，葡萄糖醛酸转移酶（Ugt）和Mrps2-4，由于阉割而显著改变。基因型只在去势的FVB小鼠和Mrp1敲除小鼠之间起作用。相比之下，Mrp1基因敲除小鼠肺中Ugts、Sult 1a1和Mrp3的表达显著下调，因此仅基于基因型。在小肠中，类固醇激素水平和基因型之间存在相互作用，因为表达差异仅在缺乏Mrp1的小鼠中发现，并且在完整和阉割的动物之间发生变化。这种表达模式背后的机制可能是由于Nrf2的调控，因为它的表达反映了II期和III期酶的表达。这些结果表明，由于Mrp1缺失引起的代偿反应根据特定的组织变化很大。这些信息将有助于理解药物摄取、处置和消除如何受到激素状态和转运蛋白表达的存在和大小的影响。版权所有©2012 John Wiley & Sons， Ltd。
The multidrug resistance‐associated protein1 (MRP1/ABCC1) is a member of the ABCC transporter subfamily that mediates the efflux of pharmaceuticals, xenobiotics and steroid hormones, typically as glutathione, glucuronide or sulfate conjugates. Since loss of one transporter can be compensated by increasing the expression of other transporters and conjugation enzymes, we sought to examine compensatory changes in phase I, II and III enzyme expression in extrahepatic tissues, including the kidney, lungs and small intestine of intact or castratedMrp1−/−male mice. In the kidney, the expression of several P450s, sulfotransferase 1a1 (Sult), glucuronosyltransferases (Ugt) and Mrps2–4, were significantly changed owing to castration alone. The only time genotype mattered was between the castrated FVB and Mrp1 knockout mice. In contrast, expression of the Ugts, Sult 1a1 and Mrp3 in the lungs was significantly downregulated in the Mrp1 knockout mice, so based exclusively on genotype. In the small intestine, there were interactions between steroid hormone levels and genotype, as the expression differences were only found in mice lacking Mrp1, and were changed between intact and castrated animals. The mechanism behind this pattern of expression may be to due to Nrf2 regulation, as its expression mirrors that of the phase II and phase III enzymes. These results indicate that compensatory responses owing to the loss of Mrp1 vary dramatically, depending on the particular tissue. This information will aid in the understanding of how drug uptake, disposition and elimination can be influenced by both hormone status and the presence and magnitude of transporter expression. Copyright © 2012 John Wiley & Sons, Ltd.