Tissue distribution and induction of the rat multidrug resistance-associated proteins 5 and 6
Tissue distribution and induction of the rat multidrug resistance-associated proteins 5 and 6
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DOI：
10.1016/j.lfs.2005.09.016
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发表时间：
2006-04-04
期刊：
影响因子：
6.1
通讯作者：
Klaassen, CD
中科院分区：
文献类型：
--
作者：
Maher, JM;Cherrington, NJ;Klaassen, CD
多药耐药相关蛋白(MRPs)是一种依赖于ATP的转运蛋白，可转运多种阴阳离子化合物。本研究的目的是确定MRP5和6在雄性和雌性SD大鼠不同组织中的组织分布，并探讨胆汁淤积和微粒体酶诱导剂(MEI)是否改变了MRP5和6的表达。这些人激活了六种不同的转录调节通路，并确定了它们对mrp5和mrp6表达的影响。定量研究胆管结扎对雄性大鼠胆汁淤积模型中MRP5和6表达的影响。MRP5在肾上腺有明显表达，在大脑皮层、小脑和胃有中等表达。MEIS多氯联苯(PCB126)、苯巴比妥和PCB99对MRP5有轻微的抑制作用，但没有单一的受体激动剂诱导或抑制MRP5。胆管结扎倾向于增加MRP5的表达，但在3天的时间点上没有统计学意义。MRP6在肠、肝、肾中的表达最高。苯巴比妥、地塞米松和异烟肼对MRP6有轻微的抑制作用，但没有一种受体激动剂能诱导或抑制MRP6的表达，胆管结扎对MRP6的表达也没有影响。总之，在大鼠中，MRP5在肾上腺中表达最高，而MRP6主要在排泄器官(肝、肠和肾)中表达，表明其功能明显不同。肝脏mrp5或mrp6的mRNA水平似乎不是通过受体介导的途径与I期酶协同调节的，也不是胆汁淤积过程中发生的肝保护性转运蛋白上调的一部分。(C)2005 Elsevier Inc.保留所有权利。
Multidrug resistance-associated proteins (Mrps) are ATP-dependent transporters which transport a wide variety of anionic and cationic compounds. The purpose of this study was to determine the tissue distribution of Mrp5 and 6 in male and female Sprague-Dawley rats in various tissues, and to investigate whether the expression is altered by cholestasis or administration of microsomal enzyme inducers (MEIs). These MEN activate six different transcriptionally-mediated pathways, and their effects on Mrp5 and Mrp6 expression were determined. The effects of bile-duct ligation, a cholestasis model, on Mrp5 and 6 expression in male rats were quantified. Mrp5 had marked expression in adrenal gland, and moderate expression in cerebral cortex, cerebellum, and stomach. The MEIs polychlorinated biphenyl (PCB)126, phenobarbital, and PCB99 slightly repressed Mrp5, but no single class of receptor agonists induced or repressed Mrp5. Bile-duct ligation tended to increase Mrp5 expression, but was not statistically significant at a 3 day timepoint. Mrp6 expression was highest in intestine, liver, and kidney. Mrp6 was slightly repressed by phenobarbital, dexamethasone, and isoniazid, but no one class of receptor agonists induced or repressed Mrp6, and expression was also unchanged bile-duct ligation. In conclusion Mrp5 in rats is most highly expressed in the adrenal gland, whereas Mrp6 is mainly expressed in excretory organs (liver, intestine, and kidney), suggesting markedly different functions. Hepatic mRNA levels of Mrp5 or Mrp6 do not seem to be coordinately regulated along with Phase I enzymes via receptor-mediated pathways, and are not part of the hepatoprotective upregulation of basolateral transporters that occurs during cholestasis. (c) 2005 Elsevier Inc. All rights reserved.