Organ distribution of multidrug resistance proteins 1, 2, and 3 (Mrp1, 2, and 3) rnRNA and hepatic induction of mrp3 by constitutive androstane receptor activators in rats
Organ distribution of multidrug resistance proteins 1, 2, and 3 (Mrp1, 2, and 3) rnRNA and hepatic induction of mrp3 by constitutive androstane receptor activators in rats
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DOI：
10.1124/jpet.300.1.97
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发表时间：
2002-01-01
影响因子：
3.5
通讯作者：
Klaassen, CD
中科院分区：
文献类型：
--
作者：
Cherrington, NJ;Hartley, DP;Klaassen, CD
许多I相和II相微粒体酶诱导剂具有共同的转录激活机制，因此具有类似的一系列协调调控的基因。许多II相代谢物被认为是通过多药耐药蛋白1、2和3（Mrp 1、2和3）转运出细胞。本研究的目的是确定这三种转运蛋白在大鼠体内的器官分布，以及它们是否与I相和II相药物代谢酶协同调节。因此，在多个组织和大鼠组织中使用分支DNA信号扩增来定量Mrp 1、2和3 mRNA，所述大鼠用18种化学物质处理，所述化学物质被认为通过6种不同的转录激活机制诱导药物代谢酶[芳香烃受体配体、组成型雄烷受体（CAR）激活剂、孕烷-X-受体配体、过氧化物酶体增殖物激活剂受体配体、亲电反应元件（EpRE）激活剂和CYP 2 E1诱导剂]。结果表明，Mrp 1在肾、肺、肠和脑中表达量较高，在肝中表达量较低。Mrp 2在肝脏和十二指肠中高度表达，Mrp 3在整个肠道中高度表达，但在肝脏中表达很低。微粒体酶诱导剂没有显着增加Mrp 1或Mrp 2的表达。然而，Mrp 3表达在肝脏中被CAR激活剂和EpRE激活剂中的每一种显著增加。Mrp 3在肾脏和大肠中没有类似的诱导，表明Mrp 3的协调诱导对肝脏是特异性的。我们的结论是，大鼠肝脏Mrp 3诱导CAR激活剂，从而提高了一些11相代谢物从肝脏到血液的矢量排泄。
Many phase I and II microsomal enzyme inducers share common mechanisms of transcriptional activation and thus share a similar battery of genes that are coordinately regulated. Many phase II metabolites are thought to be transported out of cells by multidrug resistance proteins 1, 2, and 3 (Mrp1, 2, and 3). The purpose of this study was to determine the organ distribution of these three transporters in rat, and whether they are coordinately regulated with phase I and II drug-metabolizing enzymes. Therefore, Mrp1, 2, and 3 mRNAs were quantified using branched DNA signal amplification in multiple tissues and in tissues from rats that were treated with 18 chemicals thought to induce drug-metabolizing enzymes by six different transcription activation mechanisms [aryl-hydrocarbon receptor ligands, constitutive androstane receptor (CAR) activators, pregnane-X-receptor ligands, peroxisome proliferator activator receptor ligands, electrophile response element (EpRE) activators, and CYP2E1 inducers]. It was found that Mrp1 was expressed at a high level in kidney, lung, intestine, and brain, with low expression in liver. Mrp2 was highly expressed in liver and duodenum, and Mrp3 was highly expressed throughout the intestine but very low in liver. Microsomal enzyme inducers did not markedly increase the expression of Mrp1 or Mrp2. However, Mrp3 expression was significantly increased by each of the CAR activators and an EpRE activator in liver. Mrp3 was not similarly induced in kidney and large intestine, demonstrating that the coordinate inducibility of Mrp3 is specific to the liver. We conclude that rat hepatic Mrp3 is induced by CAR activators, thus enhancing the vectoral excretion of some phase 11 metabolites from the liver to the blood.