MAPPING OF MULTIDRUG RESISTANCE GENE 1 AND MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN ISOFORM 1 TO 5 mRNA EXPRESSION ALONG THE HUMAN INTESTINAL TRACT
MAPPING OF MULTIDRUG RESISTANCE GENE 1 AND MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN ISOFORM 1 TO 5 mRNA EXPRESSION ALONG THE HUMAN INTESTINAL TRACT
复制标题
DOI：
10.1124/dmd.104.001354
复制
发表时间：
2005-02
影响因子：
3.9
通讯作者：
C. Zimmermann;H. Gutmann;P. Hruz;J. Gutzwiller;C. Beglinger;J. Drewe
中科院分区：
文献类型：
--
作者：
C. Zimmermann;H. Gutmann;P. Hruz;J. Gutzwiller;C. Beglinger;J. Drewe
肠壁中的外排转运蛋白如 P-糖蛋白和多药耐药相关蛋白 (MRP) 限制肠道药物转运。为了克服肠内药物吸收的这一限制，已经提出了盖仑靶向方法，用于在肠道区段中进行位点特异性腔内药物释放，其中相应吸收限制转运蛋白的表达是最小的。因此，我们在 10 名健康受试者中系统地研究了多药耐药基因 1 (MDR1) 和 MRP1-5 的表达。活检取自胃肠道的不同部分（十二指肠和回肠末端，以及升结肠、横结肠、降结肠和乙状结肠）。通过定量实时PCR (TaqMan)研究基因表达。在人类肠道的研究部分中，MRP3 似乎是表达最丰富的转运蛋白，但回肠末端除外，MDR1 在回肠末端的表达量最高。十二指肠转运蛋白基因表达量排序为MRP3≫MDR1>MRP2>MRP5>MRP4>MRP1。在回肠末端，排序顺序如下：MDR1 > MRP3 ≫ MRP1 ≈ MRP5 ≈ MRP4 > MRP2。在结肠的所有节段（升结肠、横结肠、降结肠和乙状结肠）中，转运蛋白基因表达呈现以下顺序：MRP3≫MDR1>MRP4≫MRP5>MRP1≫MRP2。我们首次展示了人类胃肠道中 MDR1 和 MRP mRNA 的系统位点特异性表达。所有转运蛋白从十二指肠到乙状结肠的表达水平均发生变化。 MRP2 的变化最显着，在小肠中表达量较高，而在结肠段中几乎没有表达。这些知识可能有助于开发新的肠内药物递送靶向策略。
Efflux transporters such as P-glycoprotein and multidrug resistance-associated proteins (MRPs) in the intestinal wall restrict intestinal drug transport. To overcome this limitation for enteral drug absorption, galenical targeting approaches have been proposed for site-specific luminal drug release in segments of the gut, where expression of the respective absorption-limiting transporter is minimal. Therefore, expression of multidrug resistance gene 1 (MDR1) and MRP1-5 was systematically investigated in 10 healthy subjects. Biopsies were taken from different segments of the gastrointestinal tract (from duodenum and terminal ileum, as well as ascending, transverse, descending, and sigmoid colon). Gene expression was investigated by quantitative real-time PCR (TaqMan). MRP3 appeared to be the most abundantly expressed transporter in investigated parts of the human intestine, except for the terminal ileum, where MDR1 showed the highest expression. The ranking of transporter gene expression in the duodenum was MRP3 ≫ MDR1 > MRP2 > MRP5 > MRP4 > MRP1. In the terminal ileum, the ranking order was as follows: MDR1 > MRP3 ≫ MRP1 ≈ MRP5 ≈ MRP4 > MRP2. In all segments of the colon (ascending, transverse, descending, and sigmoid colon), the transporter gene expression showed the following order: MRP3 ≫ MDR1 > MRP4 ≈ MRP5 > MRP1 ≫ MRP2. We have shown, for the first time, systematic site-specific expression of MDR1 and MRP mRNA along the gastrointestinal tract in humans. All transporters showed alterations in their expression levels from the duodenum to sigmoid colon. The most pronounced changes were observed for MRP2, with high levels in the small intestine and hardly any expression in colonic segments. This knowledge may be useful to develop new targeting strategies for enteral drug delivery.