Exposure to High-Altitude Environment Is Associated with Drug Transporters Change: microRNA-873-5p-Mediated Alteration of Function and Expression Levels of Drug Transporters under Hypoxia
Exposure to High-Altitude Environment Is Associated with Drug Transporters Change: microRNA-873-5p-Mediated Alteration of Function and Expression Levels of Drug Transporters under Hypoxia
复制标题
暴露于高海拔环境与药物转运蛋白的变化有关：缺氧条件下 miR-873-5p 介导的药物转运蛋白的功能和表达水平的改变。
DOI：
10.1124/dmd.121.000681
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发表时间：
2022-02-01
影响因子：
3.9
通讯作者：
Li, Xiangyang
中科院分区：
文献类型：
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作者：
Duan, Yabin;Bai, Xue;Li, Xiangyang
缺氧是高原环境的主要特征，影响药物代谢。然而，到目前为止，microRNA（miRNA）参与高原缺氧条件下药物代谢和转运体调控的机制尚不清楚。本研究旨在探讨多药耐药蛋白1（MDR 1）、多药耐药相关蛋白2（MRP 2）、乳腺癌耐药蛋白（BCRP）、肽转运蛋白1（PEPT 1）和有机阴离子转运多肽2B 1（OATP 2B 1）在高原低氧大鼠和结肠癌细胞（Caco-2）中的功能和表达水平。通过Western blot和qPCR测定MDR 1、MRP 2、BCRP、PEPT 1和OATP 2B 1的蛋白和mRNA表达。通过测定高原低氧大鼠肠道有效通透性和特异性底物吸收速率常数，评价MDR 1、MRP 2、BCRP、PEPT 1和OATP 2B 1的功能，并在Caco-2细胞上进行摄取和转运研究。为了筛选与缺氧相关的miRNA，通过高通量测序检测Caco-2细胞。我们观察到miR-873- 5 p在缺氧条件下显著降低，并且可能靶向MDR 1和PXR。为了阐明miR-873- 5 p是否在缺氧条件下调节MDR 1和PXR，用miR-873- 5 p的模拟物或抑制剂和阴性对照（NC）转染Caco-2细胞。缺氧后大鼠和Caco-2细胞中药物转运蛋白的功能和表达均明显增强。我们发现miR-873- 5 p调控MDR 1和PXR的表达。本研究表明，在低氧条件下，miRNA可能影响药物转运蛋白和核受体的表达。本研究探讨了高原缺氧诱导的microRNA（miRNAs）的改变是否可以转化为药物转运蛋白的改变。在低氧环境中表现出显著变化的miRNAs中，miR-873- 5 p可以作用于多药耐药蛋白1（MDR 1）基因;然而，有多种miRNAs可以作用于胆甾烷X受体（PXR）。这项研究推测miRNA-PXR-药物转运轴在药物的生理处置中是重要的。
Hypoxia is the main characteristic of a high-altitude environment, affecting drug metabolism. However, so far, the mechanism of microRNA (miRNA) involved in the regulation of drug metabolism and transporters under high-altitude hypoxia is still unclear. This study aims to investigate the functions and expression levels of multidrug resistance protein 1 (MDR1), multidrug resistanceassociated protein 2 (MRP2), breast cancer resistance protein (BCRP), peptide transport 1 (PEPT1), and organic anion-transporting polypeptides 2B1 (OATP2B1) in rats and colon cancer (Caco-2) cells after exposure to high-altitude hypoxia. The protein and mRNA expression of MDR1, MRP2, BCRP, PEPT1, and OATP2B1 were determined by Western blot and qPCR. The functions of MDR1, MRP2, BCRP, PEPT1, and OATP2B1 were evaluated by determining the effective intestinal permeability and absorption rate constants of their specific substrates in rats under high-altitude hypoxia, and uptake and transport studies were performed on Caco-2 cells. To screen the miRNA associated with hypoxia, Caco-2 cells were examined by high throughput sequencing. We observed that the miR-873-5p was significantly decreased under hypoxia and might target MDR1 and pregnane X receptor (PXR). To clarify whether miR-873-5p regulates MDR1 and PXR under hypoxia, Caco-2 cells were transfected with mimics or inhibitors of miR-873-5p and negative control (NC). The function and expression of drug transporters were found to be significantly increased in rats and Caco-2 cells under hypoxia. We found that miR-873-5p regulated MDR1 and PXR expression. Herein, it is shown that miRNA may affect the expression of drug transporter and nuclear receptor under hypoxia. SIGNIFICANCE STATEMENT This study explores if alterations to the microRNAs (miRNAs), induced by high-altitude hypoxia, can be translated to altered drug transporters. Among miRNAs, which show a significant change in a hypoxic environment, miR-873-5p can act on the multidrug resistance protein 1 (MDR1) gene; however, there are multiple miRNAs that can act on the pregnane X receptor (PXR). This study speculates that the miRNA-PXR-drug transporter axis is important in the physiological disposition of drugs.