School of Life Science, Beijing Institute of Technology, No.5 Zhongguancun South Street, Haidian District, Beijing 100081, China.
Int J Mol Sci. 2023 Mar 12;24(6):5438. doi: 10.3390/ijms24065438.
The drug efflux transporter permeability glycoprotein (P-gp) plays an important role in oral drug absorption and distribution. Under microgravity (MG), the changes in P-gp efflux function may alter the efficacy of oral drugs or lead to unexpected effects. Oral drugs are currently used to protect and treat multisystem physiological damage caused by MG; whether P-gp efflux function changes under MG remains unclear. This study aimed to investigate the alteration of P-gp efflux function, expression, and potential signaling pathway in rats and cells under different simulated MG (SMG) duration. The altered P-gp efflux function was verified by the in vivo intestinal perfusion and the brain distribution of P-gp substrate drugs. Results showed that the efflux function of P-gp was inhibited in the 7 and 21 day SMG-treated rat intestine and brain and 72 h SMG-treated human colon adenocarcinoma cells and human cerebral microvascular endothelial cells. P-gp protein and gene expression levels were continually down-regulated in rat intestine and up-regulated in rat brain by SMG. P-gp expression was regulated by the Wnt/β-catenin signaling pathway under SMG, verified by a pathway-specific agonist and inhibitor. The elevated intestinal absorption and brain distribution of acetaminophen levels also confirmed the inhibited P-gp efflux function in rat intestine and brain under SMG. This study revealed that SMG alters the efflux function of P-gp and regulates the Wnt/β-catenin signaling pathway in the intestine and the brain. These findings may be helpful in guiding the use of P-gp substrate drugs during spaceflight.
药物外排转运体渗透性糖蛋白（P-gp）在口服药物吸收和分布中发挥重要作用。在微重力（MG）下，P-gp 外排功能的变化可能会改变口服药物的疗效或导致意外的效果。目前，口服药物用于保护和治疗 MG 引起的多系统生理损伤；MG 下 P-gp 外排功能是否发生变化尚不清楚。本研究旨在探讨不同模拟 MG（SMG）持续时间下大鼠和细胞中 P-gp 外排功能、表达和潜在信号通路的变化。通过体内肠灌注和 P-gp 底物药物的脑分布来验证改变的 P-gp 外排功能。结果表明，在 7 天和 21 天 SMG 处理的大鼠肠和脑以及 72 小时 SMG 处理的人结肠腺癌细胞和人脑血管内皮细胞中，P-gp 的外排功能受到抑制。SMG 持续下调大鼠肠 P-gp 蛋白和基因表达，上调大鼠脑 P-gp 表达。SMG 下调大鼠肠 P-gp 表达受 Wnt/β-catenin 信号通路调节，该通路通过特定的激动剂和抑制剂得到验证。SMG 还证实了对乙酰氨基酚水平在大鼠肠和脑中的吸收增加和分布增加，这也证实了 P-gp 外排功能在 SMG 下受到抑制。本研究表明，SMG 改变了 P-gp 的外排功能，并调节了肠和脑中的 Wnt/β-catenin 信号通路。这些发现可能有助于指导太空飞行中 P-gp 底物药物的使用。
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