A Novel Model of P-Glycoprotein Inhibitor Screening Using Human Small Intestinal Organoids
A Novel Model of P-Glycoprotein Inhibitor Screening Using Human Small Intestinal Organoids
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DOI：
10.1111/bcpt.12680
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发表时间：
2017-03-01
影响因子：
3.1
通讯作者：
Wang, Xin
中科院分区：
文献类型：
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作者：
Zhao, Junfang;Zeng, Zhiyang;Wang, Xin
P-糖蛋白（P-gp）是肠道内重要的外排转运蛋白，调节口服药物的生物利用度。为了开发一种体外模型，该模型优选地模拟人肠道的生理微环境，我们采用了来自人正常小肠上皮的三维（3D）培养的类器官。随着培养时间的延长，肠腺可有效形成囊状类器官结构。此外，ABCB 1的生理表达在mRNA和蛋白质水平上检测培养的类器官。罗丹明123（Rh 123）是P-gp的典型底物，其被主动转运穿过3D类器官并在腔空间中积累。维拉帕米和米托坦也能抑制这种转运过程。综上所述，上述基于人小肠3D类器官的模型适合于模拟小肠上皮，并可用作新型体外模型，特别是用于P-gp抑制剂筛选。
P-glycoprotein (P-gp), an important efflux transporter in intestine, regulates the bioavailability of orally taken drugs. To develop an in vitro model that preferably mimics the physiological microenvironment of human intestine, we employed the three-dimensionally (3D) cultured organoids from human normal small intestinal epithelium. It was observed that the intestinal crypts could efficiently form cystic organoid structure with the extension of culture time. Furthermore, the physiological expression of ABCB1 was detected at both mRNA and protein levels in cultured organoids. Rhodamine 123 (Rh123), a typical substrate of P-gp, was actively transported across 3D organoids and accumulated in the luminal space. This transport process was also inhibited by verapamil and mitotane. In summary, the above-mentioned model based on human small intestinal 3D organoids is suitable to imitate the small intestinal epithelium and could be used as a novel in vitro model especially for P-gp inhibitor screening.