To develop a novel intestinal drug absorption system using intestinal epithelial cells derived from human induced pluripotent stem (iPS) cells, the cells must possess sufficient pharmacokinetic functions. However, the CYP3A4/5 activities of human iPS cell-derived small intestinal epithelial cells prepared using conventional differentiation methods is low. Further, studies of the CYP3A4/5 activities of human iPS-derived and primary small intestinal cells are not available. To fill this gap in our knowledge, here we used forskolin to develop a new differentiation protocol that activates adenosine monophosphate signaling. mRNA expressions of human iPS cell-derived small intestinal epithelial cells, such as small intestine markers, drug-metabolizing enzymes, and drug transporters, were comparable to or greater than those of the adult small intestine. The activities of CYP3A4/5 in the differentiated cells were equal to those of human primary small intestinal cells. The differentiated cells had P-glycoprotein and PEPT1 activities equivalent to those of Caco-2 cells. Differentiated cells were superior to Caco-2 cells for predicting the membrane permeability of drugs that were absorbed through a paracellular pathway and via drug transporters. In summary, here we produced human iPS cell-derived small intestinal epithelial cells with CYP3A4/5 activities equivalent to those of human primary small intestinal cells.

中文翻译：

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人诱导多能干细胞来源的小肠上皮细胞的药代动力学功能

为了使用源自人类诱导多能干 (iPS) 细胞的肠上皮细胞开发一种新型肠道药物吸收系统，这些细胞必须具有足够的药代动力学功能。然而，使用常规分化方法制备的人 iPS 细胞衍生的小肠上皮细胞的 CYP3A4/5 活性较低。此外，还没有关于人 iPS 衍生和原代小肠细胞的 CYP3A4/5 活性的研究。为了填补我们知识中的这一空白，我们在这里使用毛喉素来开发一种新的分化方案，该方案可以激活单磷酸腺苷信号传导。人 iPS 细胞衍生的小肠上皮细胞的 mRNA 表达，如小肠标志物、药物代谢酶和药物转运蛋白，与成人小肠相当或更高。分化细胞中CYP3A4/5的活性与人原代小肠细胞的活性相同。分化的细胞具有与 Caco-2 细胞相当的 P-糖蛋白和 PEPT1 活性。在预测通过细胞旁途径和药物转运蛋白吸收的药物的膜通透性方面，分化的细胞优于 Caco-2 细胞。总之，我们在这里生产了人 iPS 细胞衍生的小肠上皮细胞，其 CYP3A4/5 活性相当于人原代小肠细胞的活性。在预测通过细胞旁途径和药物转运蛋白吸收的药物的膜通透性方面，分化的细胞优于 Caco-2 细胞。总之，我们在这里生产了人 iPS 细胞衍生的小肠上皮细胞，其 CYP3A4/5 活性相当于人原代小肠细胞的活性。在预测通过细胞旁途径和药物转运蛋白吸收的药物的膜通透性方面，分化的细胞优于 Caco-2 细胞。总之，我们在这里生产了人 iPS 细胞衍生的小肠上皮细胞，其 CYP3A4/5 活性相当于人原代小肠细胞的活性。