Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
Department of Pharmacy, Hokkaido University Hospital, Sapporo 060-8648, Japan.
Drug Metab Pharmacokinet. 2017 Apr;32(2):157-163. doi: 10.1016/j.dmpk.2016.12.003. Epub 2016 Dec 27.
Organic anion transporting polypeptide 2B1 (OATP2B1) is the major uptake transporter in the intestine, and transports various clinically used therapeutic agents. Insulin acts through the insulin receptor in targeted cells, and Rab8A is one of the insulin signaling pathways. The small intestine in humans also expresses insulin receptor and Rab8A. It has been reported that insulin stimulates peptide transporter 1 (PEPT1) expression at the apical membrane and increases uptake of PEPT1 substrates in small intestine epithelial model cells (Caco-2 cells). However, the effect of insulin on OATP2B1 in the small intestine has not been fully investigated. We found that Rab8A was associated with OATP2B1-mediated estrone-3-sulfate (E3S) uptake. Insulin stimulated the uptake of E3S by Caco-2 cells and the enhancement was sustained for 120 min. The Vmax value of E3S uptake significantly increased upon insulin exposure. Caco-2 cells treated with insulin showed increased OATP2B1 expression at the cell surface. The apical-to-basal transport of E3S was also increased by insulin. The increase of E3S transport was inhibited by the cold condition (4 °C) or the OATP2B1 inhibitor, taurocholate. These results indicate that insulin acts on the small intestine to increase OATP2B1-mediated absorption.
有机阴离子转运多肽 2B1（OATP2B1）是肠道中的主要摄取转运体，可转运多种临床应用的治疗药物。胰岛素通过靶细胞中的胰岛素受体发挥作用，Rab8A 是胰岛素信号通路之一。人类的小肠也表达胰岛素受体和 Rab8A。有报道称，胰岛素可刺激肠腔侧膜上的肽转运蛋白 1（PEPT1）的表达，增加小肠上皮模型细胞（Caco-2 细胞）中 PEPT1 底物的摄取。然而，胰岛素对小肠中 OATP2B1 的作用尚未得到充分研究。我们发现 Rab8A 与 OATP2B1 介导的雌酮-3-硫酸盐（E3S）摄取有关。胰岛素可刺激 Caco-2 细胞摄取 E3S，增强作用可持续 120min。胰岛素暴露后 E3S 摄取的 Vmax 值显著增加。用胰岛素处理的 Caco-2 细胞表面 OATP2B1 表达增加。胰岛素还增加了 E3S 的顶侧到基底转运。E3S 转运的增加被冷处理（4°C）或 OATP2B1 抑制剂牛磺胆酸钠抑制。这些结果表明，胰岛素作用于小肠以增加 OATP2B1 介导的吸收。
