TY -的T1 -溶质载体的功能调查家庭35岁成员F2,三种细胞模型的灵长类动物血脑屏障JF -药物代谢和性格乔-药物金属底座Dispos SP - 3 LP - 11 - 10.1124 / dmd.120.000115六世- 49 - 1 AU Mochizuki Tatsuki盟——雷竞技客服美津浓,Tadahaya盟,黑泽明——非盟-山口,Tomoko AU - Higuchi, Kei AU - Tega, Yuma AU - Nozaki, yoshtanan AU - Kawabata, Kenji AU - Deguchi, Yoshiharu AU - Kusuhara,了解药物通过血脑屏障(BBB)的转运机制是调节中枢神经系统药物代谢动力学的一个重要问题。在本研究中,我们聚焦于溶质载体家族35,成员F2 (SLC35F2),其mRNA在血脑屏障中高表达。相对于脑匀浆,SLC35F2蛋白在小鼠和猴子的分离脑毛细血管中富集,并只定位于从人诱导多能干细胞(hiPS-BMECs)分化出来的MDCKII细胞和脑微血管内皮细胞(BMECs)的顶膜上。使用底物YM155评估SLC35F2的活性,药理实验发现SLC35F2抑制剂,如法莫替丁(半最大抑制浓度,160 μM)。法莫替丁或SLC35F2基因敲低可降低永化人BMECs(人大脑微血管内皮细胞/D3细胞)中YM155的摄取。此外,法莫替丁显著抑制了原代培养的猴子BMECs和hip -BMECs中YM155的根尖(A)到基底(B)运输。关键是,SLC35F2敲除减少了YM155在hips - bmec中的A-to-B转运和胞内积累。相比之下,在使用原位脑灌注技术的研究中,Slc35f2的缺失和法莫替丁都没有减少YM155的脑摄取,即使YM155是小鼠Slc35f2的底物。 YM155 uptake was decreased significantly by losartan and naringin, inhibitors for the organic anion transporting polypeptide (OATP) 1A4. These findings suggest SLC35F2 is a functional transporter in various cellular models of the primate BBB that delivers its substrates to the brain and that its relative importance in the BBB is modified by differences in the expression of OATPs between primates and rodents.SIGNIFICANCE STATEMENT This study demonstrated that SLC35F2 is a functional drug influx transporter in three different cellular models of the primate blood-brain barrier (i.e., human cerebral microvascular endothelial cell/D3 cells, primary cultured monkey BMECs, and human induced pluripotent stem-BMECs) but has limited roles in mouse brain. SLC35F2 facilitates apical-to-basal transport across the tight cell monolayer. These findings will contribute to the development of improved strategies for targeting drugs to the central nervous system. ER -