技术文库>资源分类>行业论文>医学论文> A Mochizuki, Tatsuki %A Mizuno, Tadahaya %A Kurosawa, Toshiki %A Yamaguchi, Tomoko %A Higuchi, Kei Tega, Yuma %A Nozaki, Yoshitane %A Kawabata, Kenji %A Deguchi, Yoshiharu %A Kusuhara, Hiroyuki T Functional Investigation of Solute Carrier Family 35, Member F2,三种细胞模型的灵长类动物血脑屏障% D 2021% R 10.1124 / dmd.120.000115 % J药物代谢和处理X % P 3-11 % V 49% N 1%理解药物运输的机制跨越雷竞技客服血脑屏障(BBB)是一个重要的问题在中枢神经系统调节药物的药物代谢动力学情况。在本研究中,我们重点研究了溶质载体家族35成员F2 (SLC35F2),其mRNA在BBB中高度表达。SLC35F2蛋白富集于小鼠和猴的脑毛细血管中,相对于脑均质,且仅定位于MDCKII细胞和人诱导多能干细胞(hipps -BMECs)分化的脑微血管内皮细胞(BMECs)的顶端膜上。利用其底物YM155评估SLC35F2的活性,药理学实验发现了SLC35F2抑制剂,如法莫替丁(半最大抑制浓度,160 μM)。法莫替丁或下调SLC35F2可降低永生化人BMECs(人大脑微血管内皮细胞/D3细胞)对YM155的摄取。此外,法莫替丁显著抑制了YM155在原代培养猴BMECs和hiPS-BMECs中的顶端(A)-基底(B)运输。至关重要的是,SLC35F2敲除减少了a - b运输和YM155在hiPS-BMECs细胞内的积累。相比之下,在使用原位脑灌注技术的研究中,尽管YM155是小鼠Slc35f2的底物,Slc35f2的缺失和法莫替丁都没有减少YM155的脑吸收。有机阴离子转运多肽(OATP) 1A4抑制剂氯沙坦和柚皮苷对YM155的吸收显著降低。 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. %U //www.1zgc.com/content/dmd/49/1/3.full.pdf