RT期刊文章SR电子T1溶质载体家族35,成员F2,在三种细胞模型的灵长类动物血脑屏障JF药物代谢和处置jo药物代谢Dispos Prodos FD美国药理学和实验治疗方法sp 3 op 11 do雷竞技客服10.1124 / DMD.120.000115 VO 49是1 A1 Mochizuki,Tatsuki A1 Kurosawa,Toshiki A1 yamaguchi,Tohoki A1 Higuchi,Kei A1 Tega,Yuma A1 Nozaki,Yoshitane A1 Kawabata,Kenji A1 Deguchi,Yoshiharu A1 Kusuhara,Hiroyuki Yr2021 ul //www.1zgc.com/content/49/1/3.Abstract ab了解血脑屏障(BBB)对血脑屏障的药物运输机制是调节中央药物药代动力学的重要问题神经系统。在该研究中,我们专注于溶质载体家族35,构件F2(SLC35F2),其MRNA在BBB中高度表达。相对于脑匀浆的分离的小鼠和猴脑毛细管中富集SLC35F2蛋白质,并专注于从人诱导的多能干细胞(HIPS-BMEC)分化的MDCKII细胞和脑微血管内皮细胞(BMEC)的顶端膜。使用其基材,YM155和药理学实验评估SLC35F2活性,显示出SLC35F2抑制剂,例如Facotidine(半最大抑制浓度,160μm)。Famotidine或SLC35F2在永生化的人BMEC(人脑微血管内皮细胞/ D3细胞)中降低了YM155的摄取。此外,Famotidine显着抑制了原发性培养的猴BMECs和HIPS-BMEC中YM155的顶端(A)-To - 基础(B)转运。至关重要的是,SLC35F2敲除降低了臀部BMEC中YM155的A-TO-B传输和细胞内积聚。 By contrast, in studies using an in situ brain perfusion technique, neither deletion of Slc35f2 nor famotidine reduced brain uptake of YM155, even though YM155 is a substrate of mouse SLC35F2. 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.