Gao B, Hagenbuch B, Kullak-Ublick G A, Benke D, Aguzzi A, Meier P J
Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital Zurich, Zurich, Switzerland.
J Pharmacol Exp Ther. 2000 Jul;294(1):73-9.
Organic anion-transporting polypeptides (Oatps) are a rapidly growing gene family of polyspecific membrane transporters. In rat brain, Oatp1 (gene symbol Slc21a1) and Oatp2 (Slc21a5) are localized at the apical and basolateral domains, respectively, of the choroid plexus epithelium. Furthermore, Oatp2 is strongly expressed at the rat blood-brain barrier (BBB). This study localizes the human OATP (now called OATP-A; SLC21A3) at the BBB in humans. Furthermore, with the Xenopus laevis oocyte system the delta-opioid receptor agonists [D-penicillamine(2,5)]enkephalin (DPDPE) and deltorphin II were identified as new transport substrates of OATP-A. This OATP-A-mediated DPDPE and deltorphin II transport exhibited apparent K(m) values of approximately 202 and 330 microM, respectively, and OATP-A-mediated deltorphin II transport was inhibited by the mu-opioid receptor agonist Tyr-D-Ala-Gly-N-methyl-Phe-glycinol, the endogenous peptide Leu-enkephalin, and the opiate antagonists naloxone and naltrindole. DPDPE also was transported by rat Oatp1 (K(m) approximately 48 microM) and Oatp2 (K(m) approximately 19 microM), whereas deltorphin II was only transported by Oatp1 (K(m) approximately 137 microM). These results demonstrate that OATP-A can mediate transport of the analgesic opioid peptides DPDPE and deltorphin II across the human BBB. Furthermore, because rat Oatp1 and Oatp2 exhibit similar but not identical transport activities as OATP-A, the results generally indicate that members of the Oatp/OATP gene family of membrane transporters play an important role in carrier-mediated transport of opioid peptides across the BBB and blood-cerebrospinal fluid barrier of the mammalian brain.
有机阴离子转运多肽（Oatps）是一个迅速发展的多特异性膜转运蛋白基因家族。在大鼠脑中，Oatp1（基因符号Slc21a1）和Oatp2（Slc21a5）分别定位于脉络丛上皮的顶端和基底外侧结构域。此外，Oatp2在大鼠血脑屏障（BBB）中强烈表达。本研究将人类OATP（现称为OATP - A；SLC21A3）定位于人类血脑屏障。此外，利用非洲爪蟾卵母细胞系统，δ - 阿片受体激动剂[D - 青霉胺（2,5）]脑啡肽（DPDPE）和强啡肽II被鉴定为OATP - A的新转运底物。这种由OATP - A介导的DPDPE和强啡肽II转运的表观K(m)值分别约为202和330微摩尔，并且由OATP - A介导的强啡肽II转运受到μ - 阿片受体激动剂酪氨酸 - D - 丙氨酸 - 甘氨酸 - N - 甲基 - 苯丙氨酸 - 甘氨醇、内源性肽亮氨酸脑啡肽以及阿片拮抗剂纳洛酮和纳曲吲哚的抑制。DPDPE也可被大鼠Oatp1（K(m)约为48微摩尔）和Oatp2（K(m)约为19微摩尔）转运，而强啡肽II仅被Oatp1（K(m)约为137微摩尔）转运。这些结果表明，OATP - A可介导镇痛阿片肽DPDPE和强啡肽II跨越人类血脑屏障的转运。此外，由于大鼠Oatp1和Oatp2表现出与OATP - A相似但不完全相同的转运活性，结果总体表明，Oatp/OATP基因家族的膜转运蛋白成员在阿片肽通过哺乳动物脑的血脑屏障和血脑脊液屏障的载体介导转运中起重要作用。
