Sun H, Johnson D R, Finch R A, Sartorelli A C, Miller D W, Elmquist W F
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Biochem Biophys Res Commun. 2001 Jun 22;284(4):863-9. doi: 10.1006/bbrc.2001.5062.
The multidrug resistant-associated protein 1 (MRP1) is a membrane-bound transport protein that is involved in the efflux of organic anions and has been implicated in multidrug resistance in cancer. MRP1 has also been reported to be ubiquitously expressed in normal tissues, including the brain. The presence of functional organic anion transporters in the blood-brain and blood-CSF barriers that influence the distribution of various compounds to the brain has long been known. The purpose of this study was to examine the role of MRP1 in the brain distribution of a model organic anion, fluorescein. The substrate specificity of MRP1 for fluorescein was initially determined by examining the accumulation of fluorescein in MDCKII MRP1-transfected cells. The distribution of fluorescein in the brain was then examined in wild-type and mrp1 gene knockout mice. The results show that in MDCKII MRP1-transfected cells, the accumulation of fluorescein was significantly lower (about 40% lower) than that in wild-type MDCKII cells. MRP1 inhibitors such as probenecid, MK-571, and LY402913 enhanced fluorescein accumulation in MDCKII MRP1-transfected cells to a greater extent than in wild-type MDCKII cells. In an in vivo study, after intravenous injection of fluorescein, the fluorescein brain-to-plasma concentration ratio in mrp1 knockout mice was not significantly different than that in wild-type mice. However, when probenecid was co-administered with fluorescein in wild-type mice, the fluorescein brain-to-plasma ratio was significantly increased (1.5-fold). These findings suggest that fluorescein is a substrate for MRP1. Furthermore, the in vivo study also suggests that MRP1 has a limited role in the transport and distribution of fluorescein in the brain. Therefore, other organic anion transport proteins, including the various isoforms of the MRP family, may be responsible for the accumulation and transport of organic anions in the brain.
多药耐药相关蛋白1（MRP1）是一种膜结合转运蛋白，参与有机阴离子的外排，并与癌症的多药耐药有关。据报道，MRP1在包括脑在内的正常组织中普遍表达。影响各种化合物向脑内分布的血脑屏障和血脑脊液屏障中功能性有机阴离子转运体的存在早已为人所知。本研究的目的是研究MRP1在模型有机阴离子荧光素脑内分布中的作用。MRP1对荧光素的底物特异性最初是通过检测荧光素在MDCKII MRP1转染细胞中的积累来确定的。然后在野生型和mrp1基因敲除小鼠中检测荧光素在脑内的分布。结果表明，在MDCKII MRP1转染细胞中，荧光素的积累明显低于野生型MDCKII细胞（约低40%）。丙磺舒、MK-571和LY402913等MRP1抑制剂比野生型MDCKII细胞更能增强荧光素在MDCKII MRP1转染细胞中的积累。在一项体内研究中，静脉注射荧光素后，mrp1基因敲除小鼠的荧光素脑血浆浓度比与野生型小鼠无显著差异。然而，当丙磺舒与荧光素在野生型小鼠中共同给药时，荧光素脑血浆比显著增加（1.5倍）。这些发现表明荧光素是MRP1的底物。此外，体内研究还表明，MRP1在荧光素在脑内的转运和分布中作用有限。因此，包括MRP家族各种同工型在内的其他有机阴离子转运蛋白可能负责有机阴离子在脑内的积累和转运。
