Involvement of Multidrug Resistance Associated Protein 1 (Mrp1) in the Efflux Transport of 17β Estradiol-D-17β-Glucuronide (E217βG) Across the Blood-Brain Barrier
Involvement of Multidrug Resistance Associated Protein 1 (Mrp1) in the Efflux Transport of 17β Estradiol-D-17β-Glucuronide (E217βG) Across the Blood-Brain Barrier
复制标题
多药耐药相关蛋白 1 (Mrp1) 参与 17β 雌二醇-D-17β-葡萄糖苷酸 (E217βG) 穿过血脑屏障的外流转运
作者：
D. Sugiyama;H. Kusuhara;Yong;Y. Sugiyama
摘要目的：本研究的目的是研究多药耐药相关蛋白1（Mrp 1）、Mrp 2和P-糖蛋白（Mdr 1a）在17β-雌二醇-D-17β-葡萄糖醛酸苷（E217βG）跨血脑屏障（BBB）外排转运中的作用。
方法.采用RT-PCR和Western blot检测Mrp 1和Mrp 2在血脑屏障的表达。在脑内显微注射后，比较了野生型、Mdr 1a/Mdr 1b和Mrp 1敲除小鼠以及正常和Mrp 2缺陷突变大鼠[分别为Sprague-Dawley和Sprague-Dawai高胆红素血症大鼠（EHBR）]脑中[3 H]E217βG剩余放射性的时间曲线。
结果RT-PCR和Western blot分析显示Mrp 1在离体大鼠脑毛细血管中表达;然而，RT-PCR无法检测到任何Mrp 2的表达。在野生型小鼠中观察到E217βG的显著消除，速率常数为0.007 min−1，在Mrp 1敲除小鼠中显著降低（0.004 min−1）。相比之下，野生型和Mdr 1a/Mdr 1b基因敲除小鼠以及正常和EHBR小鼠脑中E217βG的外排没有差异。野生型和Mrp 1基因敲除小鼠制备的脑切片中E217βG的蓄积无显著差异。
结论Mrp 1（而非Mrp 2）参与E217βG在血脑屏障的排泄，并通过将结合代谢物挤入血液提供屏障功能。
AbstractPurpose.The purpose of present study is to investigate the involvement of multidrug resistance-associated protein 1 (Mrp1), Mrp2, and P-glycoprotein (Mdr1a) in the efflux transport of 17β—estradiol-D-17β-glucuronide (E217βG) across the blood—brain barrier (BBB).
Methods. The expression of Mrp1 and Mrp2 at the BBB was investigated by RT-PCR and Western blot analyses. The time profiles of the remaining radioactivity of [3H]E217βG in the brain were compared in wild-type, Mdr1a/Mdr1b and Mrp1 knockout mice and normal and Mrp2-deficient mutant rats [Sprague-Dawley and Eisai hyperbilirubinemic rats (EHBR), respectively] after intracerebral microinjection.
Results. RT-PCR and Western blot analyses revealed the expression of Mrp1 in isolated rat brain capillary; however, RT-PCR was unable to detect any expression of Mrp2. Significant elimination of E217βG was observed in wild-type mice at a rate constant of 0.007 min−1, which was significantly decreased (0.004 min−1) in Mrp1 knockout mice. In contrast, there was no difference in the efflux of E217βG from the brain in wild-type and Mdr1a/Mdr1b knockout mice and in normal and EHBR. No significant difference was observed in the accumulation of E217βG by brain slices prepared from wild-type and Mrp1 knockout mice.
Conclusion. Mrp1, but not Mrp2, is involved in the excretion of E217βG at the BBB and provides a barrier function by extruding conjugated metabolites into the blood.
DOI：
10.1073/pnas.96.7.3900
发表时间：
1999-03-30
影响因子：
11.1
作者：
Rao, VV;Dahlheimer, JL;Piwnica-Worms, D
通讯作者：
Piwnica-Worms, D
影响因子：
3.6
作者：
Li, LQ;Meier, PJ;Ballatori, N
通讯作者：
Ballatori, N
MDCKII-MRP1 转染细胞和 mrp1 敲除小鼠中荧光素的转运。
DOI：
10.1006/bbrc.2001.5062
发表时间：
2001
期刊：
Biochemical and biophysical research communications.
影响因子：
--
作者：
Sun,H;Johnson,DR;Finch,RA;Sartorelli,AC;Miller,DW;Elmquist,WF
通讯作者：
Elmquist,WF