Noninvasive and quantitative assessment of the function of multidrug resistance-associated protein 1 in the living brain
Noninvasive and quantitative assessment of the function of multidrug resistance-associated protein 1 in the living brain
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DOI：
10.1038/jcbfm.2008.135
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发表时间：
2009-03-01
影响因子：
6.3
通讯作者：
Irie, Toshiaki
中科院分区：
文献类型：
--
作者：
Okamura, Toshimitsu;Kikuchi, Tatsuya;Irie, Toshiaki
多药耐药相关蛋白 1 (MRP1) 通过将异生物质和内源代谢物泵出大脑来发挥防御机制。目前用于研究脑到血流出的技术在其侵入性或定性评估方面具有显着的局限性。在这里，我们描述了一种体内方法，它克服了使用正电子发射断层扫描 (PET) 和 PET 探针评估 MRP1 功能的这些限制。 6-Bromo-7[C-11] 甲基嘌呤被设计为在静脉注射后容易进入大脑，并在原位有效转化为其谷胱甘肽缀合物（MRP1 底物）。动态PET扫描提供了小鼠注射6-溴-7-[C-11]甲基嘌呤后的大脑时间-活动曲线。动力学估计底物的流出速率为1.4 h(-1)，精度较高。此外，与野生型小鼠相比，Mrp1基因敲除导致流出率降低约90%。总之，我们的方法可以对活体大脑中的 MRP1 功能进行无创和定量评估。
Multidrug resistance-associated protein 1 (MRP1) acts as a defense mechanism by pumping xenobiotics and endogenous metabolites out of the brain. The currently available techniques for studying brain-to-blood efflux have significant limitations related to either their invasiveness or the qualitative assessment. Here, we describe an in vivo method, which overcomes these limitations for assessing MRP1 function, using positron emission tomography (PET) and a PET probe. 6-Bromo-7[C-11] methylpurine was designed to readily enter the brain after intravenous administration and to be efficiently converted to its glutathione conjugate (MRP1 substrate) in situ. Dynamic PET scan provided the brain time-activity curve after injection of 6-bromo-7-[C-11] methylpurine into mice. The efflux rate of the substrate was kinetically estimated to be 1.4 h(-1) with high precision. Moreover, knockout of Mrp1 gene caused approximately a 90% reduction of the efflux rate, compared with wildtype mice. In conclusion, our method allows noninvasive and quantitative assessment for MRP1 function in the living brain.