Imaging of Activity of Multidrug Resistance-Associated Protein 1 in the Lungs
Imaging of Activity of Multidrug Resistance-Associated Protein 1 in the Lungs
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DOI：
10.1165/rcmb.2012-0275ma
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发表时间：
2013-09-01
影响因子：
6.4
通讯作者：
Zhang, Ming-Rong
中科院分区：
文献类型：
--
作者：
Okamura, Toshimitsu;Kikuchi, Tatsuya;Zhang, Ming-Rong
多药耐药相关蛋白1（MRP 1）可跨细胞膜转运各种外源性物质和代谢产物，其表达的改变与某些肺部疾病有关。本研究旨在检查使用6-溴-7-[C-11]甲基嘌呤（[C-11]1）成像肺MRP 1活性的可行性。在野生型、Mrp 1敲除（KO）和P-糖蛋白/乳腺癌耐药蛋白（Pgp/Bcrp）KO小鼠中进行了[C-11]1的正电子发射断层扫描研究。野生型和Mrp 1 KO小鼠的肺放射性在[C-11]1给药后立即达到最大水平。此后，野生型小鼠肺中的放射性迅速降低，而Mrp 1 KO小鼠的肺中则主要保留放射性。Pgp/BcrpKO小鼠肺内的动力学与野生型小鼠相似。化学形式分析证实，静脉注射[C-11]1后5分钟，Mrp 1 KO小鼠肺中的放射性化合物几乎完全由谷胱甘肽结合物（一种MRP 1底物）组成。还检查了MRP 1抑制剂MK 571对[C-11]1动力学的影响。与对照小鼠相比，MK 571治疗延迟了放射性从肺中的消除。这些结果表明，[C-11]1在给药后扩散到肺组织中，并转化为亲水性结合物，然后由MRP 1特异性排出。总之，[C-11]1允许肺中体内MRP 1活性的成像。
Multidrug resistance-associated protein 1 (MRP1) transports various xenobiotics and metabolites across cell membranes, and the alteration of MRP1 expression is associated with certain lung diseases. This study sought to examine the feasibility of imaging pulmonary MRP1 activity using 6-bromo-7-[C-11]methylpurine ([C-11]1). A positron emission tomography study with [C-11]1 was performed in wild-type, Mrp1 knockout (KO), and P-glycoprotein/breast cancer resistance protein (Pgp/Bcrp) KO mice. Lung radioactivity in wildtype and Mrp1 KO mice reached a maximum level immediately after the administration of [C-11]1. Thereafter, radioactivity rapidly decreased in the lungs of wild-type mice, whereas it was mostly retained in the lungs of Mrp1 KO mice. The kinetics in the lungs of Pgp/BcrpKOmicewasquite similar to that of wild-type mice. Analysis of the chemical form confirmed that radioactive compounds in the lungs of Mrp1 KO mice were nearly completely composed of a glutathione conjugate, a MRP1 substrate, 5 minutes after the intravenous administration of [C-11]1. The effect of an MRP1 inhibitor, MK571, on the kinetics of [C-11]1 was also examined. Treatment with MK571 delayed the elimination of radioactivity from the lungs, compared with control mice. These results suggest that [C-11]1 diffuses into the lung tissue after administration and undergoes conversion into the hydrophilic conjugate, which is then specifically expelled by MRP1. In conclusion, [C-11]1 allows for the imaging of in vivo MRP1 activity in lungs.