Perspectives of P-Glycoprotein Modulating Agents in Oncology and Neurodegenerative Diseases: Pharmaceutical, Biological, and Diagnostic Potentials
Perspectives of P-Glycoprotein Modulating Agents in Oncology and Neurodegenerative Diseases: Pharmaceutical, Biological, and Diagnostic Potentials
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DOI：
10.1021/jm900743c
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发表时间：
2010-03-11
影响因子：
7.3
通讯作者：
Perrone, Roberto
中科院分区：
文献类型：
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作者：
Colabufo, Nicola Antonio;Berardi, Francesco;Perrone, Roberto
人类ATP结合盒转运蛋白（ABCa）基因家族共有49个基因，分为ABCA、ABC-B、ABC-C、ABC-D、ABC-E、ABC-F、ABC-G七个亚家族。1，2这些转运蛋白中的一些与多药耐药（MDR）有关，特别是ABC-B1，更好地称为P-糖蛋白（P-gp），ABC-G2，更好地称为乳腺癌耐药蛋白（BCRP），以及ABC-C1-6，也称为多药耐药相关蛋白（MRP 1 -6）。3这些转运蛋白在几种肿瘤细胞系中过表达，并负责药物流出细胞。4，5它们利用ATP水解的能量通过复杂的移位过程挤出化合物。6 P-gp易位的三种模型：（1）孔模型，（2）翻转酶模型，（3）疏水真空吸尘器模型。7、8在孔模型中，将P-gp结合到胞质溶胶的药物通过蛋白质通道转运出去。在翻转酶模型中，P-gp翻转药物，这些药物逆着浓度梯度从质膜的内室转运到外室。在疏水真空吸尘器模型中，脂双层中的P-gp识别的分子从膜位点进入蛋白质，并通过中心腔离开。P-gp含有12个跨膜螺旋，组成两个跨膜结构域（MSD），每个跨膜结构域含有6个跨膜螺旋，以及两个负责ATP结合的核苷酸结合结构域（NBD）。BCRP是一种“半转运蛋白”，因为它仅由一个MSD和一个NBD形成，尽管它二聚化以完全活化。MRP与P-gp不同，因为它们显示三个MSD，并且额外的结构域包含五个跨膜结构域。3本文将重点介绍P-gp的生理和病理作用，并将重点介绍P-gp在肿瘤MDR和几种屏障生理功能中的作用。
Human ATP binding cassette (ABCa) transporters belong to a family of 49 genes classified into seven subfamilies: ABCA, ABC-B, ABC-C, ABC-D, ABC-E, ABC-F, ABC-G. 1, 2 Some of these transporters are involved in multidrug resistance (MDR), in particular ABC-B1, better known as P-glycoprotein (P-gp), ABC-G2, better known as breast cancer resistance protein (BCRP), and ABC-C1-6, also known as multidrug resistance associated proteins (MRP1-6). 3 These transporters are overexpressed in several tumor cell lines and are responsible for drug efflux out of the cells. 4, 5 They use the energy of ATP hydrolysis to extrude compounds by a complex translocation process. 6 Three models for P-gp translocation have been suggested:(1) pore,(2) flippase, and (3) hydrophobic vacuum cleaner models. 7, 8 In the pore model, drugs binding P-gp to the cytosol are transported out through a protein channel. In the flippase model, P-gp flips drugs that are transported from the inner to the outer compartment of the plasma membrane against a concentration gradient. In the hydrophobic vacuum cleaner model, molecules recognized byP-gp in the lipid bilayer enter the protein from the membranous site and exit through the central cavity. P-gp contains 12 transmembrane helices organized in two membrane spanning domains (MSDs), each containing six transmembrane helices, and two nucleotide binding domains (NBDs) responsible for ATP binding. BCRP is a “half transporter” because it is formed by only one MSD and one NBD although it dimerizes to be fully active. MRPs differ from P-gp because they display three MSDs, and the additional domain contains five transmembrane domains. 3 This review will focus on the physiological and pathological role of P-gp and will highlight the involvement of this protein both in MDR of tumors and in the physiological function of several barriers.