Roepe P D, Wei L Y, Hoffman M M, Fritz F
Molecular Pharmacology and Therapeutics Program, Raymond & Beverly Sackler Foundation Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
J Bioenerg Biomembr. 1996 Dec;28(6):541-55. doi: 10.1007/BF02110444.
Overexpression of the MDR protein, or p-glycoprotein (p-GP), in cells leads to decreased initial rates of accumulation and altered intracellular retention of chemotherapeutic drugs and a variety of other compounds. Thus, increased expression of the protein is related to increased drug resistance. Since several homologues of the MDR protein (CRP, ItpGPA, PDR5, sapABCDF) are also involved in conferring drug resistance phenomena in microorganisms, elucidating the function of the MDR protein at a molecular level will have important general applications. Although MDR protein function has been studied for nearly 20 years, interpretation of most data is complicated by the drug-selection conditions used to create model MDR cell lines. Precisely what level of resistance to particular drugs is conferred by a given amount of MDR protein, as well as a variety of other critical issues, are not yet resolved. Data from a number of laboratories has been gathered in support of at least four different models for the MDR protein. One model is that the protein uses the energy released from ATP hydrolysis to directly translocate drugs out of cells in some fashion. Another is that MDR protein overexpression perturbs electrical membrane potential (delta psi) and/or intracellular pH (pHi) and thereby indirectly alters translocation and intracellular retention of hydrophobic drugs that are cationic, weakly basic, and/or that react with intracellular targets in a pHi or delta psi-dependent manner. A third model proposes that the protein alternates between drug pump and Cl- channel (or channel regulator) conformations, implying that both direct and indirect mechanisms of altered drug translocation may be catalyzed by MDR protein. A fourth is that the protein acts as an ATP channel. Our recent work has tested predictions of these models via kinetic analysis of drug transport and single-cell photometry analysis of pHi, delta psi, and volume regulation in novel MDR and CFTR transfectants that have not been exposed to chemotherapeutic drugs prior to analysis. This paper reviews these data and previous work from other laboratories, as well as relevant transport physiology concepts, and summarizes how they either support or contradict the different models for MDR protein function.
MDR蛋白，即P - 糖蛋白（p - GP）在细胞中的过表达会导致化疗药物及多种其他化合物的初始积累速率降低，并改变其在细胞内的滞留情况。因此，该蛋白表达增加与耐药性增强有关。由于MDR蛋白的几种同源物（CRP、ItpGPA、PDR5、sapABCDF）也参与微生物的耐药现象，从分子水平阐明MDR蛋白的功能将具有重要的普遍应用价值。尽管对MDR蛋白功能的研究已近20年，但用于创建MDR模型细胞系的药物选择条件使大多数数据的解读变得复杂。给定数量的MDR蛋白究竟赋予对特定药物何种程度的耐药性，以及其他各种关键问题，目前尚未得到解决。多个实验室的数据已收集起来，以支持至少四种不同的MDR蛋白模型。一种模型认为，该蛋白利用ATP水解释放的能量以某种方式直接将药物转运出细胞。另一种模型是，MDR蛋白过表达扰乱膜电位（δψ）和/或细胞内pH值（pHi），从而间接改变阳离子、弱碱性和/或以pHi或δψ依赖方式与细胞内靶点反应的疏水性药物的转运和细胞内滞留。第三种模型提出，该蛋白在药物泵和Cl - 通道（或通道调节剂）构象之间交替，这意味着MDR蛋白可能催化改变药物转运的直接和间接机制。第四种模型是，该蛋白作为一个ATP通道。我们最近的工作通过对药物转运的动力学分析以及对新型MDR和CFTR转染细胞（在分析前未接触化疗药物）的pHi、δψ和体积调节进行单细胞光度分析，对这些模型的预测进行了测试。本文回顾了这些数据以及其他实验室的前期工作，以及相关的转运生理学概念，并总结了它们如何支持或反驳MDR蛋白功能的不同模型。
