Pharmaceutical Institute, Rheinische Friedrich-Wilhelms-University of Bonn, Bonn, Germany.
Med Res Rev. 2019 Nov;39(6):2031-2081. doi: 10.1002/med.21573. Epub 2019 Apr 3.
Several mechanisms of pharmacokinetic, metabolic, and regulatory nature have been elucidated to take part or act in concert in the phenomenon of multidrug resistance (MDR). MDR is characterized by cross-resistance of cells against chemotherapeutic agents, which are used for treatment of e.g., cancer, bacterial infections, or human immunodeficiency virus (HIV) infections. One group of proteins that combines all three stated aspects-the metabolism and distribution of drugs as well as their own regulation-is adenosine triphosphate-binding cassette (ABC) transporters. These efflux pumps use the energy of adenosine triphosphate hydrolysis for drug translocation from the membrane and the cytosol to the extracellular space, often with cotransport of a cosubstrate. Multidrug resistance-associated protein 1 (MRP1, ABCC1) had been discovered as one major key player in cancer-related MDR. The xenobiotic substrates include anthracyclines, vinca alkaloids, podophyllotoxins, as well as glutathione (GSH)-adducts of certain cytostatics. Contrary to other transport proteins involved in cancer-related MDR the activity of MRP1 is related to the GSH content of cells. A modern strategy to overcome MRP1-associated MDR is besides its inhibition the activation of GSH efflux, enforcing cell death due to cellular stress. In addition, it has recently been found that MRP1 contributes to the β-amyloid protein clearance in Alzheimer's disease (AD). Collectively, transport activation of MRP1 is of therapeutic value, and furthermore helps to elucidate the transport protein function and the mechanisms behind it. This review is meant to summarize the known concepts of MRP1 activation, which might contribute to a further understanding of MRP1 in particular and ABC transporters in general.
已经阐明了几种药代动力学、代谢和调节性质的机制，以参与或协同多药耐药（MDR）现象。MDR 的特征是细胞对用于治疗例如癌症、细菌感染或人类免疫缺陷病毒（HIV）感染的化疗药物的交叉耐药。一组将药物的代谢和分布以及自身调节结合在一起的蛋白质是三磷酸腺苷结合盒（ABC）转运蛋白。这些外排泵利用三磷酸腺苷水解的能量将药物从膜和细胞质转运到细胞外空间，通常与共转运一种共底物一起进行。多药耐药相关蛋白 1（MRP1，ABCC1）已被发现是癌症相关 MDR 的主要关键因素之一。外源性底物包括蒽环类抗生素、长春花生物碱、鬼臼毒素以及某些细胞抑制剂的谷胱甘肽（GSH）加合物。与参与癌症相关 MDR 的其他转运蛋白不同，MRP1 的活性与细胞内 GSH 的含量有关。克服与 MRP1 相关的 MDR 的一种现代策略是除了抑制其作用外，还激活 GSH 外排，由于细胞应激导致细胞死亡。此外，最近发现 MRP1 有助于阿尔茨海默病（AD）中β-淀粉样蛋白的清除。总之，MRP1 转运的激活具有治疗价值，并且有助于阐明转运蛋白的功能及其背后的机制。这篇综述旨在总结已知的 MRP1 激活概念，这可能有助于进一步了解 MRP1 特别是 ABC 转运蛋白。
