Multidrug Resistance Proteins (MRPs, ABCCs): Importance for Pathophysiology and Drug Therapy
Multidrug Resistance Proteins (MRPs, ABCCs): Importance for Pathophysiology and Drug Therapy
复制标题
DOI：
10.1007/978-3-642-14541-4_8
复制
发表时间：
2011-01-01
期刊：
影响因子：
--
通讯作者：
Keppler, Dietrich
中科院分区：
文献类型：
--
作者：
Keppler, Dietrich
这9个多药耐药蛋白（MRPs）代表了MRP/CFTR亚家族12个成员的主要部分，属于48个人类atp结合盒（ABC）转运体。大多数MRP亚家族成员的克隆、功能表征和细胞定位已经确定它们是atp依赖的外排泵，具有广泛的底物特异性，用于运输定位于细胞膜的内源性和外源性阴离子物质。原型底物包括谷胱甘肽偶联物，如MRP1、MRP2和MRP4的白三烯C-4， MRP2和MRP3的胆红素糖醛酸苷，MRP4、MRP5和MRP8的环AMP和环GMP。还原性谷胱甘肽（GSH）以毫摩尔浓度存在于活细胞中，可改变几种MRPs的底物特异性，例如MRP1可将新碱与谷胱甘肽共同运输，MRP4可将谷胱甘肽与胆汁酸或谷胱甘肽与白三烯B-4共同运输。MRP亚家族成员在病理生理中的作用可以通过MRP介导的促炎和免疫调节介质（如白三烯和前列腺素）的释放来说明。在杜宾-约翰逊综合征中与共轭高胆红素血症相关的遗传性MRP2缺陷、MRP6 （ABCC6）基因突变引起的弹性假黄色瘤、或MRP8 （ABCC8）基因单核苷酸多态性决定的人耳垢和渗音类型中，可以观察到许多遗传变异导致质膜中功能性MRP蛋白缺乏的病理生理后果。许多药物及其代谢物的肝胆肾消除是由肝细胞小管膜中的MRP2和肾近端小管管腔膜中的MRP4和MRP2介导的。因此，这些外排泵的抑制会影响药代动力学，除非被具有重叠底物特异性的其他atp依赖性外排泵补偿。
The nine multidrug resistance proteins (MRPs) represent the major part of the 12 members of the MRP/CFTR subfamily belonging to the 48 human ATP-binding cassette (ABC) transporters. Cloning, functional characterization, and cellular localization of most MRP subfamily members have identified them as ATP-dependent efflux pumps with a broad substrate specificity for the transport of endogenous and xenobiotic anionic substances localized in cellular plasma membranes. Prototypic substrates include glutathione conjugates such as leukotriene C-4 for MRP1, MRP2, and MRP4, bilirubin glucuronosides for MRP2 and MRP3, and cyclic AMP and cyclic GMP for MRP4, MRP5, and MRP8. Reduced glutathione (GSH), present in living cells at millimolar concentrations, modifies the substrate specificities of several MRPs, as exemplified by the cotransport of vincristine with GSH by MRP1, or by the cotransport of GSH with bile acids or of GSH with leukotriene B-4 by MRP4.The role of MRP subfamily members in pathophysiology may be illustrated by the MRP-mediated release of proinflammatory and immunomodulatory mediators such as leukotrienes and prostanoids. Pathophysiological consequences of many genetic variants leading to a lack of functional MRP protein in the plasma membrane are observed in the hereditary MRP2 deficiency associated with conjugated hyperbilirubinemia in Dubin-Johnson syndrome, in pseudoxanthoma elasticum due to mutations in the MRP6 (ABCC6) gene, or in the type of human earwax and osmidrosis determined by single nucleotide polymorphisms in the MRP8 (ABCC8) gene. The hepatobiliary and renal elimination of many drugs and their metabolites is mediated by MRP2 in the hepatocyte canalicular membrane and by MRP4 as well as MRP2 in the luminal membrane of kidney proximal tubules. Therefore, inhibition of these efflux pumps affects pharmacokinetics, unless compensated by other ATP-dependent efflux pumps with overlapping substrate specificities.