Kruh G D, Zeng H, Rea P A, Liu G, Chen Z S, Lee K, Belinsky M G
Medical Sciences Division, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
J Bioenerg Biomembr. 2001 Dec;33(6):493-501. doi: 10.1023/a:1012827221844.
The MRP subfamily of ABC transporters from mammals consists of at least seven members, six of which have been implicated in the transport of amphipathic anions. MRP1, MRP2, and MRP3 bear a close structural resemblance, confer resistance to a variety of natural products as well as methotrexate, and have the facility for transporting glutathione and glucuronate conjugates. MRP1 is a ubiquitously expressed efflux pump for the products of phase II of xenobiotic detoxification, while MRP2, whose hereditary deficiency results in Dubin-Johnson syndrome, functions to extrude organic anions into the bile. MRP3 is distinguished by its capacity to transport the monoanionic bile constituent glycocholate, and may function as a basolateral back-up system for the detoxification of hepatocytes when the usual canalicular route is impaired by cholestatic conditions. MRP4 and MRP5 resemble each other more closely than they resemble MRPs 1-3 and confer resistance to purine and nucleotide analogs which are either inherently anionic, as in the case of the anti-AIDS drug PMEA, or are phosphorylated and converted to anionic amphiphiles in the cell, as in the case of 6-MP. Given their capacity for transporting cyclic nucleotides, MRP4 and MRP5 have also been implicated in a broad range of cellular signaling processes. The drug resistance activity and physiological substrates of MRP6 are unknown. However, its hereditary deficiency results in pseudoxanthoma elasticum, a multisystem disorder affecting skin, eyes, and blood vessels. It is hoped that elucidation of the resistance profiles and physiological functions of the different members of the MRP subfamily will provide new insights into the molecular basis of clinical drug resistance and spawn new strategies for combating this phenomenon.
哺乳动物 ABC 转运蛋白的 MRP 亚家族至少由七个成员组成，其中六个与两亲性阴离子的转运有关。MRP1、MRP2 和 MRP3 在结构上非常相似，赋予对多种天然产物以及甲氨蝶呤的抗性，并且具有转运谷胱甘肽和葡萄糖醛酸结合物的能力。MRP1 是一种普遍表达的外排泵，用于外源性解毒第二阶段的产物，而 MRP2 的遗传性缺陷会导致 Dubin-Johnson 综合征，其功能是将有机阴离子排入胆汁。MRP3 的特点是能够转运单阴离子胆汁成分甘氨胆酸盐，当通常的胆小管途径因胆汁淤积性疾病而受损时，它可能作为肝细胞解毒的基底外侧备用系统。MRP4 和 MRP5 彼此之间的相似性比它们与 MRP1 - 3 的相似性更高，并且赋予对嘌呤和核苷酸类似物的抗性，这些类似物要么本质上是阴离子型的，如抗艾滋病药物 PMEA 的情况，要么在细胞中被磷酸化并转化为阴离子两亲物，如 6 - MP 的情况。鉴于它们转运环核苷酸的能力，MRP4 和 MRP5 也参与了广泛的细胞信号传导过程。MRP6 的耐药活性和生理底物尚不清楚。然而，其遗传性缺陷会导致弹性假黄瘤，这是一种影响皮肤、眼睛和血管的多系统疾病。希望对 MRP 亚家族不同成员的抗性谱和生理功能的阐明将为临床耐药性的分子基础提供新的见解，并催生对抗这种现象的新策略。
