Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Kingston, ON, Canada, K7L 3N6.
Essays Biochem. 2011 Sep 7;50(1):179-207. doi: 10.1042/bse0500179.
Subfamily C of the human ABC (ATP-binding cassette) superfamily contains nine proteins that are often referred to as the MRPs (multidrug-resistance proteins). The 'short' MRP/ABCC transporters (MRP4, MRP5, MRP8 and ABCC12) have a typical ABC structure with four domains comprising two membrane-spanning domains (MSD1 and MSD2) each followed by a nucleotide-binding domain (NBD1 and NBD2). The 'long' MRP/ABCCs (MRP1, MRP2, MRP3, ABCC6 and MRP7) have five domains with the extra domain, MSD0, at the N-terminus. The proteins encoded by the ABCC6 and ABCC12 genes are not known to transport drugs and are therefore referred to as ABCC6 and ABCC12 (rather than MRP6 and MRP9) respectively. A large number of molecules are transported across the plasma membrane by the MRPs. Many are organic anions derived from exogenous sources such as conjugated drug metabolites. Others are endogenous metabolites such as the cysteinyl leukotrienes and prostaglandins which have important signalling functions in the cell. Some MRPs share a degree of overlap in substrate specificity (at least in vitro), but differences in transport kinetics are often substantial. In some cases, the in vivo substrates for some MRPs have been discovered aided by studies in gene-knockout mice. However, the molecules that are transported in vivo by others, including MRP5, MRP7, ABCC6 and ABCC12, still remain unknown. Important differences in the tissue distribution of the MRPs and their membrane localization (apical in contrast with basolateral) in polarized cells also exist. Together, these differences are responsible for the unique pharmacological and physiological functions of each of the nine ABCC transporters known as the MRPs.
人类 ABC（ATP 结合盒）超家族的 C 亚家族包含 9 种蛋白，通常称为 MRP（多药耐药蛋白）。“短”MRP/ABCC 转运蛋白（MRP4、MRP5、MRP8 和 ABCC12）具有典型的 ABC 结构，由四个域组成，包括两个跨膜域（MSD1 和 MSD2），每个域后面都有一个核苷酸结合域（NBD1 和 NBD2）。“长”MRP/ABCC（MRP1、MRP2、MRP3、ABCC6 和 MRP7）具有五个域，在 N 端有额外的域 MSD0。ABCC6 和 ABCC12 基因编码的蛋白未知是否转运药物，因此分别称为 ABCC6 和 ABCC12（而不是 MRP6 和 MRP9）。大量分子通过 MRP 跨质膜转运。许多是来自外源性来源的有机阴离子，如共轭药物代谢物。其他是内源性代谢物，如半胱氨酰白三烯和前列腺素，它们在细胞中具有重要的信号功能。一些 MRP 在底物特异性上具有一定程度的重叠（至少在体外），但转运动力学的差异往往很大。在某些情况下，基因敲除小鼠的研究有助于发现一些 MRP 的体内底物。然而，其他 MRP（包括 MRP5、MRP7、ABCC6 和 ABCC12）在体内转运的分子仍然未知。MRP 的组织分布和它们在极化细胞中的膜定位（与基底外侧相反的顶端）存在重要差异。这些差异共同导致了已知的 9 种 ABCC 转运蛋白（即 MRP）中的每一种的独特药理学和生理学功能。
