Multidrug resistance proteins (MRPs/ABCCs) in cancer chemotherapy and genetic diseases

The ATP‐binding cassette (ABC) transporters are a superfamily of membrane proteins that are best known for their ability to transport a wide variety of exogenous and endogenous substances across membranes against a concentration gradient via ATP hydrolysis. There are seven subfamilies of human ABC transporters, one of the largest being the ‘C’ subfamily (gene symbol ABCC). Nine ABCC subfamily members, the so‐called multidrug resistance proteins (MRPs) 1–9, have been implicated in mediating multidrug resistance in tumor cells to varying degrees as the efflux extrude chemotherapeutic compounds (or their metabolites) from malignant cells. Some of the MRPs are also known to either influence drug disposition in normal tissues or modulate the elimination of drugs (or their metabolites) via hepatobiliary or renal excretory pathways. In addition, the cellular efflux of physiologically important organic anions such as leukotriene C4 and cAMP is mediated by one or more of the MRPs. Finally, mutations in several MRPs are associated with human genetic disorders. In this minireview, the current biochemical and physiological knowledge of MRP1–MRP9 in cancer chemotherapy and human genetic disease is summarized. The mutations in MRP2/ABCC2 leading to conjugated hyperbilirubinemia (Dubin–Johnson syndrome) and in MRP6/ABCC6 leading to the connective tissue disorder Pseudoxanthoma elasticum are also discussed. The nine MRP/ABCC members utilize ATP to transport physiological substrates such as LTC4, LTB4, GSH, cAMP, cGMP, E217ßG etc across plasma membranes. They are also involved in modulating disposition and elimination of several pharmacological substrates including anticancer drugs. Mutations in at least three genes ABCC2, ABCC6,and ABCC11 cause hereditary human diseases/disorders (Dubin‐Johnson syndrome, Pseudoxanthoma elasticum, wet‐dry earwax types, respectively).