MRP family

Konig, J., et al. Conjugate export pumps of the multidrug resistance protein (MRP) family localization, substrate specificity, and MRP2-mediated drug resistance. Biochim. Biophys. Acta 1999, 1461, 377-394. 

The presence at the BBB of members of the multidrug resistance-associated protein (MRPs) family, whose members preferentially transport anionic compounds, is still controversial. The seven members of the MRP family belong, like P-gp, to the ATP-binding cassette (ABC) protein superfamily. Mrpl has been found at the BBB in isolated rat brain capillaries, primary cultures of brain capillary endothelial cells and in immortalized capillary endothelial cells, but not in human brain capillaries [59]. Another member, MRP2 has been found at the luminal membrane of the brain endothelial cells [60]. However, further studies are required to show that there are MRP transporters at the BBB (Figure 15.5). As for P-gp, a functional Mrpl was found in primary cultured rat astrocytes [56] and it has been shown to take part in the release of glutathione disulfide from brain astrocytes under oxidative stress [61]. 

Localization, substrate specificity, and drug resistance conferred by conjugate export pumps of the MRP family. Advances in Enzyme Regulation, 40, 339-349. 

Maher JM, Slitt AL, Cherrington NJ, et al. Tissue distribution and hepatic and renal ontogeny of the multidrug resistance-associated protein (Mrp) family in mice. Drug Metab Dispos 2005 33 947-955. 

MDR1 and members of the MRP family have substantial substrate overlaps (Borst et al. 2000). 

The MRP family of transporters is closely related and structurally similar to the MDR family (64/ 65). MRPl was initially identified in lung cellS/ which were known not to express P-gp. It has been shown to pump anionic compounds (as opposed to the cations pumped by P-gp). Substrates for MRPl include anionic natural products glutathione/ glucuronyl/ and sulfate conjugates and/ in some caseS/ neutral molecules coupled to glutathione transport without conjugation. In liver cellS/ MRPl is present on the sinusoidal surface of the hepatocyte. MRP2 is similar to MRPl/ except in its tissue distribution and localization. In liver cellS/... 

In addition to Pgp-mediated MDR, there is also a non-Pgp-mediated MDR phenomenon. This comprises another ABC transporter subfamily that is called the MRP-family. At least seven members have been identified, and five (MRP 1, -3, -4, -5, and -6) of them are expressed at the BBB [(44,91) reviewed by Borst (92,93)]. The MRPs are membrane-fixed systems that vary in size from 1325 to 1545 amino acids (92). They comprise two transmembrane domains of six alpha hehces, a cytoplasmic linker region, and two intracellular ABCs. The linker region is essential for its transport function (94,95). In addition, MRP1, -2, -3, and -6 have an extra domain structure comprising five additional transmembrane-segments at the animo-end (92,96). Today, MRPs are considered amphipatic anion efflux pumps. 

The role of BGRP in drug accumulation into milk can be illustrated by examining the M/S of BGRP substrates in knockout mice (Table 7.5). Members of the OATP and MRP families also have been detected in human mammary epithelial cells. P-GP is not highly expressed in mammary epithelial cells and lactation appears to down regulate its mRNA levels (Alcorn et al., 2002). 

Kruh GD and Belinsky MG. The MRP family of drug efflux pumps. Oncogene 2003 22 7537-7552. 

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