Multidrug resistance-associated proteins MRPs

Both influx and efflux transporters are located in intestinal epithelial cells and can either increase or decrease oral absorption. Influx transporters such as human peptide transporter 1 (hPEPTl), apical sodium bile acid transporter (ASBT), and nucleoside transporters actively transport drugs that mimic their native substrates across the epithelial cell, whereas efflux transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP) actively pump absorbed drugs back into the intestinal lumen. 

Aukunuru, JV, Sunkara, G, Bandi, N, Thoreson, WB, and Kompella, UB, 2001. Expression of multidrug resistance-associated protein (MRP) in human retinal pigment epithelial cells and its interaction with BAPSG, a novel aldose reductase inhibitor. Pharm Res 18, 565-572. 

Organic anion transporters can be divided into three major families organic anion transporters (OATs), organic anion transporting polypeptides (OATPs), and multidrug resistance associated proteins (MRPs) [201]. 

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]. 

Zaman, G.J., Flens, M.J., van Leusden, M.R., de Haas, M., Mulder, H.S., Lankelma, J., Pinedo, H.M., Scheper, R. J., Baas, F. and Broxterman, H.J., (1994) The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Proceedings of the National Academy of Sciences of the United States of America, 91, 8822-8826. 

Zhang, Y, Han, H, Elmquist, WF, MMiiler, DW (2000) Expression of various multidrug resistance-associated protein (MRP) homologues in brain microvessel endothelial cells. Brain Res 876 148-153. 

Zhang Y, Schuetz JD, Elmquist WF, Miller DW (2004) Plasma membrane localization of multidrug resistance-associated protein (MRP) homologues in brain capillary endothelial cells. J Pharmacol Exp Ther 311 449-55... 

Johnson BM, Zhang P, Schuetz J, Brouwer KL (2006) Characterization of transport protein expression in multidrug resistance-associated protein (MRP)2-deficant rats. Drug Metab Dispos 34 556-62... 

Active efflux transporters also exist in the placenta, analogous to the gut and blood-brain barrier. These are Pgp, multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP). These transport proteins are located in many tissues but also appear to be expressed in the placenta. Though the substrate specificities of these proteins have not been completely described, they appear to function as efflux transporters, moving endogenous and exogenous chemicals from the placental cells back to the systemic circulation. In this way, they serve as a mechanism to protect the fetus from exposure to unintended chemicals. 

Klein M, Burla B, Martinoia E. 2006. The multidrug resistance-associated protein (MRP/ABCC) subfamily of ATP-binding cassette transporters in plants. FEBS Lett 580 1112-1122. 

Zaman, G.J., et al. 1994. The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Proc Natl Acad Sci 91 8822. 

Carrier-mediated membrane transport proteins on the RPE selectively transport nutrients, metabolites, and xenobiotics between the choriocapillaris and the cells of the distal retina, and include amino acid [33 35], peptide [36], dicarboxylate, glucose [37], monocarboxylic acid [38,39], nucleoside[40], and organic anion and organic cation [41] transporters. Membrane barriers such as the efflux pumps, including multidrug resistance protein (P-gp), and multidrug resistance-associated protein (MRP) pumps have also been identified on the RPE. Exploitation of these transport systems may be the key to circumventing the outer BRB. 

Miller, D., E. Batrakova, and A. Kabanov. 1999. Inhibition of multidrug resistance-associated protein (MRP) functional activity with pluronic block copolymers. Pharm Res 16 396. 

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. 

Zamek-GI i szczy nski MJ, Nezasa K, Tian X, et al. Evaluation of the role of multidrug resistance-associated protein (Mrp) 3 and Mrp4 in hepatic basolateral excretion of sulfate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol in Abcc3-/- and Abcc4-/- mice. J Pharmacol Exp Ther 2006 319 1485-1491. 

Moffit JS, Aleksunes LM, Maher JM, et al. Induction of hepatic transporters multidrug resistance-associated proteins (Mrp) 3 and 4 by clofibrate is regulated by peroxisome proliferator-activated receptor alpha. J Pharmacol Exp Ther 2006 317 537-545. 

Peng KC, Cluzeaud F, Bens M, Van Huyen JP, Wioland MA, Lacave R, Vandewalle A. Tissue and cell distribution ofthe multidrug resistance-associated protein (MRP) in mouse intestine and kidney. J Histochem Cytochem 1999 47 757-768. 

---