Multidrug resistance-associated transporters

Baron, J. M., Holler, D., Schiffer, R., et al. Expression of multiple cytochrome P450 enzymes and multidrug resistance—associated transport proteins in human skin keratinocytes. J. Invest. Dermatol. 116(4) 541-548, 2001. 

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. 

Sasaki M, Suzuki H, Aoki J, Ito K, Meier PJ and Sugiyama Y. Prediction of in vivo biliary clearance from the in vitro transcellular transport of organic anions across a double-transfected Madin-Darby canine kidney II monolayer expressing both rat organic anion transporting polypeptide 4 and multidrug resistance associated protein 2. Mol Pharmacol 2004 66 450-9. 

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]. 

Borst, P., et al. A family of drug transporters the multidrug resistance-associated proteins. J. Natl. Cancer Inst. 2000, 92, 1295-1302. 

Hirohashi, T., H. Suzuki, and Y. Sugiyama. Characterization of the transport properties of cloned rat multidrug resistance-associated protein 3 (MRP3)./. Biol. Chem. 1999, 274, 15181-15185. 

Hirohashi T, Suzuki H, Takikawa H, Sugiyama Y. ATP-dependent transport of bile salts by rat multidrug resistance-associated protein 3 (Mrp3). J Biol Chem 2000 275(4)2905-2910. 

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]. 

J. A family of dmg transporters The multidrug resistance-associated proteins. 

Jedlitschky, G., Leier, I., Buchholz, U., Center, M. and Keppler, D. (1994) ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein. Cancer Research, 54, 4833—4836. 

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. 

Efflux transporters, such as multidrug resistant protein, known as P-glycoprotein (Pgp), and related multidrug-resistant associated protein isoforms (MRPs), have been shown to be important for structurally diverse lipophilic compounds. Pgp and several MRPs, which were first identified in... 

MDR1, multidrug resistance protein-1 MRP1, multidrug resistance-associated protein 1 NET, norepinephrine transporter SERT, serotonin reuptake transporter VMAT, vesicular monoamine transporter. 

Goodman CD, Casati P, Walbot V. 2004. A multidrug resistance-associated protein involved in anthocyanin transport in Zea mays. Plant Cell 16 1812-1826. 

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. 

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