Multidrug-resistance associated protein system

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. 

Figure 8.3 Pathway of absorption and metabolism of flavonols in the digestive system (MRP-2 multidrug resistance-associated protein-2 LPH lactose phlorizin hydrolaze).

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. 

Efflux systems of major importance in the intestinal epithelium are P-glycoprotein (P-gp) (Mizuno et al. 2003), multidrug resistance-associated protein 2 (MRP2) (Jansen et al. 1993), and breast cancer resistance protein (BCRP) (Doyle et al. 1998, Doyle and Ross 2003). The latter is described as a half-transporter and possibly functions as a homodimer (Schinkel and Jonker 2003). Details on the molecular weight, structure, substrates, and expression of P-gp, MRP2, and BCRP are listed in Table 3.2. It needs to be mentioned that expression of these intestinal efflux transporter systems shows high... 

Mroczkowska JE, Roux FS, Nalecz MJ, Nalecz KA (2000) Blood-brain barrier controls carnitine level in the brain a study on a model system with RBE4 cells. Biochem Bio-phys Res Commun 267 433-437 Regina A, Koman A, Piciotti M et al. (1998) Mrpl multidrug resistance-associated protein and P-glycoprotein expression in rat brain microvessel endothelial cells. J Neurochem 71 705-715... 

Dallas, S., Miller, D. S., 8c Bendayan, R. (2006). Multidrug resistance-associated proteins Expression and function in the central nervous system. Pharmacological Reviews, 58, 140—161. 

For example, see the B-Clear system at www.qualyst.com/products/bclear.php5. See also Sasaki, M., et al. 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 59. 

Intestinal excretion is an important mechanism in the elimination of flavonoid conjugates [82-84]. This is likely mediated by the multidrug resistance-associated protein (MRP) pumps. MRPs actively export conjugated metabolites out of the small intestine back into the intestinal lumen and so prevent or reduce systemic circulation [85]. An experiment using cultured Caco-2 cells showed that two metabolites of epicatechin were excreted on the apical side of the cells. Their elimination has been attributed to MRP-2, as efflux was significantly reduced by a competitive MRP-2 inhibitor [86]. Conversely, intestinal perfusion experiments with catechin indicate that catechin metabolites are not substrates for these transport proteins [49]. 

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