Export pumps for anionic conjugates encoded by MRP genes.
Several members of the multidrug resistance protein (MRP) family mediate the ATP-dependent transport of amphiphilic anions across membranes. The substrate specificity of recombinant human MRP1 has been most extensively defined by use of inside-out membrane vesicles. Substrates include the glutathione S-conjugate leukotriene C4, 17 beta-glucuronosyl estradiol, glucuronosyl bilirubin, glutathione disulfide, in addition to the fluorescent lipophilic anion Fluo-3. These substances are also substrates for the apical isoform MRP2, also termed canalicular multispecific organic anion transporter, cMOAT, which shares only 49% amino acid sequence identity with MRP1. The K(m) of leukotriene C4 for MRP2 is 10-fold higher than for MRP1, and the K(m) of 17 beta-glucuronosyl estradiol is 4.8-fold higher for MRP2 than for recombinant human MRP1. Human as well as rat MRP2 confer multidrug resistance to polarized MDCKII cells permanently expressing the recombinant glycoprotein in their apical plasma membrane. Resistance of cells transfected with human and rat MRP2 to etoposide was enhanced 5-fold and 3.8-fold, and resistance to vincristine was enhanced 2.3-fold and 6.0-fold, respectively. Conjugate-transporting members of the MRP family with a related sequence and a similar function have been detected recently. In addition to several MRP isoforms (MRP1-6) and orthologs in mammals (human, rat, rabbit, mouse), MRP family members have been identified in the nematode Caenorhabditis elegans, in the yeast Saccharomyces cerevisiae, and in the plant Arabidopsis thaliana. These conjugate export pumps of the MRP family play a widespread role in detoxification, drug resistance, and, because of the role in the export of glutathione disulfide by MRP1 and MRP2, in the defense against oxidative stress.
Keppler
D
D
Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Cui
Y
Y
König
J
J
Leier
I
I
Nies
A
A
D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D027321:Anion Transport Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D004285:Dogs; D018432:Drug Resistance, Multiple / Q000235:genetics / Q000502:physiology; D019450:Genes, MDR; D006801:Humans; D066298:In Vitro Techniques; D017136:Ion Transport; D007700:Kinetics; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010802:Phylogeny; D011817:Rabbits; D051381:Rats; D014162:Transfection
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D027321:Anion Transport Proteins; D002352:Carrier Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins