title: Differential modulation of the human liver conjugate transporters MRP2 and MRP3 by bile acids and organic anions.
abstract: The multidrug resistance proteins MRP2 (ABCC2) and MRP3 (ABCC3) are key primary active transporters involved in anionic conjugate and drug extrusion from the human liver. The major physiological role of MRP2 is to transport conjugated metabolites into the bile canaliculus, whereas MRP3 is localized in the basolateral membrane of the hepatocytes and transports similar metabolites back to the bloodstream. Both proteins were shown to interact with a large variety of transported substrates, and earlier studies suggested that MRPs may work as co-transporters for different molecules. In the present study we expressed the human MRP2 and MRP3 proteins in insect cells and examined their transport and ATPase characteristics in isolated, inside-out membrane vesicles. We found that the primary active transport of estradiol-17-beta-d-glucuronide (E217betaG), a major product of human steroid metabolism, was differently modulated by bile acids and organic anions in the case of human MRP2 and MRP3. Active E217betaG transport by MRP2 was significantly stimulated by the organic anions indomethacin, furosemide, and probenecid and by several conjugated bile acids. In contrast, all of these agents inhibited E217betaG transport by MRP3. We found that in the case of MRP2, ATP-dependent vesicular bile acid transport was increased by E217betaG, and the results indicated an allosteric cross-stimulation, probably a co-transport of bile acids and glucuronate conjugates through this protein. There was no such stimulation of bile acid transport by MRP3. In conclusion, the different transport modulation of MRPs by bile acids and anionic drugs could play a major role in regulating physiological and pathological metabolite fluxes in the human liver.
authors.affiliation: National Medical Center, Institute of Haematology and Immunology, Membrane Research Group of the Hungarian Academy of Sciences.
authors.forename: Adrienn
authors.initials: A
authors.lastname: Bodo
authors.forename: Eva
authors.initials: E
authors.lastname: Bakos
authors.forename: Flora
authors.initials: F
authors.lastname: Szeri
authors.forename: Andras
authors.initials: A
authors.lastname: Varadi
authors.forename: Balazs
authors.initials: B
authors.lastname: Sarkadi
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001648:Bile Canaliculi / Q000378:metabolism; D001692:Biological Transport; D001769:Blood / Q000378:metabolism; D002264:Carboxylic Acids / Q000378:metabolism; D002460:Cell Line; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism; D020719:Glucuronides / Q000378:metabolism*; D006801:Humans; D024101:Mitochondrial Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D011849:Radioactive Tracers; D012269:Ribosomal Proteins / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D014162:Transfection
chemical_list: D001647:Bile Acids and Salts; D002264:Carboxylic Acids; D004958:Estradiol; D020719:Glucuronides; D024101:Mitochondrial Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011849:Radioactive Tracers; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; C000715087:ABCC2 protein, human; C093947:MRP2 protein, S cerevisiae; C025483:estradiol-17 beta-glucuronide; C114462:multidrug resistance-associated protein 3