Multidrug resistance protein Mrp2 mediates ATP-dependent transport of classic renal organic anion p-aminohippurate

2000 ◽  
Vol 279 (4) ◽  
pp. F713-F717 ◽  
Author(s):  
Rémon A. M. H. Van Aubel ◽  
Janny G. P. Peters ◽  
Rosalinde Masereeuw ◽  
Carel H. Van Os ◽  
Frans G. M. Russel
Keyword(s):  
Multidrug Resistance ◽  
Organic Anion ◽  
Basolateral Membrane ◽  
Membrane Vesicles ◽  
Maximal Velocity ◽  
Multidrug Resistance Protein ◽  
Resistance Protein ◽  
Dependent Transport ◽  
Menten Constant ◽  
Isolated Membrane Vesicles

p-Aminohippurate (PAH) is widely used as a model substrate to characterize organic anion transport in kidney proximal tubules. The carrier responsible for uptake of PAH across the basolateral membrane has been cloned and well characterized, whereas transporters mediating PAH excretion across the brush-border (apical) membrane are yet unknown. In this study we investigated whether PAH is a substrate for the apical multidrug resistance protein 2 (Mrp2). Overexpression of recombinant rabbit Mrp2 in Sf9 cells significantly increased ATP-dependent [14C]PAH uptake into isolated membrane vesicles compared with endogenous ATP-dependent uptake. The Michaelis-Menten constant and maximal velocity for Mrp2-mediated ATP-dependent [14C]PAH transport were 1.9 ± 0.8 mM and 187 ± 29 pmol · mg−1 · min−1, respectively. On the basis of the inhibitory profile, the endogenous ATP-dependent PAH transporter does not appear to be an ortholog of Mrp2. Together, our results show that Mrp2 is a low-affinity ATP-dependent PAH transporter, indicating that Mrp2 might contribute to urinary PAH excretion.

scholarly journals ATP-dependent transport of bilirubin glucuronides by the multidrug resistance protein MRP1 and its hepatocyte canalicular isoform MRP2

1997 ◽  
Vol 327 (1) ◽  
pp. 305-310 ◽  
Author(s):  
Gabriele JEDLITSCHKY ◽  
Inka LEIER ◽  
Ulrike BUCHHOLZ ◽  
Johanna HUMMEL-EISENBEISS ◽  
Brian BURCHELL ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Membrane Vesicle ◽  
Organic Anion ◽  
Membrane Vesicles ◽  
Organic Anion Transporter ◽  
Multidrug Resistance Protein ◽  
Leukotriene C4 ◽  
Anion Transporter ◽  
Resistance Protein ◽  
Dependent Transport

Bilirubin is secreted from the liver into bile mainly as monoglucuronosyl and bisglucuronosyl conjugates. We demonstrate for the first time that ATP-dependent transport of both bilirubin glucuronides is mediated by the multidrug resistance protein (MRP1) as well as by the distinct canalicular (apical) isoform MRP2, also termed cMRP or cMOAT (canalicular multispecific organic anion transporter). In membrane vesicles from MRP1-transfected HeLa cells mono[3H]glucuronosylbilirubin and bis[3H]glucuronosylbilirubin (each at 0.5 μM) were transported with rates of 5.3 and 3.1 pmol/min per mg of protein respectively. Rat hepatocyte canalicular membrane vesicles, which contain Mrp2 (the rat equivalent of MRP2), transported mono[3H]glucuronosylbilirubin and bis[3H]glucuronosylbilirubin at rates of 8.9 and 8.5 pmol/min per mg of protein, whereas membrane vesicles from mutant liver lacking Mrp2 showed no transport of the conjugates. In membrane vesicles from human hepatoma Hep G2 cells, which predominantly expressed MRP2, transport rates were 8.3 and 4.4 pmol/min per mg of protein for monoglucuronosylbilirubin and bisglucuronosylbilirubin respectively. ATP-dependent transport of the glutathione S-conjugate [3H]leukotriene C4, an established high-affinity substrate for MRP1 and MRP2, was inhibited by both bilirubin glucuronides with IC50 values between 0.10 and 0.75 μM. The ratios of leukotriene C4 transport and bilirubin glucuronide transport, determined in the same membrane vesicle preparation, indicated substrate specificity differences between MRP1 and MRP2 with a preference of MRP2 for the glucuronides.

scholarly journals Steroid and bile acid conjugates are substrates of human multidrug-resistance protein (MRP) 4 (ATP-binding cassette C4)

2003 ◽  
Vol 371 (2) ◽  
pp. 361-367 ◽  
Author(s):  
Noam ZELCER ◽  
Glen REID ◽  
Peter WIELINGA ◽  
Annemieke KUIL ◽  
Ingrid van der HEIJDEN ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Bile Acid ◽  
Bile Acids ◽  
Mammalian Cells ◽  
Physiological Role ◽  
Membrane Vesicles ◽  
Dependent Manner ◽  
Multidrug Resistance Protein ◽  
Resistance Protein ◽  
Dependent Transport

Human multidrug-resistance protein (MRP) 4 transports cyclic nucleotides and when overproduced in mammalian cells mediates resistance to some nucleoside analogues. Recently, it has been shown that Mrp4 is induced in the livers of Fxr(-/-) mice, which have increased levels of serum bile acids. Since MRP4, like MRP1–3, also mediates transport of a model steroid conjugate substrate, oestradiol 17-β-d-glucuronide (E217βG), we tested whether MRP4 may be involved in the transport of steroid and bile acid conjugates. Bile salts, especially sulphated derivatives, and cholestatic oestrogens inhibited the MRP4-mediated transport of E217βG. Inhibition by oestradiol 3,17-disulphate and taurolithocholate 3-sulphate was competitive, suggesting that these compounds are MRP4 substrates. Furthermore, we found that MRP4 transports dehydroepiandrosterone 3-sulphate (DHEAS), the most abundant circulating steroid in humans, which is made in the adrenal gland. The ATP-dependent transport of DHEAS by MRP4 showed saturable kinetics with Km and Vmax values of 2μM and 45pmol/mg per min, respectively (at 27°C). We further studied the possible involvement of other members of the MRP family of transporters in the transport of DHEAS. We found that MRP1 transports DHEAS in a glutathione-dependent manner and exhibits Km and Vmax values of 5μM and 73pmol/mg per min, respectively (at 27°C). No transport of DHEAS was observed in membrane vesicles containing MRP2 or MRP3. Our findings suggest a physiological role for MRP1 and MRP4 in DHEAS transport and an involvement of MRP4 in transport of conjugated steroids and bile acids.

scholarly journals Regorafenib Is Transported by the Organic Anion Transporter 1B1 and the Multidrug Resistance Protein 2

2015 ◽  
Vol 38 (4) ◽  
pp. 582-586 ◽  
Author(s):  
Hiroki Ohya ◽  
Yoshihiko Shibayama ◽  
Jiro Ogura ◽  
Katsuya Narumi ◽  
Masaki Kobayashi ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Multidrug Resistance Protein ◽  
Multidrug Resistance Protein 2 ◽  
Anion Transporter ◽  
Resistance Protein

scholarly journals ATP- and glutathione-dependent transport of chemotherapeutic drugs by the multidrug resistance protein MRP1

1999 ◽  
Vol 126 (3) ◽  
pp. 681-688 ◽  
Author(s):  
Johan Renes ◽  
Elisabeth G E De Vries ◽  
Edith F Nienhuis ◽  
Peter L M Jansen ◽  
Michael Müller
Keyword(s):  
Multidrug Resistance ◽  
Multidrug Resistance Protein ◽  
Chemotherapeutic Drugs ◽  
Resistance Protein ◽  
Dependent Transport

Kupffer cells alter organic anion transport through multidrug resistance protein 2 in the post-cold ischemic rat liver

Hepatology ◽  
2004 ◽  
Vol 39 (4) ◽  
pp. 1099-1109 ◽  
Author(s):  
Atsushi Kudo ◽  
Satoshi Kashiwagi ◽  
Mayumi Kajimura ◽  
Yasunori Yoshimura ◽  
Koji Uchida ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Rat Liver ◽  
Kupffer Cells ◽  
Organic Anion ◽  
Anion Transport ◽  
Multidrug Resistance Protein ◽  
Organic Anion Transport ◽  
Multidrug Resistance Protein 2 ◽  
Resistance Protein

Characterization of the amino-terminal regions in the human multidrug resistance protein (MRP1)

2000 ◽  
Vol 113 (24) ◽  
pp. 4451-4461
Author(s):  
E. Bakos ◽  
R. Evers ◽  
G. Calenda ◽  
G.E. Tusnady ◽  
G. Szakacs ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Drug Transport ◽  
Cellular Localization ◽  
Membrane Vesicles ◽  
Sf9 Cells ◽  
Multidrug Resistance Protein ◽  
Hydrophobic Membrane ◽  
Amino Terminal ◽  
Mdckii Cells ◽  
Resistance Protein

The human multidrug resistance protein (MRP1) contributes to drug resistance in cancer cells. In addition to an MDR1-like core, MRP1 contains an N-terminal membrane-bound (TMD(0)) region and a cytoplasmic linker (L(0)), both characteristic of several members of the MRP family. In order to study the role of the TMD(0) and L(0) regions, we constructed various truncated and mutated MRP1, and chimeric MRP1-MDR1 molecules, which were expressed in insect (Sf9) and polarized mammalian (MDCKII) cells. The function of the various proteins was examined in isolated membrane vesicles by measuring the transport of leukotriene C(4) and other glutathione conjugates, and by vanadate-dependent nucleotide occlusion. Cellular localization, and glutathione-conjugate and drug transport, were also studied in MDCKII cells. We found that chimeric proteins consisting of N-terminal fragments of MRP1 fused to the N terminus of MDR1 preserved the transport, nucleotide occlusion and apical membrane routing of wild-type MDR1. As shown before, MRP1 without TMD(0)L(0) (Delta MRP1), was non-functional and localized intracellularly, so we investigated the coexpression of Delta MRP1 with the isolated L(0) region. Coexpression yielded a functional MRP1 molecule in Sf9 cells and routing to the lateral membrane in MDCKII cells. Interestingly, the L(0) peptide was found to be associated with membranes in Sf9 cells and could only be solubilized by urea or detergent. A 10-amino-acid deletion in a predicted amphipathic region of L(0) abolished its attachment to the membrane and eliminated MRP1 transport function, but did not affect membrane routing. Taken together, these experiments suggest that the L(0) region forms a distinct domain within MRP1, which interacts with hydrophobic membrane regions and with the core region of MRP1.

The human multidrug resistance protein MRP1 translocates sphingolipid analogs across the plasma membrane

1999 ◽  
Vol 112 (3) ◽  
pp. 415-422 ◽  
Author(s):  
R.J. Raggers ◽  
A. van Helvoort ◽  
R. Evers ◽  
G. van Meer
Keyword(s):  
Plasma Membrane ◽  
Multidrug Resistance ◽  
Abc Transporter ◽  
Basolateral Membrane ◽  
Brefeldin A ◽  
Apical Plasma Membrane ◽  
Multidrug Resistance Protein ◽  
Vesicular Traffic ◽  
P Glycoprotein ◽  
Resistance Protein

Recently, we have provided evidence that the ABC-transporter MDR1 P-glycoprotein translocates analogs of various lipid classes across the apical plasma membrane of polarized LLC-PK1 cells transfected with MDR1 cDNA. Here, we show that expression of the basolateral ABC-transporter MRP1 (the multidrug resistance protein) induced lipid transport to the exoplasmic leaflet of the basolateral plasma membrane of LLC-PK1 cells at 15 degreesC. C6-NBD-glucosylceramide synthesized on the cytosolic side of the Golgi complex, but not C6-NBD-sphingomyelin synthesized in the Golgi lumen, became accessible to depletion by BSA in the basal culture medium. This suggests the absence of vesicular traffic and direct translocation of C6-NBD-glucosylceramide by MRP1 across the basolateral membrane. In line with this, transport of the lipid to the exoplasmic leaflet depended on the intracellular glutathione concentration and was inhibited by the MRP1-inhibitors sulfinpyrazone and indomethacin, but not by the MDR1 P-glycoprotein inhibitor PSC 833. In contrast to the broad substrate specificity of the MDR1 P-glycoprotein, MRP1 selectively transported C6-NBD-glucosylceramide and C6-NBD-sphingomyelin, the latter only when it was released from the Golgi lumen by brefeldin A. This shows the specific nature of the lipid translocation. We conclude that the transport activity of MDR1 P-glycoprotein and MRP1 must be taken into account in studies on the transport of lipids to the cell surface.

ATP-Dependent Transport of Aflatoxin B1 and Its Glutathione Conjugates by the Product of the Multidrug Resistance Protein (MRP) Gene

1997 ◽  
Vol 51 (6) ◽  
pp. 1034-1041 ◽  
Author(s):  
Douglas W. Loe ◽  
Richard K. Stewart ◽  
Thomas E. Massey ◽  
Roger G. Deeley ◽  
Susan P. C. Cole
Keyword(s):  
Multidrug Resistance ◽  
Aflatoxin B1 ◽  
Multidrug Resistance Protein ◽  
Glutathione Conjugates ◽  
Resistance Protein ◽  
Dependent Transport
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