Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions

E. Bakos, Raymond Evers, Emese Sinkó, A. Váradi, Piet Borst, B. Sarkadi

Research output: Contribution to journalArticle

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Abstract

The human multidrug resistance protein MRP1 and its homolog, MRP2, are both suggested as being involved in cancer drug resistance and the transport of organic anions. We expressed MRP1 and MRP2 in Spodoptera frugiperda ovarian cells and compared their ATP-dependent transport properties and vanadate-sensitive ATPase activities in isolated membrane vesicles. Both MRP1 and MRP2 actively transported leukotriene C4 and N-ethylmaleimide glutathione (NEM-GS), although the relative affinity of MRP2 for these substrates was found to be significantly lower than that of MRP1. Methotrexate was actively transported by both proteins, although more efficiently by MRP2. ATP-dependent NEM-GS transport by MRP1 and MRP2 was variably modulated by organic anions. Probenecid and furosemide inhibited, whereas under certain conditions sulfinpyrazone, penicillin G, and indomethacin greatly stimulated, MRP2-mediated NEM-GS uptake. Vanadate- sensitive ATPase activity in isolated membranes containing MRP1 or MRP2 was significantly stimulated by NEM-GS and reduced GS, although these compounds acted only at higher concentrations in MRP2. ATP hydrolysis by MRP2 was also effectively stimulated by methotrexate. Probenecid, sulfinpyrazone, indomethacin, furosemide, and penicillin G all significantly increased MRP2- ATPase activity, whereas these compounds acted more as ATPase inhibitors on MRP1. These results indicate that MRP1 is a more efficient transporter of glutathione conjugates and free glutathione than MRP2, whereas several anions are preferred substrates for MRP2. Our data suggest that MRP2 may be responsible for the active secretion of pharmacologically relevant organic anions, such as diuretics and antibiotics, and indicate different modulation possibilities for MRP1 or MRP2 in drug-resistant tumor cells.

Original languageEnglish
Pages (from-to)760-768
Number of pages9
JournalMolecular Pharmacology
Volume57
Issue number4
Publication statusPublished - 2000

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Anions
Sulfinpyrazone
Probenecid
Penicillin G
Adenosine Triphosphate
Furosemide
Methotrexate
Indomethacin
Glutathione
Adenosine Triphosphatases
P-Glycoproteins
Spodoptera
Leukotriene C4
Ethylmaleimide
Membranes
Diuretics
Drug Resistance
Neoplasms
Hydrolysis
Anti-Bacterial Agents

ASJC Scopus subject areas

  • Pharmacology

Cite this

Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions. / Bakos, E.; Evers, Raymond; Sinkó, Emese; Váradi, A.; Borst, Piet; Sarkadi, B.

In: Molecular Pharmacology, Vol. 57, No. 4, 2000, p. 760-768.

Research output: Contribution to journalArticle

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