Premium
ATP‐ and glutathione‐dependent transport of chemotherapeutic drugs by the multidrug resistance protein MRP1
Author(s) -
Renes Johan,
De Vries Elisabeth G E,
Nienhuis Edith F,
Jansen Peter L M,
Müller Michael
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702360
Subject(s) - daunorubicin , glutathione , p glycoprotein , multiple drug resistance , chemistry , membrane transport , vesicle , atp binding cassette transporter , biochemistry , pharmacology , vincristine , multidrug resistance associated proteins , transporter , biology , membrane , enzyme , chemotherapy , genetics , cyclophosphamide , gene , antibiotics
The present study was performed to investigate the ability of the multidrug resistance protein (MRP1) to transport different cationic substrates in comparison with MDR1 ‐P‐glycoprotein (MDR1). Transport studies were performed with isolated membrane vesicles from in vitro selected multidrug resistant cell lines overexpressing MDR1 (A2780AD) or MRP1 (GLC 4 /Adr) and a MRP1 ‐transfected cell line (S1(MRP)). As substrates we used 3 H‐labelled derivatives of the hydrophilic monoquaternary cation N ‐(4′,4′‐azo‐ n ‐pentyl)‐21‐deoxy‐ajmalinium (APDA), the basic drug vincristine and the more hydrophobic basic drug daunorubicin. All three are known MDR1‐substrates. MRP1 did not mediate transport of these substrates per se . In the presence of reduced glutathione (GSH), there was an ATP‐dependent uptake of vincristine and daunorubicin, but not of APDA, into GLC 4 /Adr and S1(MRP) membrane vesicles which could be inhibited by the MRP1‐inhibitor MK571. ATP‐ and GSH‐dependent transport of daunorubicin and vincristine into GLC 4 /Adr membrane vesicles was inhibited by the MRP1‐specific monoclonal antibody QCRL‐3. MRP1‐mediated daunorubicin transport rates were dependent on the concentration of GSH and were maximal at concentrations 10 m M . The apparent K M value for GSH was 2.7 m M . Transport of daunorubicin in the presence of 10 m M GSH was inhibited by MK571 with an IC 50 of 0.4 μ M . In conclusion, these results demonstrate that MRP1 transports vincristine and daunorubicin in an ATP‐ and GSH‐dependent manner. APDA is not a substrate for MRP1.British Journal of Pharmacology (1999) 126 , 681–688; doi: 10.1038/sj.bjp.0702360