Anthracyclines modulate multidrug resistance protein (MRP) mediated organic anion transport.

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Heijn M, Hooijberg JH, Scheffer GL, Szabo G, Westerhoff HV, Lankelma J

Anthracyclines modulate multidrug resistance protein (MRP) mediated organic anion transport.

Biochim Biophys Acta. 1997 May 22;1326(1):12-22.

PubMed ID

9188796 [ View in PubMed

]

Abstract

We studied the ATP-dependent uptake of dinitrophenyl-glutathione (GS-DNP) into plasma membrane vesicles derived from parental GLC4 cells and from multidrug resistant GLC4/ADR cells. The latter have a high expression of the multidrug resistance protein (MRP). Uptake of GS-DNP into membrane vesicles from GLC4/ADR cells was highly stimulated by the addition of ATP, compared to the uptake into membrane vesicles from GLC4 cells. This ATP-dependent uptake into membrane vesicles from GLC4/ADR cells was saturable with a Km of 1.2 +/- 0.2 microM and a Vmax of 560 +/- 80 pmol/mg prot./min. ATP stimulated GS-DNP uptake with a Km of 187 +/- 4 microM. This uptake was specifically inhibited by a polyclonal serum raised against a fusion protein containing a segment of MRP. The ATP-dependent uptake of GS-DNP was not only inhibited by organic anions, such as oxidized glutathione (GSSG), methotrexate (MTX) and some bile acids, but also by non-anionic natural product drugs, such as anthracyclines, vinca alkaloids and etoposide (VP-16). Uptake of GSSG and MTX into membrane vesicles from GLC4/ADR cells could be stimulated by ATP. The ATP-dependent uptake of GSSG had a Km of 43 +/- 3 microM and a Vmax of 900 +/- 200 nmol/mg protein/min. The ATP-dependent uptake of GS-DNP seemed to be non-competitively inhibited by the anthracycline daunorubicin (DNR), whereas the ATP-dependent GSSG uptake seemed to be competitively inhibited by DNR. A substrate binding site on MRP is proposed that comprises a pocket in which both DNR and GS-DNP or GSSG bind in random order to different, only partly overlapping sites. In this pocket binding of a second compound is influenced by the compound which was bound first.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Daunorubicin	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Substrate Inhibitor	Details
Etoposide	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Substrate Inhibitor	Details
Glutathione	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Substrate Inhibitor	Details
Idarubicin	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Inhibitor	Details
Methotrexate	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Substrate Inhibitor	Details
Paclitaxel	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Inhibitor	Details
Taurocholic acid	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Inhibitor Inducer	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Daunorubicin	Multidrug resistance-associated protein 1	Ki (nM)	950	N/A	N/A	Details