The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs.

Article Details

Citation

Reid G, Wielinga P, Zelcer N, van der Heijden I, Kuil A, de Haas M, Wijnholds J, Borst P

The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs.

Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9244-9. Epub 2003 Jun 30.

PubMed ID
12835412 [ View in PubMed
]
Abstract

Prostaglandins are involved in a wide variety of physiological and pathophysiological processes, but the mechanism of prostaglandin release from cells is not completely understood. Although poorly membrane permeable, prostaglandins are believed to exit cells by passive diffusion. We have investigated the interaction between prostaglandins and members of the ATP-binding cassette (ABC) transporter ABCC [multidrug resistance protein (MRP)] family of membrane export pumps. In inside-out membrane vesicles derived from insect cells or HEK293 cells, MRP4 catalyzed the time- and ATP-dependent uptake of prostaglandin E1 (PGE1) and PGE2. In contrast, MRP1, MRP2, MRP3, and MRP5 did not transport PGE1 or PGE2. The MRP4-mediated transport of PGE1 and PGE2 displayed saturation kinetics, with Km values of 2.1 and 3.4 microM, respectively. Further studies showed that PGF1alpha, PGF2alpha, PGA1, and thromboxane B2 were high-affinity inhibitors (and therefore presumably substrates) of MRP4. Furthermore, several nonsteroidal antiinflammatory drugs were potent inhibitors of MRP4 at concentrations that did not inhibit MRP1. In cells expressing the prostaglandin transporter PGT, the steady-state accumulation of PGE1 and PGE2 was reduced proportional to MRP4 expression. Inhibition of MRP4 by an MRP4-specific RNA interference construct or by indomethacin reversed this accumulation deficit. Together, these data suggest that MRP4 can release prostaglandins from cells, and that, in addition to inhibiting prostaglandin synthesis, some nonsteroidal antiinflammatory drugs might also act by inhibiting this release.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
AlprostadilATP-binding cassette sub-family C member 4ProteinHumans
Unknown
Substrate
Details
AlprostadilATP-binding cassette sub-family C member 5ProteinHumans
Unknown
Inhibitor
Details
CelecoxibATP-binding cassette sub-family C member 4ProteinHumans
Unknown
Inhibitor
Details
DexibuprofenATP-binding cassette sub-family C member 4ProteinHumans
Unknown
Not AvailableDetails
DexibuprofenMultidrug resistance-associated protein 1ProteinHumans
Unknown
Not AvailableDetails
DiclofenacATP-binding cassette sub-family C member 4ProteinHumans
Unknown
Inhibitor
Details
DiclofenacMultidrug resistance-associated protein 1ProteinHumans
Unknown
Inhibitor
Details
DinoprostoneATP-binding cassette sub-family C member 4ProteinHumans
Unknown
Substrate
Details
DinoprostoneATP-binding cassette sub-family C member 5ProteinHumans
Unknown
Inhibitor
Details
FlurbiprofenATP-binding cassette sub-family C member 4ProteinHumans
Unknown
Inhibitor
Details
IbuprofenATP-binding cassette sub-family C member 4ProteinHumans
Unknown
Inhibitor
Details
IbuprofenMultidrug resistance-associated protein 1ProteinHumans
Unknown
Inhibitor
Details
IndomethacinATP-binding cassette sub-family C member 4ProteinHumans
Unknown
Inhibitor
Details
IndomethacinMultidrug resistance-associated protein 1ProteinHumans
Unknown
Inhibitor
Details
KetoprofenATP-binding cassette sub-family C member 4ProteinHumans
Unknown
Inhibitor
Details
RofecoxibATP-binding cassette sub-family C member 4ProteinHumans
Unknown
Inhibitor
Details