The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs.
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.
Reid
Glen
G
Division of Molecular Biology and Center of Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Wielinga
Peter
P
Zelcer
Noam
N
van der Heijden
Ingrid
I
Kuil
Annemieke
A
de Haas
Marcel
M
Wijnholds
Jan
J
Borst
Piet
P
D000255:Adenosine Triphosphate / Q000378:metabolism; D000527:Alprostadil / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001692:Biological Transport; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004058:Diffusion; D015237:Dinoprost / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007313:Insecta; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011453:Prostaglandins / Q000378:metabolism*; D011454:Prostaglandins A / Q000378:metabolism; D011460:Prostaglandins F / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012269:Ribosomal Proteins / Q000737:chemistry* / Q000502:physiology*; D013929:Thromboxane B2 / Q000378:metabolism; D013997:Time Factors
D000255:Adenosine Triphosphate; D000527:Alprostadil; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015237:Dinoprost; D015232:Dinoprostone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011453:Prostaglandins; D011454:Prostaglandins A; D011460:Prostaglandins F; D034741:RNA, Small Interfering; D012269:Ribosomal Proteins; D013929:Thromboxane B2; C073492:ABCC4 protein, human; C100573:prostaglandin A1; C100006:prostaglandin F1