Multidrug resistance associated protein 2 mediates transport of prostaglandin E2.
OBJECTIVE
Inactivation of prostaglandin E(2) (PGE(2)) in the liver is a rapid process and occurs mainly through beta-oxidation in the peroxisome of the hepatocyte. Biliary excretion of PGE(2) is also a means of elimination from the liver. We investigated the role of multidrug resistance-associated protein 2 (MRP2) in the transport of PGE(2).


METHODS
Biliary PGE(2) elimination was measured in liver perfusions in Wistar and MRP2-deficient TR(-) rats. Furthermore, transport experiments were performed in membrane vesicles from human MRP2-infected Spodoptera frugiperda 21 (Sf21) insect cells.


RESULTS
The liver perfusions showed a 3.5 times higher percentage of undegraded [(3)H]PGE(2) in bile of Wistar rats in comparison with MRP2 deficient (TR(-)) rats (3.6% vs. 1.1%, respectively; P<0.05). MRP2-mediated transport of the model substrate [(3)H]DNP-SG was inhibited by PGE(2). Half maximal inhibition was achieved at a concentration of approximately 15 microM PGE(2). In addition, [(3)H]PGE(2) uptake in these vesicles was detected, and determined to be ATP dependent.


CONCLUSIONS
MRP2 mediates the transport of PGE(2) and its breakdown products. The biliary excretion of PGE(2) via MRP2 may contribute to rapid elimination of the prostaglandin but might also serve to relay prostaglandin signalling to the biliary tree.
de Waart
Dirk R
DR
Department of Experimental Hepatology, Academic Medical Center, Amsterdam, the Netherlands. d.r.dewaart@amc.uva.nl
Paulusma
Coen C
CC
Kunne
Cindy
C
Oude Elferink
Ronald P J
RP
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D015232:Dinoprostone / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D010120:Oxytocics / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D018411:Spodoptera / Q000166:cytology; D022161:Transport Vesicles / Q000187:drug effects; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D015232:Dinoprostone; D000089762:Multidrug Resistance-Associated Protein 2; D010120:Oxytocics; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C000715087:ABCC2 protein, human