Differential modulation of the human liver conjugate transporters MRP2 and MRP3 by bile acids and organic anions

被引:129
作者
Bodó, A
Bakos, E
Szeri, F
Váradi, A
Sarkadi, B [1 ]
机构
[1] Hungarian Acad Sci, Natl Med Ctr, Inst Haematol & Immunol, Membrane Res Grp, H-1113 Budapest, Hungary
[2] Hungarian Acad Sci, Inst Enzymol, Biol Res Ctr, H-1113 Budapest, Hungary
关键词
D O I
10.1074/jbc.M303515200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The multidrug resistance proteins MRP2 (ABCC2) and MRP3 (ABCC3) are key primary active transporters involved in anionic conjugate and drug extrusion from the human liver. The major physiological role of MRP2 is to transport conjugated metabolites into the bile canaliculus, whereas MRP3 is localized in the basolateral membrane of the hepatocytes and transports similar metabolites back to the bloodstream. Both proteins were shown to interact with a large variety of transported substrates, and earlier studies suggested that MRPs may work as co-transporters for different molecules. In the present study we expressed the human MRP2 and MRP3 proteins in insect cells and examined their transport and ATPase characteristics in isolated, inside-out membrane vesicles. We found that the primary active transport of estradiol-17-beta-D-glucuronide (E(2)17betaG), a major product of human steroid metabolism, was differently modulated by bile acids and organic anions in the case of human MRP2 and MRP3. Active E(2)17betaG transport by MRP2 was significantly stimulated by the organic anions indomethacin, furosemide, and probenecid and by several conjugated bile acids. In contrast, all of these agents inhibited E(2)17betaG transport by MRP3. We found that in the case of MRP2, ATP-dependent vesicular bile acid transport was increased by E(2)17betaG, and the results indicated an allosteric cross-stimulation, probably a cotransport of bile acids and glucuronate conjugates through this protein. There was no such stimulation of bile acid transport by MRP3. In conclusion, the different transport modulation of MRPs by bile acids and anionic drugs could play a major role in regulating physiological and pathological metabolite fluxes in the human liver.
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页码:23529 / 23537
页数:9
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