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Originally published In Press as doi:10.1074/jbc.M303515200 on April 19, 2003
J. Biol. Chem., Vol. 278, Issue 26, 23529-23537, June 27, 2003
Differential Modulation of the Human Liver Conjugate Transporters MRP2 and MRP3 by Bile Acids and Organic Anions*
Adrienn Bodó   ,
Éva Bakos ,
Flóra Szeri ,
András Váradi and
Balázs Sarkadi ¶
From the
National Medical Center, Institute of
Haematology and Immunology, Membrane Research Group of the Hungarian Academy
of Sciences and the Institute of Enzymology,
Biological Research Center, Hungarian Academy of Sciences, Budapest, 1113
Hungary
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- -D-glucuronide (E217G), 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
E217G 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
E217G transport by MRP3. We found that in the case of MRP2,
ATP-dependent vesicular bile acid transport was increased by
E217G, and the results indicated an allosteric
cross-stimulation, probably a co-transport 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.
Received for publication, April 4, 2003
, and in revised form, April 17, 2003.
* This work was supported by Grants T31952, T35926, and T38337 from OTKA and
by funds from ETT (Hungary). The costs of publication of this article were
defrayed in part by the payment of page charges. This article must therefore
be hereby marked "advertisement" in accordance with 18
U.S.C. Section 1734 solely to indicate this fact.
¶
Recipient of a Howard Hughes International Scholarship. To whom correspondence
should be addressed: National Medical Center, Institute of Haematology and
Immunology, 1113 Budapest, Diószegi u. 64, Hungary. Tel./Fax:
36-1-372-4353; E-mail:
sarkadi{at}biomembrane.hu.
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Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.
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