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PMID: 9355767 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

ATP-dependent transport of bilirubin glucuronides by the multidrug resistance protein MRP1 and its hepatocyte canalicular isoform MRP2.

The Biochemical journal ·Vol. 327 ( Pt 1) ·1997-10-01 ·Pages 305-10

Jedlitschky G, Leier I, Buchholz U, Hummel-Eisenbeiss J, Burchell B, Keppler D

Abstract

Bilirubin is secreted from the liver into bile mainly as monoglucuronosyl and bisglucuronosyl conjugates. We demonstrate for the first time that ATP-dependent transport of both bilirubin glucuronides is mediated by the multidrug resistance protein (MRP1) as well as by the distinct canalicular (apical) isoform MRP2, also termed cMRP or cMOAT (canalicular multispecific organic anion transporter). In membrane vesicles from MRP1-transfected HeLa cells mono[3H]glucuronosylbilirubin and bis[3H]glucuronosylbilirubin (each at 0.5 microM) were transported with rates of 5.3 and 3.1 pmol/min per mg of protein respectively. Rat hepatocyte canalicular membrane vesicles, which contain Mrp2 (the rat equivalent of MRP2), transported mono[3H]glucuronosylbilirubin and bis[3H]glucuronosylbilirubin at rates of 8.9 and 8.5 pmol/min per mg of protein, whereas membrane vesicles from mutant liver lacking Mrp2 showed no transport of the conjugates. In membrane vesicles from human hepatoma Hep G2 cells, which predominantly expressed MRP2, transport rates were 8.3 and 4.4 pmol/min per mg of protein for monoglucuronosylbilirubin and bisglucuronosylbilirubin respectively. ATP-dependent transport of the glutathione S-conjugate -3H-leukotriene C4, an established high-affinity substrate for MRP1 and MRP2, was inhibited by both bilirubin glucuronides with IC50 values between 0.10 and 0.75 microM. The ratios of leukotriene C4 transport and bilirubin glucuronide transport, determined in the same membrane vesicle preparation, indicated substrate specificity differences between MRP1 and MRP2 with a preference of MRP2 for the glucuronides.

MeSH Terms
ATP Binding Cassette Transporter, Subfamily B ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ATP-Binding Cassette Transporters/metabolism Adenosine Triphosphate/pharmacology Animals Bilirubin/analogs & derivatives,metabolism,pharmacology Biological Transport Carrier Proteins/metabolism Cell Membrane/chemistry,metabolism Humans Kinetics Leukotriene C4/analogs & derivatives,metabolism Liver/chemistry,metabolism Membrane Transport Proteins Rats Rats, Wistar Substrate Specificity Transfection/genetics Tumor Cells, Cultured
Chemicals
ATP Binding Cassette Transporter, Subfamily B ATP Binding Cassette Transporter, Subfamily B, Member 1 ATP-Binding Cassette Transporters Carrier Proteins Membrane Transport Proteins glutathione transporter bilirubin glucuronate Leukotriene C4 Adenosine Triphosphate multidrug resistance protein 3 Bilirubin
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Jedlitschky G
Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, In Neuenheimer Feld 280, D-69120 Heidelberg, Federal Republic of Germany.
Leier I
Buchholz U
Hummel-Eisenbeiss J
Burchell B
Keppler D
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Article Info
Journal
The Biochemical journal
Abbr.
Biochem J
ISSN
0264-6021
DOI
10.1042/bj3270305
Published
1997-10-01
Pages
305-10
Language
English
Region
England
NLM ID
2984726R
PMCID
PMC1218795
Subset
IM
External Links
PubMed source DOI: 10.1042/bj3270305 PMC Full Text View journal details
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