RT Journal Article
SR Electronic
T1 Transport Function and Hepatocellular Localization of mrp6 in Rat Liver
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 634
OP 641
DO 10.1124/mol.57.3.634
VO 57
IS 3
A1 Jerzy Madon
A1 Bruno Hagenbuch
A1 Lukas Landmann
A1 Peter J. Meier
A1 Bruno Stieger
YR 2000
UL http://molpharm.aspetjournals.org/content/57/3/634.abstract
AB The multidrug resistance-associated proteins (Mrps) constitute a family of cellular export pumps of the ATP-binding cassette transporter superfamily and play an important role in hepatobiliary excretion. We investigated the transport function and subcellular localization of mrp6, a novel member of the mrp family, in rat liver. Transport studies in vesicles isolated from mrp6 expressing Sf9 cells identified the anionic cyclopentapeptide and endothelin receptor antagonist BQ-123 as a substrate of mrp6 (K m ∼ 17 μM). Besides BQ-123, which is also a substrate of mrp2 (K m ∼ 124 μM), no other common substrates were found for mrp2, mrp6, and the canalicular bile salt export pump Bsep. The cyclic peptides endothelin I and Arg8-vasopressin were transported by mrp2 but not by mrp6. Using a polyclonal antiserum raised against a C-terminal peptide, mrp6 was found to be localized at the lateral and, to a lesser extent, at the canalicular plasma membrane of hepatocytes. The limited overlap of the substrate specificity with the canalicular export pumps mrp2 and Bsep indicates that mrp6 does not play a major role in canalicular organic anion excretion. However, its dual localization at the lateral and canalicular plasma membrane suggests that mrp6 might fulfill a “housekeeping” transport function involved in the regulation of paracellular and/or transcellular solute movement from blood into bile.