Abstract
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.
Footnotes
- Received July 16, 1999.
- Accepted December 1, 1999.
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Send reprint requests to: Dr. Bruno Stieger, University Hospital, Department of Medicine, Division of Clinical Pharmacology and Toxicology, 8091 Zurich, Switzerland. E-mail:bstieger{at}kpt.unizh.ch
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This work was supported by the Swiss National Science Foundation (Grant 31-45536.95) and the Hartmann Müller Foundation, University of Zurich, Switzerland.
- The American Society for Pharmacology and Experimental Therapeutics
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