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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

ATP-Dependent Transport of Leukotrienes B₄ and C₄ by the Multidrug Resistance Protein ABCC4 (MRP4)

Division of Tumor Biochemistry, German Cancer Research Center, Heidelberg, Germany

The proinflammatory mediators leukotriene (LT) B₄ and LTC₄ must be transported out of cells before they can interact with LT receptors. Previously, we identified the multidrug resistance protein ABCC1 (MRP1) as an efflux pump for LTC₄. However, the molecular basis for the efflux of LTB₄ was unknown. Here, we demonstrate that human ABCC4 mediates the ATP-dependent efflux of LTB₄ in the presence of reduced glutathione (GSH), whereby the latter can be replaced by S-methyl GSH. Transport studies were performed with inside-out membrane vesicles from V79 fibroblasts and Sf9 insect cells that contained recombinant ABCC4, with vesicles from human platelets and myelomonocytic U937 cells, which were rich in endogenous ABCC4, but ABCC1 was below detectability. Moreover, human polymorphonuclear leukocytes contained ABCC4. K_m values for LTB₄ were 5.2 µM with vesicles from fibroblasts and 5.6 µM with vesicles from platelets. ABCC4, with its broad substrate specificity, also functioned as an ATP-dependent efflux pump for LTC₄ with a K_m of 0.13 µM in vesicles from fibroblasts and 0.32 µM in vesicles from platelets. However, GSH was not required for the transport of this glutathionylated leukotriene. The transport of LTC₄ by ABCC4 explains its release from platelets during transcellular synthesis. ATP-dependent transport of LTB₄ and LTC₄ by ABCC4 was inhibited by several organic anions, including S-decyl GSH, sulindac sulfide, and by the LTD₄ receptor antagonists montelukast and 3-(((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-((3-dimethyl-amino-3-oxopropyl)-thio)-methyl)thio)propanoic acid (MK571). Thus, as an efflux pump for the proinflammatory mediators LTB₄ and LTC₄, ABCC4 may represent a novel target for anti-inflammatory therapies.

Address correspondence to: Dr. Maria Rius, Division of Tumor Biochemistry, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. E-mail: m.rius{at}dkfz.de

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