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Research ArticleMetabolism, Transport, and Pharmacogenomics

Sphingolipid Signaling Reduces Basal P-Glycoprotein Activity in Renal Proximal Tubule

David S. Miller
Journal of Pharmacology and Experimental Therapeutics March 2014, 348 (3) 459-464; DOI: https://doi.org/10.1124/jpet.113.210641
David S. Miller
Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina; and Mount Desert Island Biological Laboratory, Salsbury Cove, Maine
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Abstract

P-glycoprotein is an ATP-driven xenobiotic export pump that is highly expressed in barrier and excretory tissues, where it greatly influences drug pharmacokinetics. Recent studies in the blood-brain and spinal cord barriers identified a sphingolipid-based signaling pathway that regulates basal activity of P-glycoprotein. Here we use an established comparative renal model that permits direct measurement of P-glycoprotein activity to determine whether such signaling occurs in another tissue, killifish renal proximal tubule. Isolated killifish tubules exposed to 0.01–1.0 μM sphingosine-1-phosphate (S1P) exhibited a profound decrease in P-glycoprotein transport activity, measured as specific accumulation of a fluorescent cyclosporine A derivative in the tubule lumen. Loss of activity had a rapid onset and was fully reversible when the S1P was removed. Transport mediated by multidrug resistance-associated protein 2 (Mrp2) or a teleost fish organic anion transporter (Oat) was not affected. S1P effects were blocked by a specific S1P receptor 1 (S1PR1) antagonist and mimicked by a S1PR agonist. Sphingosine also reduced P-glycoprotein transport activity and those effects were blocked by an inhibitor of sphingosine kinase and by the S1PR1 antagonist. These results for a comparative renal model suggest that sphingolipid signaling to P-glycoprotein is not just restricted to the blood-brain and blood–spinal cord barriers, but occurs in other excretory and barrier tissues.

Footnotes

    • Received October 22, 2013.
    • Accepted December 30, 2013.
  • This work was supported by the Intramural Research Program of the National Institutes of Health [National Institute of Environmental Health Sciences].

  • dx.doi.org/10.1124/jpet.113.210641.

  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 348 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 348, Issue 3
1 Mar 2014
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Sphingolipid Signaling in Renal Proximal Tubule

David S. Miller
Journal of Pharmacology and Experimental Therapeutics March 1, 2014, 348 (3) 459-464; DOI: https://doi.org/10.1124/jpet.113.210641

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Sphingolipid Signaling in Renal Proximal Tubule

David S. Miller
Journal of Pharmacology and Experimental Therapeutics March 1, 2014, 348 (3) 459-464; DOI: https://doi.org/10.1124/jpet.113.210641
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