P-glycoprotein (P-gp) function in T cells: implications for organ transplantation |
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Authors: | Vera S Donnenberg Gilbert J Burckart Albert D Donnenberg |
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Institution: | a Department of Surgery, University of Pittsburgh, Cancer Institute Hillman Cancer Research PavilionSuite 2.42 5117 Centre Avenue, Pittsburgh, PA 15213, USA b School of Pharmacy, University of Pittsburgh, Cancer Institute Hillman Cancer Research Pavilion Suite 2.42 5117 Centre Avenue, Pittsburgh, PA 15213, USA c Department of Medicine, University of Pittsburgh, Cancer Institute Hillman Cancer Research Pavilion Suite 2.42 5117 Centre Avenue, Pittsburgh, PA 15213, USA |
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Abstract: | P-glycoprotein (P-gp), a member of the adenosine triphosphate (ATP)-binding cassette (ABC) family of transporter molecules, is responsible for maintaining low intracellular concentrations of a variety of extracellular compounds and xenobiotics, and for transport of various intracellular molecules. Many drugs are P-gp substrates and intracellular concentrations of these agents may be critical for drug action. Experience in oncology indicates that repeated exposure to P-gp substrate cytotoxic drugs leads to the selection of drug-resistant tumor cells that overexpress P-gp. Since immunosuppressive agents such as cyclosporine, tacrolimus, sirolimus and corticosteroids are substrates for P-gp and since T-cells also express P-gp, it is conceivable that an analogous mechanism exits for therapy-resistant graft rejection. As will be discussed in this article, P-gp may interfere with the response to immunosuppressive therapy through several distinct mechanisms, and as such may represent an attractive therapeutic target. |
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Keywords: | P-glycoprotein MDR1 Organ transplantation Rhodamine 123 T-cells Graft rejection Cyclosporin A Drug interactions Physiological functions Apoptosis |
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