P-glycoprotein (P-gp) is upregulated in peripheral T-cell subsets from solid organ transplant recipients

Vera S. Donnenberg, Gilbert J. Burckart, Bartley P. Griffith, Ashokkumar Jain, Adriana Zeevi, Albert D. Donnenberg

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Immunosuppressive agents such as cyclosporine, tacrolimus, sirolimus, and corticosteroids are substrates for the transmembrane multidrug resistance pump P-glycoprotein (P-gp). Experience in oncology has suggested that chronic exposure to P-gp substrates induces upregulation of P-gp activity, which could result in resistance to immunosuppressive drugs. The authors investigated P-gp function in CD4+ and CD8+ T cells from the peripheral blood of solid organ transplant recipients (SOTX). Subjects included 14 stable SOTX (10 liver, 4 lung) and 16 healthy controls. Four-color flow cytometry was used to simultaneously measure intracellular concentration of the fluorescent P-gp substrate Rhodamine 123 (Rh123) and surface expression of CD45RO (nominal memory/effector), CD45RA (naive), and either CD4 or CD8. P-glycoprotein function was measured by a dye efflux assay in which activity was inferred from a decrease in Rh123 fluorescence. CD4+ and CD8+ T cells from patients and control subjects eliminated Rh123, and this activity was inhibited by verapamil, a known P-gp substrate. CD8+ T cells had greater P-gp activity than CD4+ cells, and naive and transitional T cells displayed greater activity than memory T cells. Activity was bimodal in CD8+ CD45RO+ T cells, with a subset of these cells expressing the greatest P-gp activity. Patient CD8+ naive and transitional T cells had upregulated P-gp activity compared to control subjects. We conclude that (1) P-gp activity is significantly upregulated in specific T-cell subsets (CD8+/CD45RA+) in the peripheral blood of SOTX, and (2) the bimodal nature of P-gp response in CD8+ T cells complicates analysis of the effect of chronic administration of P-gp substrates to SOTX.

Original languageEnglish (US)
Pages (from-to)1271-1279
Number of pages9
JournalJournal of Clinical Pharmacology
Volume41
Issue number12
DOIs
StatePublished - Dec 12 2001

Fingerprint

P-Glycoprotein
T-Lymphocyte Subsets
Transplants
T-Lymphocytes
Rhodamine 123
Immunosuppressive Agents
Transplant Recipients
Multiple Drug Resistance
Tacrolimus
Sirolimus
Verapamil
Cyclosporine
Flow Cytometry
Adrenal Cortex Hormones
Coloring Agents
Up-Regulation
Color
Fluorescence

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Donnenberg, Vera S. ; Burckart, Gilbert J. ; Griffith, Bartley P. ; Jain, Ashokkumar ; Zeevi, Adriana ; Donnenberg, Albert D. / P-glycoprotein (P-gp) is upregulated in peripheral T-cell subsets from solid organ transplant recipients. In: Journal of Clinical Pharmacology. 2001 ; Vol. 41, No. 12. pp. 1271-1279.
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P-glycoprotein (P-gp) is upregulated in peripheral T-cell subsets from solid organ transplant recipients. / Donnenberg, Vera S.; Burckart, Gilbert J.; Griffith, Bartley P.; Jain, Ashokkumar; Zeevi, Adriana; Donnenberg, Albert D.

In: Journal of Clinical Pharmacology, Vol. 41, No. 12, 12.12.2001, p. 1271-1279.

Research output: Contribution to journalArticle

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AU - Donnenberg, Vera S.

AU - Burckart, Gilbert J.

AU - Griffith, Bartley P.

AU - Jain, Ashokkumar

AU - Zeevi, Adriana

AU - Donnenberg, Albert D.

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