Cholesterol modulates P-glycoprotein activity in human peripheral blood mononuclear cells |
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Authors: | Troost Joachim Albermann Nadine Emil Haefeli Walter Weiss Johanna |
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Institution: | Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Bergheimer Str. 58, D-69115 Heidelberg, Germany. |
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Abstract: | P-glycoprotein (P-gp) is expressed in a wide range of cell types including peripheral blood mononuclear cells (PBMCs) where it may restrict intracellular accumulation of substrates like antineoplastic agents, HIV protease inhibitors, or rhodamine123. P-gp is known to be located in membrane microdomains, whose structure and function are susceptible to cholesterol alterations. This study evaluated the effect of cholesterol alteration in human PBMCs on P-gp activity. Whereas cholesterol depletion had no effect, cholesterol repletion of depleted cells significantly decreased intracellular rhodamine123 concentrations in lymphocytes to 32.2%+/-2.7 (p<0.001) and to 41.9%+/-3.5 (p<0.001) in monocytes. After cholesterol saturation of native cells intracellular rhodamine123 fluorescence decreased to 12.4%+/-1.6 (p<0.001) in lymphocytes and 12.9%+/-3.5 (p<0.001) in monocytes. These data demonstrate that elevated cellular cholesterol levels can markedly increase P-gp activity in human PBMCs. |
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Keywords: | Cholesterol P-glycoprotein Cyclodextrins Rhodamine123 Membrane microdomains Caveolae Rafts Lymphocytes Monocytes |
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