Cholesterol modulates P-glycoprotein activity in human peripheral blood mononuclear cells.
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.
Troost
Joachim
J
Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Bergheimer Str. 58, D-69115 Heidelberg, Germany.
Albermann
Nadine
N
Emil Haefeli
Walter
W
Weiss
Johanna
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000378:metabolism*; D000328:Adult; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D021962:Membrane Microdomains; D009000:Monocytes / Q000378:metabolism; D011487:Protein Conformation; D020112:Rhodamine 123 / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005456:Fluorescent Dyes; D020112:Rhodamine 123; D002784:Cholesterol