Troost Joachim, Albermann Nadine, Emil Haefeli Walter, Weiss Johanna
Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Bergheimer Str. 58, D-69115 Heidelberg, Germany.
Biochem Biophys Res Commun. 2004 Apr 9;316(3):705-11. doi: 10.1016/j.bbrc.2004.02.102.
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.
P-糖蛋白（P-gp）在多种细胞类型中表达，包括外周血单核细胞（PBMCs），在这些细胞中它可能会限制诸如抗肿瘤药物、HIV蛋白酶抑制剂或罗丹明123等底物的细胞内蓄积。已知P-gp定位于膜微区，其结构和功能易受胆固醇变化的影响。本研究评估了人PBMCs中胆固醇变化对P-gp活性的影响。胆固醇耗竭没有影响，而对耗竭细胞补充胆固醇则显著降低了淋巴细胞内罗丹明123的浓度，降至32.2%±2.7（p<0.001），单核细胞内降至41.9%±3.5（p<0.001）。在天然细胞胆固醇饱和后，淋巴细胞内罗丹明123荧光降至12.4%±1.6（p<0.001），单核细胞内降至12.9%±3.5（p<0.001）。这些数据表明，细胞胆固醇水平升高可显著增加人PBMCs中的P-gp活性。
