Cholesterol-Mediated Activation of P-Glycoprotein: Distinct Effects on Basal and Drug-Induced ATPase Activities
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2009-05
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Journal Article
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yes
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Abstract
Cholesterol promotes basal and verapamil-induced ATPase activity of P-glycoprotein (P-gp). We investigated whether these effects are related to each other and to the impact of the sterol on bilayer fluidity and verapamil membrane affinity. P-gp was reconstituted in egg-phosphatidylcholine (PhC) liposomes with or without cholesterol, 1,2-dipalmitoyl-phosphatidylcholine (DPPC), α-tocopherol (α-Toc) or 2,2,5,7,8-pentamethyl-6-chromanol (PMC). Basal and verapamil-induced ATPase activities were studied with an enzymatic assay. Membrane fluidity was characterized with diphenyl-hexatriene anisotropy measurements and membrane affinity by equilibrium dialysis. DPPC (70% mol/mol) decreased the fluidity of PhC bilayers to the same level as 20% cholesterol. PMC (20%) and α-Toc (20%) decreased the fluidity to lesser extents. α-Toc and PMC, but not DPPC increased the verapamil membrane affinity. While 20% cholesterol strikingly enhanced the basal ATPase activity, none of the other constituents had a similar effect. In contrast, verapamil stimulation of P-gp ATPase activity was not only enabled by cholesterol but also by α-Toc and DPPC. PMC had no effect. In conclusion, cholesterol exerts distinct effects on basal and verapamil-induced ATPase activity. The influence on basal ATPase activity is sterol-specific while its effect on verapamil-induced ATPase activity is unspecific and not related to its influence on membrane fluidity and on verapamil membrane affinity.
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published
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98 (5)
Pages / Article No.
1905 - 1918
Publisher
Wiley
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Subject
P-glycoprotein; cholesterol; ATPase activity; membrane fluidity; membrane affinity
Organisational unit
03244 - Wunderli-Allenspach, Heidi (emeritus)
08830 - Krämer, Stefanie (Tit.-Prof.)
Notes
Received 2 July 2008, Accepted 24 July 2008, Published Online 20 October 2008.