Multidrug Resistance P-Glycoprotein Is Not Involved in Cholesterol Esterification

The aim of the present paper is to reinvestigate the role of multidrug resistance P-glycoprotein MDR1 and MDR-associated protein (MRP1) in cholesterol esterification using well-characterized inhibitors. Using specific substrate efflux assay, we show that GF120918 (0.2 μM) and probenecid (5 mM) were...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2000-12, Vol.279 (2), p.369-377
Main Authors: Issandou, Marc, Grand-Perret, Thierry
Format: Article
Language:English
Subjects:
Acridines - pharmacology
Anticholesteremic Agents - pharmacology
Atorvastatin Calcium
ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors
ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism
Cholesterol - metabolism
Cholesterol Esters - metabolism
DNA-Binding Proteins - antagonists & inhibitors
DNA-Binding Proteins - metabolism
Fluoresceins - pharmacokinetics
Fluorescent Dyes
Heptanoic Acids - pharmacology
Humans
Isoquinolines - pharmacology
Kinetics
Multidrug Resistance-Associated Proteins
MutS Homolog 3 Protein
Probenecid - pharmacology
Progesterone - pharmacology
Pyrroles - pharmacology
Sterol O-Acyltransferase - antagonists & inhibitors
Sterol O-Acyltransferase - metabolism
Tetrahydroisoquinolines
Tumor Cells, Cultured
Verapamil - pharmacology
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Summary:The aim of the present paper is to reinvestigate the role of multidrug resistance P-glycoprotein MDR1 and MDR-associated protein (MRP1) in cholesterol esterification using well-characterized inhibitors. Using specific substrate efflux assay, we show that GF120918 (0.2 μM) and probenecid (5 mM) were specific inhibitors of MDR1 and MRP1, respectively. In HepG2 cells, neither of them affect the esterification of cholesterol derived from the uptake of cholesterol-rich lipoprotein, while both verapamil (100 μM) and progesterone (100 μM) were able to inhibit cholesterol esterification. Similar results were obtained with verapamil, progesterone, and GF120918 in the MDR1-overexpressing cells MCF7/ADR. The capacity of progesterone to reduce cholesterol esterification is not correlated with its ability to inhibit MDR1 but is rather due to direct inhibition of acyl-CoA:cholesterol acyltransferase (ACAT). We conclude that the esterification of cholesterol is not correlated with MDR1 or MRP1 activity, thus excluding their role in the intracellular transport of endocytosis-derived cholesterol.
ISSN:0006-291X
1090-2104
DOI:10.1006/bbrc.2000.3939