Quantitative analysis of hydrophobic amine inhibition of intracellular cholesterol transport.
U18666A and imipramine are hydrophobic amines that inhibit intracellular cholesterol transport pathways. In this study, we conducted dose-response curves for each of the cholesterol transport pathways. Our analyses indicate that hydrophobic amine inhibition of LDL-stimulated cholesterol esterification is much more sensitive to inhibition than either the combined bulk movement of cholesterol from lysosomes to the plasma membrane and from the plasma membrane to the endoplasmic reticulum. Hydrophobic amines must inhibit a previously uncharacterized pathway from lysosomes to the endoplasmic reticulum or a signaling event that activates acyl CoA:cholesterol acyltransferase. Possible mechanisms for U18666A action were evaluated. The function of p-glycoprotein, which has been implicated in cholesterol transport, was unaffected by U18666A. We have evidence for a specific membrane U18666A binding site, which we hypothesize is involved in the plasma membrane to endoplasmic reticulum cholesterol transport pathway. Identification of the binding site and mechanism of hydrophobic amine action may provide information essential for understanding intracellular cholesterol transport.
Underwood
K W
KW
Department of Physiology, Tufts University School of Medicine, Boston, MA 02111, USA.
Andemariam
B
B
McWilliams
G L
GL
Liscum
L
L
D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001665:Binding Sites; D001692:Biological Transport / Q000187:drug effects; D016466:CHO Cells; D002784:Cholesterol / Q000378:metabolism*; D002789:Cholesterol Oxidase / Q000378:metabolism; D006224:Cricetinae; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004951:Esterification; D007099:Imipramine / Q000494:pharmacology; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013108:Sphingomyelin Phosphodiesterase / Q000494:pharmacology
D000736:Androstenes; D000924:Anticholesteremic Agents; D008077:Lipoproteins, LDL; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D002784:Cholesterol; D002789:Cholesterol Oxidase; D013108:Sphingomyelin Phosphodiesterase; D007099:Imipramine