QUANTITATIVE-ANALYSIS OF HYDROPHOBIC AMINE INHIBITION OF INTRACELLULAR CHOLESTEROL TRANSPORT

U18666A and imipramine are hydrophobic amines that inhibit intracellul ar cholesterol transport pathways. In this study, we conducted dose-re sponse curves for each of the cholesterol transport pathways. Our anal yses indicate that hydrophobic amine inhibition of LDL-stimulated chol esterol esterification is much more sensitive to inhibition than eithe r the combined bulk movement of cholesterol from lysosomes to the plas ma membrane and from the plasma membrane to the endoplasmic reticulum. Hydrophohic 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 fo r U18666A action were evaluated. The function of p-glycoprotein, which has teen implicated in cholesterol transport, was unaffected by U1866 6A. We have evidence for a specific membrane U18666A binding site, whi ch we hypothesize is involved in the plasma membrane to endoplasmic re ticulum cholesterol transport pathway. Identification of the binding s ite and mechanism of hydrophobic amine action may provide information essential for understanding intracellular cholesterol transport.