Characterization of Chinese hamster ovary cells that are resistant to 3-beta-[2-(diethylamino)ethoxy]androst-5-en-17-one inhibition of low density lipoprotein-derived cholesterol metabolism.
The pharmacological agent U18666A (3-beta-[2-(diethylamino)ethoxy]androst-5-en-17-one inhibits the intracellular transport of low density lipoprotein (LDL)-derived cholesterol in Chinese hamster ovary (CHO) cells. LDL-derived cholesterol accumulates in the lysosomes of U18666A-treated cells causing delayed LDL-mediated regulation of cellular cholesterol metabolism and impaired movement of LDL-derived cholesterol to other cell membranes. As a result of impaired LDL-derived cholesterol transport, LDL-dependent growth of CHO cells is also inhibited by U18666A. By selecting for cell growth in the presence of U18666A, we have identified a CHO cell line, designated U18R, that is resistant to U18666A-inhibition of LDL-derived cholesterol trafficking. When compared to parental CHO cells, U18R cells are relatively resistant to U18666A inhibition of LDL-derived cholesterol transport as well as LDL-mediated regulation of cellular cholesterol metabolism. In cell fusion experiments, the U18666A resistance observed in U18R cells displays a dominant phenotype. Identification of the U18666A-resistant factor may provide important insights toward the understanding of intracellular LDL-derived cholesterol regulation and trafficking.
Liscum
L
L
Department of Physiology, Tufts University School of Medicine, Boston, Massachusetts 02111.
Collins
G J
GJ
D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001692:Biological Transport; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D008078:Cholesterol, LDL / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003078:Colchicine / Q000494:pharmacology; D006224:Cricetinae; D003630:Daunorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004951:Esterification; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D010641:Phenotype; D011973:Receptors, LDL / Q000378:metabolism
D000736:Androstenes; D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D011973:Receptors, LDL; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D006903:Hydroxymethylglutaryl CoA Reductases; D007654:Ketoconazole; D003078:Colchicine; D003630:Daunorubicin