Effect of doxazosin on cholesterol synthesis in cell culture.
The effect of doxazosin on cholesterol synthesis was determined by measuring the content of deuterium-enriched cholesterol in rabbit fibroblasts with and without receptors for low-density lipoproteins (LDL) and in hepatoma (Hep G2 cells). Doxazosin, at concentrations of 5-20 mumol/L, increased LDL binding to hepatic cells in a dose-related manner. Also, in these hepatic cells, doxazosin produced dose-related decreases in both newly synthesized cholesterol and cholesterol ester. In rabbit fibroblasts that were LDL receptor negative, de novo cholesterol synthesis was markedly reduced by increasing concentrations of doxazosin. Taken together, these results suggest that doxazosin may have a direct inhibitory effect on cholesterol synthesis independent of the LDL receptor. The inhibition of cholesterol synthesis by doxazosin may cause cells to compensate by upregulating the LDL receptor, thereby increasing the importation of lipoprotein cholesterol and reducing LDL cholesterol in the medium. This hypothesis supports findings in the clinical setting whereby doxazosin has a beneficial effect on the lipid profile, and suggests a useful additional property for this antihypertensive agent.
D'Eletto
R D
RD
Division of Hepatic Diseases, New York University Medical Center, New York 10016.
Javitt
N B
NB
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D002788:Cholesterol Esters / Q000096:biosynthesis; D003903:Deuterium; D017292:Doxazosin; D005347:Fibroblasts / Q000378:metabolism; D008114:Liver Neoplasms, Experimental; D011224:Prazosin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011973:Receptors, LDL / Q000502:physiology; D014407:Tumor Cells, Cultured
D000317:Adrenergic alpha-Antagonists; D002788:Cholesterol Esters; D011973:Receptors, LDL; D002784:Cholesterol; D003903:Deuterium; D017292:Doxazosin; D011224:Prazosin