Chlorpromazine inhibits arterial ACAT and reduces arterial cholesterol and cholesteryl ester accumulation in cholesterol-fed rabbits.
Rabbits were fed an atherogenic diet concurrently with chlorpromazine for 2 weeks (10 mg/kg/day in the diet) or 12 weeks (20 mg/kg/day given orally in a single capsule). After 2 weeks, arterial acyl CoA: cholesterol acyltransferase (ACAT) activity tended to be reduced by chlorpromazine treatment with no affect on net arterial cholesterol. After 12 weeks of treatment, arterial ACAT activity was significantly reduced and was paralleled by a reduction in net arterial cholesterol, a reduction in the esterified cholesterol/unesterified cholesterol ratio, and a reduction in lipid staining intensity as determined histologically with oil red O staining of aortic cross sections. Paradoxically, there was no histological evidence for a reduction in the size of atheromatous lesions with chlorpromazine treatment as determined by morphometric analysis of tissue cross sections. The results support the hypothesis that the increased esterification of cholesterol that characteristically accompanies the atherogenic process serves as a biochemical trapping mechanism for cholesterol entering the vessel wall and suggest that regulation of the enzyme in vivo can reduce the net accumulation of arterial cholesterol.
D000818:Animals; D001158:Arteries / Q000378:metabolism*; D001161:Arteriosclerosis / Q000201:enzymology*; D001835:Body Weight / Q000187:drug effects; D002746:Chlorpromazine / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism*; D004036:Diet, Atherogenic; D008055:Lipids / Q000097:blood; D008297:Male; D011817:Rabbits; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
D002788:Cholesterol Esters; D008055:Lipids; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; D002746:Chlorpromazine