Phenothiazines inhibit cholesteryl ester formation in J 774 monocyte-like cells.
The effect of phenothiazines (trifluoperazine and chlorpromazine) on cholesteryl ester metabolism has been investigated in J 774 mouse monocyte-macrophages. The incorporation of oleic acid into cholesteryl ester and the activity of acylcoenzyme A: cholesterol-O-acyltransferase were strongly decreased in cells pretreated for 24 h with trifluoperazine or chlorpromazine. Furthermore, trifluoperazine or chlorpromazine decreased the degradation of acetylated low density lipoprotein by J 774 cells. When cell homogenates were preincubated in vitro with trifluoperazine or chlorpromazine, a marked inhibition of acylcoenzyme A: cholesterol-O-acyltransferase activity was observed. In cells incubated with acetylated low density lipoprotein loaded with radiolabeled cholesteryl-linoleate, trifluoperazine and chlorpromazine dramatically reduced the radioactivity recovered in cholesteryl esters. The radioactivity recovered in free cholesterol was also decreased, but to a lesser extent. These results suggest that phenothiazines could efficiently antagonize cholesteryl ester accumulation in macrophages by at least two different mechanisms: a reduction of modified LDL catabolism, and a direct inhibition of the enzyme acylcoenzyme A: cholesterol-O-acyltransferase.
Houtia
N E
NE
Laboratoire de Biochemie, CNRS UA 524, Faculté de Médecine Saint-Antoine, Paris, France.
Mazière
J C
JC
Mazière
C
C
Auclair
M
M
Gardette
J
J
Polonovski
J
J
D000818:Animals; D002460:Cell Line; D002746:Chlorpromazine / Q000494:pharmacology*; D002788:Cholesterol Esters / Q000096:biosynthesis / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D019301:Oleic Acid; D009829:Oleic Acids / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000378:metabolism; D014268:Trifluoperazine / Q000494:pharmacology*; D014280:Triglycerides / Q000096:biosynthesis
D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D009829:Oleic Acids; D014280:Triglycerides; D014268:Trifluoperazine; D019301:Oleic Acid; D002785:Sterol O-Acyltransferase; D002746:Chlorpromazine