[Effect of the monooxygenase activity inhibitor ketoconazole on cholesterol esterification in mouse peritoneal macrophages].
In order to determine the feasible role of monooxygenases in regulation of the macrophage acyl-CoA: cholesterol acyltransferase (ACAT) activity, the effects of ketoconazole on the activities of benz(a)pyrene hydroxylase and ACAT as well as on the [14C]oleate incorporation into cholesterol esters in cultured mouse peritoneal macrophages (MPM) were studied. Ketoconazole (0.5-50 M) inhibited the benz(a)pyrene hydroxylase activity but increased the free cholesterol (FC) level in MPM cultured with an acetylated low density lipoprotein (acetyl-LDL). An addition of ketoconazole (1-50 M) eliminated the increase in the rate of FC esterification after incubation of MPM with acetyl-LDL (but not with 25-hydroxycholesterol). In contrast, progesterone, an ACAT activity inhibitor, used at 5-30 M diminished the rate of FC esterification, when MPM were incubated with acetyl-LDL of 25-hydroxycholesterol. Ketoconazole provoked a dose-dependent decrease of the [3H]FC incorporation into macrophage polar oxysteroids. The data obtained suggest that the ketoconazole (1-30 M) effect on FC esterification in MPM cultured with acetyl-LDL is determined by its inhibiting monooxygenases, which produce oxidized forms of FC that are potential activators of ACAT.
Dushkin
M I
MI
Mandrikova
E V
EV
Liubimov
G Iu
GIu
Vol'skiĭ
N N
NN
Dolgov
A V
AV
D000818:Animals; D001579:Benzopyrene Hydroxylase / Q000037:antagonists & inhibitors; D002788:Cholesterol Esters / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D019301:Oleic Acid; D009829:Oleic Acids / Q000378:metabolism; D010105:Oxygenases / Q000037:antagonists & inhibitors*; D010529:Peritoneal Cavity / Q000166:cytology; D011374:Progesterone / Q000494:pharmacology; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors
D002788:Cholesterol Esters; D065607:Cytochrome P-450 Enzyme Inhibitors; D008077:Lipoproteins, LDL; D009829:Oleic Acids; C032629:acetyl-LDL; D019301:Oleic Acid; D011374:Progesterone; D010105:Oxygenases; D001579:Benzopyrene Hydroxylase; D002785:Sterol O-Acyltransferase; D007654:Ketoconazole
Vliianie ingibitora monooksigenaznoĭ aktivnosti ketokonazola na ésterifizkatsiiu kholesterina v peritoneal'nykh makrofagakh myshi.