Effects of MK-733 (simvastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on intestinal acylcoenzyme A: cholesterol acyltransferase activity in rabbits

• Published in: Biochimica et biophysica acta Vol. 1004; no. 1; pp. 117 - 123
• Main Authors: Ishida, Fumiaki, Sato, Akiko, Iizuka, Yuri, Kitani, Koichi, Sawasaki, Yoshio, Kamei, Toshio
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 17.07.1989; Elsevier; North-Holland
• Subjects: Acyl-CoA; Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; Cholesterol - metabolism; cholesterol acyltransferase; Cholesterol esterification; Cholesterol, Dietary - pharmacology; Cholestyramine Resin - pharmacology; Cytosol - metabolism; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intestinal Absorption - drug effects; Intestinal Mucosa - enzymology; Lipids - blood; Lovastatin - analogs & derivatives; Lovastatin - pharmacokinetics; Lovastatin - pharmacology; Male; MHG-CoA reductase inhibitor; Microsomes - metabolism; Rabbit; Rabbits; Simvastatin; Sterol Esterase - metabolism; Sterol O-Acyltransferase - antagonists & inhibitors; Transferases; Rabbit; Cholesterol esterification; Acyl-CoA; Simvastatin; MHG-CoA reductase inhibitor; Radiolabelling; Gut; HPLC chromatography; Enzyme inhibitor; Lipoprotein; Lagomorpha; Microsome; Blood plasma; Thin layer chromatography; Vertebrata; Mammalia; Enzymatic activity; Cholesterol acyltransferase; Mechanism of action; Quantitative analysis
• ISSN: 0005-2760; 0006-3002; 1879-145X; 1878-2434
• DOI: 10.1016/0005-2760(89)90221-X

MK-733 (simvastatin), a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, was found to inhibit the absorption of cholesterol from the gastrointestinal tract in cholesterol-fed rabbits (Ishida et al. (1988) Biochim. Biophys. Acta 963, 35–41). To clarify the mechanism of action, the effects of MK-733 on acyl coenzyme A:cholesterol acyltransferase (ACAT) and cholesterol esterase activities, which are thought to participate in the absorption of cholesterol, were examined. Dietary administration (0.03% in a 1% cholesterol diet for 7 days, approx. 10 mg/kg) of MK-733 to cholesterol-fed rabbits was found to inhibit the increase in serum total cholesterol levels, and caused a 70% reduction in ACAT activity in microsomes of intestinal mucosa relative to those observed in concurrent control rabbits. MK-733 did not affect cholesterol esterase activity in the cytosol of the intestinal mucosa. The inhibitory effect of MK-733 on cholesterol absorption in cholesterol-fed rabbits is thought to be related to a reduction in microsomal ACAT activity in the intestinal mucosa.