Effects of MK-733 (simvastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on intestinal acylcoenzyme A:cholesterol acyltransferase activity in rabbits.
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 though to be related to a reduction in microsomal ACAT activity in the intestinal mucosa.
Ishida
F
F
Central Research Laboratories, Banyu Pharmaceutical Co., Ltd., Tokyo, Japan.
Sato
A
A
Iizuka
Y
Y
Kitani
K
K
Sawasaki
Y
Y
Kamei
T
T
D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000494:pharmacology; D002792:Cholestyramine Resin / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000201:enzymology*; D008055:Lipids / Q000097:blood; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008861:Microsomes / Q000378:metabolism; D011817:Rabbits; D019821:Simvastatin; D002787:Sterol Esterase / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
D002791:Cholesterol, Dietary; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D002792:Cholestyramine Resin; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin; D002785:Sterol O-Acyltransferase; D002787:Sterol Esterase