Inhibition of acyl coenzyme A: Cholesterol acyltransferase by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

Ishida, Fumiaki; Satô, Akiko; Iizuka, Yuri; Kamei, Takeshi

doi:10.1248/cpb.37.1635

Cited by 24 publications

(8 citation statements)

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“…Although we did indeed find that compactin induced phospholipid synthesis when the incubation was done in the presence of acetyl LDL ( Figure 5), further experiments are needed to test these hypotheses. Recently, it has been reported that simvastatin is able to decrease the intestinal absorption of free cholesterol in cholesterol-fed rabbits 28 and that the acid forms of both lovastatin and simvastatin act as inhibitors of ACAT activity in microsomes of the rabbit intestine, 29 with half-maximal inhibitory concentrations on the order of 10 5 M. These findings are in line with other data that true ACAT inhibitors can decrease cholesterol absorption. 30 More recently, lovastatin was reported to block the transport of labeled cholesterol through a monolayer of CaCo-2 cells, a model of human small intestinal mucosal cells, 31 in parallel with a decrease in the incorporation of oleate in cholesterol esters.…”

Section: Association Degradationsupporting

confidence: 87%

Vastatins inhibit cholesterol ester accumulation in human monocyte-derived macrophages.

Kempen¹,

Vermeer²,

Wit³

et al. 1991

Arterioscler Thromb

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u C]oleate in CE (by 70-90%) in incubations with or without added lipoproteins. The half-maximal inhibitory concentration for this effect of compactin was 30 nM. Lovastatin and simvastatin were more potent, but pravastatin was about 100-fold less potent Although compactin also caused a clear inhibition of cholesterol synthesis in the presence of acetyl LDL, the effect on CE formation did not seem to be related to decreased cholesterol synthesis, since this was already very low in the presence of acetyl LDL. Compactin did not affect the association and degradation of labeled acetyl LDL and also had no effect on the rate of cholesterol loss after preloading the cells with CE by incubation with acetyl LDL. However, compactin had a slight stimulatory effect on the synthesis of phosphatidylcholine and sphingomyelin when compactin was added to incubations in the presence of acetyl LDL. We conclude that vastatins can decrease the supply of FC toward the enzyme, acyl-coenzyme A:cholesterol acyitransferase, by trapping it in phospholipid-containing pools. {Arteriosclerosis and Thrombosis 1991;11:146-153) F oam cells in atherosclerotic lesions contain large amounts of cholesterol esters. There is considerable evidence that a substantial part of these foam cells originate from monocyte-derived macrophages.1 -4 Macrophages cultured in vitro are able to accumulate cholesterol esters from /3-very low density lipoprotein (/3-VLDL) or from various forms of modified low density lipoproteins (LDLs) like acetyl LDL or endothelial-cell-modified LDL. The uptake of these modified LDLs is mediated by the so-called scavenger receptor, 5 -8 while uptake of 0-VLDL occurs by way of a low-affinity LDL receptor.9 Both receptors seem to be resistant to downregulation by loading the cells with cholesterol. CoA) reductase inhibitors, of which mevastatin (compactin, ML-236B) and lovastatin (mevinolin) comprise the first-discovered representatives. 10 -11 They are efficacious in lowering the plasma LDL level, 12 which is brought about by a reduction in cholesterol synthesis and by an increased receptormediated uptake and degradation of LDL in the liver. 13 By lowering the LDL level in plasma, these drugs are probably effective antiatherosclerotic agents.So far, the direct effect of vastatins on cholesterol ester accumulation in macrophages has not been described. It was the purpose of this study, therefore, to examine whether vastatins are able to interfere with cholesterol ester formation and accumulation in macrophages induced by incubation with acetyl LDL and /3-VLDL. -514) was donated by Y. Tsujita, Sankyo Co., Tokyo, Japan. The compounds were used as supplied (i.e., all in the lactone form except pravastatin, which was supplied as a sodium salt). Methods Serum and LipoproteinsHuman inactivated sterilized serum was obtained from the blood bank of the Academic Hospital Leiden. It was stored at -20°C. LDL was obtained from fresh human serum by density gradient ultracentrifugation.14 The LDL band, conspicuous by its yellow-orange color, wa...

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Section: Association Degradationsupporting

confidence: 87%

Vastatins inhibit cholesterol ester accumulation in human monocyte-derived macrophages.

Kempen¹,

Vermeer²,

Wit³

et al. 1991

Arterioscler Thromb

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“…To assess whether the sterol biosynthesis pathway plays a pro- or anti-viral role in regulating mCMV replication, we exploited the pharmacologic compound “simvastatin,” a potent and selective inhibitor of HMGCR [48]. Inhibition of HMGCR is known to result in a reduction of the metabolic intermediate mevalonate (Figure 3) and an accompanying drop in cholesterol synthesis by the cell [49].…”

Section: Resultsmentioning

confidence: 99%

Host Defense against Viral Infection Involves Interferon Mediated Down-Regulation of Sterol Biosynthesis

et al. 2011

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“…25,26). However, isoforms of this enzyme are sensitive to inhibition by ester drugs, namely, cyclandelate and lovastatin (27,28), as is the case for REH. Lovastatin appears to function as an inhibitor of retinyl ester hydrolysis by acting as an alternative substrate; as an ester-type drug it requires carboxylesterase-mediated bioactivation in order to elicit pharmacological activity (29).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of purified pig and human liver retinyl ester hydrolase by pharmacologic agents

Schindler

2001

Lipids

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Identification of inhibitors of retinyl ester hydrolase (REH) would help to elucidate its role in vitamin A metabolism in vivo. By using standard incubation conditions, the effects of 215 drugs as potential inhibitors of purified pig and human liver REH when acting on micellar substrate retinyl palmitate were evaluated at 16.7, 167, and 1670 microM. Out of the compounds tested, 103 were inhibitors of the pig liver enzyme. The most potent compounds, in order of decreasing activity, were chloral hydrate, lovastatin, phytomenadione, alimemazine, physostigmine, thioridazine, phenoxybenzamine, probucol, cinnarizine, cyclandelate, amiodarone, flupenthixol, and naftidrofuryl; this order is roughly similar to that of their inhibition of human liver REH. Of the 10 tricyclic ring-containing drugs tested, alimemazine was the most potent enzyme inhibitor. The concentrations necessary for 50% enzyme inhibition ranged from <2.6 up to >540 microM. Moreover, inhibitory kinetic studies showed that at least two pharmaceuticals, chloral hydrate and amiodarone, are potent REH inhibitors at therapeutically achievable serum concentrations. First-pass metabolites were inactive as REH inhibitors compared to that of the parent compounds, in the cases of chloral hydrate, lovastatin, and cyclandelate.

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Inhibition of acyl coenzyme A: Cholesterol acyltransferase by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

Cited by 24 publications

References 0 publications

Vastatins inhibit cholesterol ester accumulation in human monocyte-derived macrophages.

Vastatins inhibit cholesterol ester accumulation in human monocyte-derived macrophages.

Host Defense against Viral Infection Involves Interferon Mediated Down-Regulation of Sterol Biosynthesis

Inhibition of purified pig and human liver retinyl ester hydrolase by pharmacologic agents

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