| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Inhibitors of cholesterol biosynthesis. 1. trans-6-(2-pyrrol-1-ylethyl)-4-hydroxypyran-2-ones, a novel series of HMG-CoA reductase inhibitors. 1. Effects of structural modifications at the 2- and 5-positions of the pyrrole nucleus Roth, B. D., D. F. Ortwine, et al. (1990), J Med Chem 33(1): 21-31. Abstract: A novel series of trans-6-(2-pyrrol-1-ylethyl)-4-hydroxypyran-2-ones and their dihydroxy acid derivatives were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase in vitro. A systematic study of substitution at the 2- and 5-positions of the pyrrole ring revealed that optimum potency was realized with the 2-(4-fluorophenyl)-5-isopropyl derivative 8x, which possessed 30% of the in vitro activity of the potent fungal metabolite compactin (I). A molecular modeling analysis led to the description of a pharmacophore model characterized by (A) length limits of 5.9 and 3.3 A for the 2- and 5-substituents, respectively, as well as an overall width limit of 10.6 A across the pyrrole ring from the 2- to the 5-substituent and (B) an orientation of the ethyl(ene) bridge to the 4-hydroxypyran-2-one ring nearly perpendicular to the planes of the parent pyrrole, hexahydronaphthalene, and phenyl rings of the structures examined (Figure 3, theta = 80-110 degrees). Attempts to more closely mimic compactin's polar isobutyric ester side chain with the synthesis of 2-phenylpyrroles containing polar phenyl substituents resulted in analogues with equal or slightly reduced potencies when compared to the 2-(unsubstituted or 4-fluoro)phenylpyrroles, supporting the hypothesis that inhibitory potency is relatively insensitive to side-chain polarity or charge distribution in this area. |
| Inhibitors of cholesterol biosynthesis. 2. 1,3,5-trisubstituted 2-(tetrahydro-4-hydroxy-2-oxopyran-6-yl)ethylpyrazoles Sliskovic, D. R., B. D. Roth, et al. (1990), J Med Chem 33(1): 31-8. Abstract: A series of 1,3,5-trisubstituted pyrazole mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase in vitro. Since previous studies suggested that the 5-(4-fluorophenyl) and 3-(1-methylethyl) substituents afforded optimum potency, attention was focused on variations in position 1 of the pyrazole ring. Biological evaluation of analogues bearing a variety of 1-substituents suggested that, although most substituents were tolerated, none afforded an advantage over phenyl, which exhibited potency comparable to that of compactin in vitro. |
| Inhibitors of cholesterol biosynthesis. 2. 3,5-Dihydroxy-7-(N-pyrrolyl)-6-heptenoates, a novel series of HMG-CoA reductase inhibitors Procopiou, P. A., C. D. Draper, et al. (1993), J Med Chem 36(23): 3658-62. Abstract: A series of 7-2,3-diaryl-5-(1-methylethyl)-1H-pyrrol-1-yl-3,5- dihydroxy-6-heptenoates was prepared and evaluated for its ability to inhibit the enzyme HMG-CoA reductase in vitro. Maintaining a 5-(1-methylethyl) substituent found to be optimal in related studies, structure-activity relationships were established for compounds modified at positions 2, 3, and 4 of the pyrrole ring. The 4-fluorophenyl group was preferred at the pyrrole 2-position, while incorporation of a range of substituted phenyl groups and pyridyl substituents at the 3-position provided compounds with equivalent enzyme inhibitory activities and widely different lipophilicities. Pentasubstituted pyrrole 3h was found to have a 10-fold greater potency than lovastatin. |
| Inhibitors of cholesterol biosynthesis. 2. Hypocholesterolemic and antioxidant activities of benzopyran and tetrahydronaphthalene analogues of the tocotrienols Pearce, B. C., R. A. Parker, et al. (1994), J Med Chem 37(4): 526-41. Abstract: Tocotrienols exhibit antioxidant and cholesterol-biosynthesis-inhibitory activities and may be of value as antiatherosclerotic agents. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase (HMGR) in a manner mimicking the action of putative non-sterol feedback inhibitors. The in vitro cholesterol-biosynthesis-inhibitory and HMGR-suppressive activities in HepG2 cells of an expanded series of benzopyran and tetrahydronaphthalene isosteres and the hypocholesterolemic activity of selected compounds assessed in orally dosed chickens are presented. Preliminary antioxidant data of these compounds have been obtained using cyclic voltammetry and Cu-induced LDL oxidation assays. The farnesyl side chain and the methyl/hydroxy substitution pattern of gamma-tocotrienol deliver a high level of HMGR suppression, unsurpassed by synthetic analogues of the present study. In orally dosed chickens, 8-bromotocotrienol (4o), 2-desmethyltocotrienol (4t), and the tetrahydronaphthalene derivative 35 exhibit a greater degree of LDL cholesterol lowering than the natural tocotrienols. |
| Inhibitors of cholesterol biosynthesis. 6. trans-6-2-(2-N-heteroaryl-3,5-disubstituted- pyrazol-4-yl)ethyl/ethenyltetrahydro-4-hydroxy-2H-pyran-2-ones Sliskovic, D. R., C. J. Blankley, et al. (1992), J Med Chem 35(11): 2095-103. Abstract: A series of N-heteroaryl-substituted mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and in vivo, and to lower plasma cholesterol in a hypercholesterolemic dog model. The goal of the strategy employed was to design an inhibitor which possessed the pharmacological properties of lovastatin (1), and the physicochemical properties (increased hydrophilicity) of pravastatin (2). Two compounds 20a and 20b, were more potent than lovastatin at inhibiting cholesterol biosynthesis both in vitro and in vivo. In terms of plasma cholesterol lowering, 20a was much more efficacious than lovastatin. In addition to possessing increased biological activity, these compounds are significantly less lipophilic than lovastatin, in fact, 20b has a CLOGP value comparable to pravastatin. |
| Inhibitors of sterol synthesis. Effects of fluorine substitution at carbon atom 25 of cholesterol on its spectral and chromatographic properties and on 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells Wilson, W. K., S. Swaminathan, et al. (1994), Steroids 59(5): 310-7. Abstract: 25-Fluorocholesterol (III) was prepared by treatment of 25-hydroxycholesterol (IV) with hydrogen fluoride-pyridine. Compounds III, IV, and cholesterol (I) were fully characterized by 1H and 13C NMR, and stereochemical assignments were established for the C-22 and C-23 protons. The side-chain proton assignments, which apply to most other sterols with a saturated eight-carbon side chain, were based on conformational analysis and comparisons with NMR data for 25,26,26,26,27,27,27-heptafluorocholesterol (II). The chromatographic behavior of I, II, and III were compared on thin-layer chromatography, high performance liquid chromatography, and gas chromatography. Major fragment ions in electron-impact mass spectra of III were analogous to ions of either cholesterol or desmosterol, and a similar analogy was observed for the trimethylsilyl ethers. The 25-hydroxysterol IV and the 25-fluorosterol III differed markedly in their effects on the levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells. Whereas 25-hydroxycholesterol caused a approximately 66% lowering of reductase activity in cells at 0.1 microM, the 25-fluorosterol III had no effect at this concentration. |
| Inhibitors of sterol synthesis: effects of a 7 alpha-alkyl analog of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one on 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in cultured mammalian cells and on serum cholesterol levels and other parameters in rats Siddiqui, A. U., N. Gerst, et al. (1994), Chem Phys Lipids 70(2): 163-78. Abstract: The 7 alpha-methyl analog (II) of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15- one (I) was prepared by chemical synthesis and evaluated with respect to its effects on HMG-CoA reductase activity in CHO-K1 cells and on serum cholesterol levels in rats. The 7 alpha-methyl substitution had no detectable effect on the potency of I in lowering HMG-CoA reductase activity in the cultured cells. In contrast, the 7 alpha-methyl substitution had a marked effect on the action of I in the suppression of food consumption in rats. Whereas II was less potent than I in lowering serum cholesterol levels in rats, it did so at dosage levels at which only slight or moderate effects on food consumption were observed. Full 1H and 13C-NMR assignments for II and intermediates in its synthesis have been presented. Conformational analysis, based on 1H-1H coupling constants, NMR shieldings and force-field calculations, indicated that the 7 alpha-methyl substitution had virtually no effect on the conformation of the 15-ketosterol apart from minor distortions of ring B. |
| Inhibitory action of conventional food-grade natural antioxidants and of natural antioxidants of new development on the thermal-induced oxidation of cholesterol Valenzuela, A., J. Sanhueza, et al. (2004), Int J Food Sci Nutr 55(2): 155-62. Abstract: Cholesterol is a molecule with an unsaturated bond; therefore, like polyunsaturated fatty acids, it is prone to oxidation. Cholesterol oxidation products (COPs) are found in many common foods and have been shown to be atherogenic, cytotoxic, mutagenic and possibly carcinogenic. Therefore, efforts to prevent or to avoid COPs formation during manufacture and/or processing of foods are of high priority. The effect of natural antioxidants on COPs formation has not been extensively studied. We assayed the effect of some widely applied natural antioxidants, such as tocopherol homologs (alpha-T, gamma-T, and delta-T) and rosemary extract, and of some natural products of newly developed as antioxidants, such as the flavonoids quercetin, catechin, morin, and rutin, and also of an alkaloid-derived product, boldine, to inhibit cholesterol oxidation of soybean oil, added of cholesterol, induced in the Rancimat test conditions (150 degrees C and air bubbling). Formation of six different COPs at the induction period and at the 100 microS conductivity value was monitored by gas chromatography. Under the experimental conditions gamma-T, quercetin, and rosemary extract prove effective to inhibit both soybean oil oxidation and COP formation. alpha-T, catechin, and morin are less efficient to prevent COP formation. delta-T, rutin and boldine are devoid of protective action against COP formation. gamma-T, quercetin and rosemary extract may inhibit COP formation from the nucleus and from the lateral chain of the cholesterol molecule. |
| Inhibitory action of cyclobutyrol on the secretion of biliary cholesterol and phospholipids Monte, M. J., R. A. Parslow, et al. (1990), Biochem J 266(1): 165-71. Abstract: A number of organic anions are known to decrease biliary secretion of cholesterol and phospholipid without affecting bile acid secretion. Cyclobutyrol (CB) is a choleretic agent which also inhibits biliary lipid secretion. Using isolated perfused rat liver we have studied this inhibition in relation to possible mechanisms suggested for other anions. Shortly after its administration to the isolated perfused liver, CB decreases biliary outputs of cholesterol and phospholipid, without changes in bile acid secretion, at low (450 nmol/min), high (1350 nmol/min) and nil taurocholate infusion rates. The absolute inhibition does not appear to be decreased by elevated bile acid secretion. There is a differential effect on secretion of cholesterol and phospholipid, more marked at low bile acid secretion rates. Biliary outputs of the canalicular membrane enzymes 5'-nucleotidase and alkaline phosphodiesterase I are also depressed by CB administration, but the anion does not affect the biliary output of bovine serum albumin or the output of rat serum albumin into the perfusion fluid. Since CB does not inhibit intracellular vesicular transport or apparently inhibit intracanalicular events, its effect is different from the effect of several other anions. From these studies it appears that the most likely effect of CB is exerted at the level of the canalicular membrane. |
| Inhibitory action of gemfibrozil on cholesterol absorption in rat intestine Umeda, Y., Y. Kako, et al. (2001), J Lipid Res 42(8): 1214-9. Abstract: This study was designed to determine whether gemfibrozil inhibits intestinal lipid absorption. Male Sprague-Dawley rats received an oral dose of 30 mg gemfibrozil/kg body weight for 14 days. Mesenteric lymph cannulation was performed, and a lipid infusion containing 40 micromol/h (35.4 mg/h) of radiolabeled triolein and 2.74 micromol/h (1.06 mg/h) of radiolabeled cholesterol with the addition of 1 mg/h of gemfibrozil was infused intraduodenally at a rate of 3 ml/h for 8 h. The lymph was collected, and the radioactivity levels of the lumen and gut mucosa were measured after the infusion. Lymph cholesterol transport was depressed in gemfibrozil-treated rats, in terms of mass measurements as well as radioactivity in a lesser degree. More radioactive cholesterol remained in the proximal portion of the intestinal lumen and mucosa in the treated rats than in the control rats. More radioactive triglycerides also remained in the proximal intestinal lumen of treated rats, although no difference in lymphatic triglyceride transport was observed between the groups. A significant portion of the radioactive cholesterol remained in the lumen in the gemfibrozil-treated rats. Gemfibrozil increased biliary cholesterol excretion. Thus, this study shows that gemfibrozil inhibits cholesterol absorption in rat intestine. |
| Inhibitory action of natural compounds of microbial origin on cholesterol metabolism Fujioka, T. (1997), Nippon Yakurigaku Zasshi 110 Suppl 1: 75P-80P. Abstract: 1) Repeated administration of pravastatin significantly increased serum and liver cholesterol in rats. Hepatic LDL receptor activity was not changed and VLDL cholesterol secretion from the liver was increased. Net cholesterol synthesis in rat liver was increased after 7 days of repeated pravastatin administration. These results suggest that for rats, unlike other animals for which serum cholesterol is decreased, induced HMG-CoA reductase activity due to pravastatin treatment might overcome the inhibitory capability of pravastatin. 2) In the course of screening for squalene synthase inhibitors, novel zaragozic acids-F10863A, B, C and D-containing zaragozic acid D3 were isolated. F10863A was most potent and selectively inhibited cholesterol synthesis in freshly isolated rat hepatocytes among several cultured and isolated cells. It also showed in vivo serum cholesterol-lowering effects in hamsters and marmosets. However, the inhibition for squalene synthase proved to cause acidosis due to the accumulation of farnesol-derived dicarboxylic acids in urines. 3) A novel acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor, designated epi-cochlioquinone A, a stereoisomer of cochlioquinone A, which has been previously reported as a nematocidal agent, was isolated from the fermentation broth of Stachybotrys bisbyi. It inhibited in vivo cholesterol absorption in rats by 50% at 75 mg/kg. |
| Inhibitory effect of cholesterol oxides on low density lipoprotein receptor gene expression Peng, S. K., X. Zhang, et al. (1996), Artery 22(2): 61-79. Abstract: The effects of the cholesterol oxides on low density lipoprotein receptor (LDLR) gene expression were investigated. Cultured rabbit aortic smooth muscle cells were incubated with 1, 2, and 5 micrograms/ml culture medium concentrations of pure cholesterol, 25-hydroxycholesterol (25-OH), 7-ketocholesterol (7-keto), cholestane-3 beta, 5 alpha, 6 beta-triol (triol) and cholesterol-5 alpha, 6 alpha-epoxide (epoxide) for 12 hours and with vehicle only as control. Total mRNAs were extracted and electrophoresed. Northern blot hybridization analyses were performed. The results showed mRNA expressions of LDLR gene were inhibited to 16.1 +/- 4.4%, 33.8 +/- 0.6%, 42.8 +/- 1.8% and 46.9 +/- 3.9% of control by 25-OH, 7-keto, epoxide and triol respectively. Pure cholesterol showed only minimal inhibition. The inhibitions were time dependent. Although cholesterol oxides have been shown to alter many membrane-related functions and the LDLR domain are located in the cell membrane. The findings of this study suggested that the cholesterol oxides exerted their repressive actions on LDLR function primarily by down-regulating LDLR gene expression rather than directly upon cell membrane. |
| Inhibitory effect of liposomes containing sulfatide or cholesterol sulfate on syncytium formation induced by bovine immunodeficiency virus-infected cells Watarai, S., M. Onuma, et al. (1990), J Biochem (Tokyo) 108(4): 507-9. Abstract: The effect of galactocerebroside 3'-sulfate (sulfatide) or cholesterol sulfate on syncytium formation induced by bovine immunodeficiency virus (BIV)-infected cells was investigated in vitro. Sulfatide was purified from bovine brain and incorporated in liposomes which were composed of egg phosphatidylcholine (PC), cholesterol (Chol), and dipalmitoylphosphatidic acid (DPPA). Either sulfatide- or cholesterol sulfate-containing liposomes effectively prevented syncytium formation induced by BIV-infected cells, but the inhibitory effect of sulfatide alone on syncytium formation was low. On the other hand, neither liposomes containing galactocerebroside nor liposomes composed of egg PC, Chol, and DPPA had any effect on syncytium formation induced by BIV-infected cells. These results suggest that liposomes containing sulfatide or cholesterol sulfate are an efficient agent to inhibit syncytium formation induced by BIV-infected cells, and that sulfate residue might play an important role in the inhibition of syncytium formation. |
| Inhibitory effect of monatepil maleate on acyl-CoA:cholesterol acyltransferase activity in the liver of cholesterol-fed Japanese monkeys Sumiya, T., A. Ikeno, et al. (1997), Am J Hypertens 10(7 Pt 1): 779-85. Abstract: We have previously demonstrated that monatepil maleate, AJ-2615, a new calcium antagonist endowed with alpha1-adrenoceptor blocking property, has antiatherosclerotic and plasma lipid-lowering effects in Japanese monkeys fed on a cholesterol-rich diet. To clarify the mechanisms on plasma lipid-lowering action, we investigated the effect of monatepil maleate in these monkeys on hepatic acyl-CoA:cholesterol acyltransferase (ACAT) activity. Both ACAT activity and esterified cholesterol content in the livers of monkeys fed on a cholesterol-rich diet for 6 months significantly increased about 7- and 16-fold, respectively, as compared with those in monkeys fed on a standard diet. Monatepil maleate (30 mg/kg/day for 6 months, orally) inhibited the increases of ACAT activity and esterified cholesterol content by 51% and 71%, respectively. In in vitro experiments, monatepil maleate inhibited ACAT activity in a concentration-dependent manner, whereas it did not affect 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity. A kinetic analysis revealed that monatepil maleate was a noncompetitive type inhibitor of ACAT. Hepatic ACAT activity was significantly correlated to hepatic esterified cholesterol content (r = 0.775, P <.0001), to plasma very low density lipoprotein (VLDL) content (r = 0.765, P <.0001) and to plasma total cholesterol content (r = 0.573, P <.005) in the monkeys. These results suggest that ACAT-inhibiting effect of monatepil maleate plays an important role in the reduction of hyperlipidemia. |
| Inhibitory effect of perindopril, a novel angiotensin-converting enzyme inhibitor, on neointima formation after balloon injury in rats and cholesterol-fed rabbits Shibutani, T., A. Kanda, et al. (1994), J Cardiovasc Pharmacol 24(3): 509-16. Abstract: We investigated the effect of perindopril, a novel angiotensin-converting enzyme (ACE) inhibitor, on neointima formation in vessel walls after balloon injury in rats (carotid artery) and cholesterol-fed rabbits (thoracic aorta). Continuous treatment with perindopril significantly reduced neointima formation in both species, as compared with the control group: intima/media (I/M) ratio (rats -62%; p < 0.001; rabbits -25%, p < 0.05); neointima area (rats -65%, p < 0.01; rabbits -24%, p < 0.05). These changes involved reduction of intimal smooth muscle cells (SMC) in rats and of macrophages in rabbits. Furthermore, perindopril also significantly decreased ACE activity in both aortic tissue and serum 11.38 +/- 0.87 vs. 34.93 +/- 6.44 pmol His-Leu (HL)/mg/min (p < 0.01) and 2.79 +/- 0.28 vs. 38.50 +/- 5.41 pmol HL/mg/min (p < 0.001), respectively, aortic contraction evoked by angiotensin I (AI) and mean blood pressure (BP, 84.9 +/- 3.5 vs. 109.3 +/- 3.8 mm Hg, p < 0.001) as compared with control values. These results indicate that perindopril may reduce neointima formation by suppressing the aortic renin-angiotensin system (RAS). These findings indicate that perindopril may be capable of preventing restenotic lesions after angioplasty in humans corrected. |
| Inhibitory effect of the new calcium antagonist AJ-2615 on progression of atherosclerosis in cholesterol-fed rabbits Minato, H., A. Ikeno, et al. (1993), J Cardiovasc Pharmacol 21(4): 663-9. Abstract: The effects of a new calcium antagonist, AJ-2615, on progression of atherosclerosis were investigated in rabbits fed a diet high in cholesterol and compared with those of prazosin, diltiazem, and their combination. In the AJ-2615 (30 mg/kg p.o. once daily) group, high cholesterol diet-induced increases in plasma concentrations of total cholesterol, free cholesterol, and phospholipid were significantly decreased. In addition, increases in aortic lipids and calcium content, as well as those in the atherosclerotic lesion area were clearly reduced by AJ-2615. On the other hand, prazosin (3 mg/kg p.o. twice daily) and diltiazem (50 mg/kg p.o. twice daily) groups displayed no such inhibitory effects. However, the group receiving the combination of prazosin and diltiazem at their respective dose levels exhibited a significant reduction in the increase in calcium content of the aorta and a slight decrease in the atherosclerotic lesion area, although there was no decrease in plasma or aortic lipid content. These results suggest that in addition to its calcium antagonistic and alpha 1-adrenoceptor blocking actions, some other yet-unidentified properties of AJ-2615 might contribute to the antiatherosclerotic effect of this agent. |
| Inhibitory effects of fluvastatin, a new HMG-CoA reductase inhibitor, on the increase in vascular ACE activity in cholesterol-fed rabbits Mitani, H., T. Bandoh, et al. (1996), Br J Pharmacol 119(6): 1269-75. Abstract: 1. The effects of fluvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on the vascular angiotensin converting enzyme (ACE) activity in hyperlipidaemic rabbits were compared with those of enalapril, an ACE inhibitor. 2. Rabbits were fed a 1.5% cholesterol containing diet or normal diet for 16 weeks and treated with either fluvastatin or enalapril in the diet at the respective doses of 2 and 10 mg kg-1 day-1. The total cholesterol, triglyceride and phospholipid levels in serum were significantly increased in rabbits fed the high cholesterol diet. Treatment with fluvastatin but not enalapril resulted in a decrease in serum lipids. 3. The vascular ACE activities assessed via the cleavage rate from synthetic substrate in the aortic arches and upper thoracic aortae were increased by 8 to 10 times when the rabbits were made hyperlipidaemic. Fluvastatin as well as enalapril significantly lowered the tissue ACE in the aortae. 4. The ACE activities in serum did not alter in hyperlipidaemic rabbits either in the presence or absence of fluvastatin. The serum ACE activity was lowered by enalapril. 5. The lipid peroxide in serum as well as the plaque area in the thoracic aorta was significantly increased in the cholesterol diet-fed rabbits. Treatment with fluvastatin or enalapril reduced both serum lipid peroxide and plaque formation. The relaxant responses to acetylcoholine (ACh) were significantly suppressed in the cholesterol-fed rabbits. Treatment with fluvastatin or enalapril significantly reversed the suppression of ACh-induced relaxation. 6. It seems that the reduction of vascular ACE is not coupled to lipids and ACE activity in serum, but rather to lipid peroxidation. Thus, the decrease in vascular ACE activity by fluvastatin as well as the lipid-lowering effect may reduce the risk of atherosclerosis progression in the vasculature. |
| Inhibitory effects of lipid oxidation on the activity of plasma lecithin-cholesterol acyltransferase Kamiyama, S., T. Yamato, et al. (1998), Biosci Biotechnol Biochem 62(5): 941-6. Abstract: We investigated the effects of free radical generation on the esterification of cholesterol by lecithin-cholesterol acyltransferase (LCAT). A water-soluble free radical initiator, 2,2'-azobis-amidinopropane dihydrochloride (AAPH), inhibited the activity of plasma LCAT as a function of the incubation time after its addition. When a small amount of oxidized HDL was added to plasma, LCAT activity was dose-dependently inhibited. To identify the effects of HDL oxidation on LCAT activity, a purified enzyme and cofactor in a vesicle solution (an artificial substrate) were used. i) LCAT activity was inhibited by the oxidation of substrate vesicles, this inhibition being related to the degree of oxidation. ii) This inhibition was observed even if apolipoprotein A-I was not oxidized. iii) Oxidized phosphatidylcholine, but not oxidized cholesterol, in the vesicles affected LCAT activity. iv) The addition of 0-40% of oxidized vesicles to normal substrate vesicles resulted in the activity of LCAT being inhibited in a dose-dependent manner. These results suggest that the esterification of cholesterol by LCAT may be affected by the oxidation of substrate phosphatidylcholine via free radical generation in the plasma. |
| Inhibitory effects of N-(3,5-dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylphenyl)piperazine (YIC-C8-434), an acyl-CoA:cholesterol O-acyltransferase inhibitor, on cholesterol esterification in the intestine and liver Ohishi, K., H. Sawada, et al. (2003), Biol Pharm Bull 26(8): 1125-8. Abstract: The effects of an acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor, N-(3,5-dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylphenyl)piperazine (YIC-C8-434), on cholesterol esterification in the intestine and liver were investigated in vitro and in vivo. YIC-C8-434 inhibited the formation of cholesteryl (3)Holeate from (3)Holeic acid and cholesterol both in human colon adenocarcinoma Caco2 cells and in human hepatoma HepG2 cells with IC(50) values of 0.38 and 0.49 microM, respectively. However, it did not influence the incorporation of (3)Holeic acid into triacylglycerols and phospholipids. Oral administration of YIC-C8-434 at a dose of 8.3 mg/kg/d inhibited (14)Ccholesterol absorption by 17% (p<0.01) in rats. YIC-C8-434 also significantly reduced the secretion of very low-density lipoprotein (VLDL) cholesterol from the liver into the plasma at an oral dose of 100 mg/kg/d after an intravenous injection of Triton WR-1339. These results suggest that oral administration of YIC-C8-434 reduces intestinal cholesterol absorption and hepatic VLDL cholesterol secretion by direct inhibition of ACAT in the intestinal epithelium and hepatocytes, respectively. However, the inhibitory action of YIC-C8-434 on cholesterol absorption rather than hepatic cholesterol secretion may play a more important role in its hypocholesterolemic activity, because the effective dose for the former was 12-fold lower than that for the latter. |
| Inhibitory effects of Polygonum cuspidatum water extract (PCWE) and its component resveratrol correction of rasveratrol on acyl-coenzyme A-cholesterol acyltransferase activity for cholesteryl ester synthesis in HepG2 cells Park, C. S., Y. C. Lee, et al. (2004), Vascul Pharmacol 40(6): 279-84. Abstract: The pharmacological effects of Polygonum cuspidatum water extract (PCWE) on lipid biosynthesis were investigated in cultured human hepatocyte HepG2 cells. The addition of PCWE (5 and 20 microg/ml), which had no effect on cell proliferation and cellular protein content, caused a marked decrease in the cellular cholesterol content, particularly, the cholesteryl ester content following 24 h of incubation. The incorporation of (14)C-oleate into the cellular cholesteryl ester fraction was also reduced remarkably during incubation for 6 and 24 h. The effect of PCWE on acyl-coenzyme A-cholesterol acyltransferase (ACAT) activity were studied in vitro to explore the mechanism by which PCWE inhibits cholesterol ester formation. The data confirmed that PCWE, in a dose dependent manner, remarkably inhibits ACAT activity. Among the main active chemicals of P. cuspidatum, resveratrol, a kind of flavonoid, decreased ACAT activity in a dose-dependent manner from the level of 10(-3) M. Theses results strongly suggest that PCWE reduces the cholesteryl ester formation in human hepatocytes by inhibiting ACAT. |