Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cholesterol regulates hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity by feedback inhibition. It has been suggested that oxidized derivatives of cholesterol (oxysterols) play an important role, as an intracellular mediator, in the feedback inhibition of cholesterol biosynthesis. We, therefore, investigated the role of intracellular oxysterols in the regulation of HMG-CoA reductase activity. Rats were fed with food (control), cholesterol, clofibrate as a potentiator of the microsomal monooxygenase cytochrome P-450 enzyme system, ketoconazole as a strong inhibitor of the system, or butylated hydroxytoluene (BHT) as an antioxidant. We analyzed and compared hepatic microsomal oxysterol levels among the groups. The results of this study indicated that the oxysterol level, especially 7beta-hydroxycholesterol and 7-ketocholestrol, in the liver was lowered by the administration of ketoconazole and BHT, and HMG-CoA reductase activity was increased in response to these agents. However, there was no change in the HMG-CoA reductase activity, after the administration of clofibrate. We conclude that reduced levels of oxysterol may release the inhibitory effect on the HMG-CoA reductase enzyme and lead to up-regulation of the enzyme.
Atherosclerosis 1997 Jun
PMID:Reduction of oxysterol levels up-regulates HMG-CoA reductase activity in rat liver. 919 77

The in vitro metabolism of SDZ HDL 376, a thiocarbamide developed for the treatment of atherosclerosis, was investigated in rat, dog, monkey, and human liver microsomes, as well as in rat and human liver slices. [14C]SDZ HDL 376 was extensively metabolized in all the species except human. In rat liver microsomes an S-oxide was the major metabolite. In human and monkey microsomes, carbon hydroxylation was favored. The NADPH-dependent oxidation of SDZ HDL 376 resulted in covalent binding to microsomal protein. Addition of GSH to the incubations decreased protein binding in a concentration-dependent manner and resulted in a novel SDZ HDL 376-GSH adduct. Adduct formation required NADPH and was mediated predominantly by cytochrome P450. Inhibition of cytochrome P450 by 1-aminobenzotriazole resulted in a 95% decrease in adduct formation, while heat inactivation of flavin-containing monooxygenases resulted in a 10% decrease. Unlike other thiocarbamides which form disulfide adducts with GSH, the SDZ HDL 376 adduct contained a thioether linkage as characterized by LC/MS/MS and reference to a synthetic standard. Reactions performed with [35S]GSH resulted in a [35S]SDZ HDL 376-GSH adduct, demonstrating the sulfur was derived from GSH. Adduct formation was faster in rat microsomal reactions compared to human microsomes. Other structurally unrelated thiocarbamides (phenylthiourea, methimazole, 2-mercaptobenzimidazole, 2-mercaptoquinazoline, and 2-propyl-6-thiouracil) did not form similar adducts in rat liver microsomes supplemented with GSH. Therefore, the GSH adduct of SDZ HDL 376 is unique for this type of thiocarbamide. These results suggest that the bioactivation and detoxification of SDZ HDL 376 differ significantly from other thiocarbamides. Furthermore, the in vitro formation of S-oxides and GSH adducts in rat hepatic tissue, and ring hydroxylation and glucuronidation in human hepatic tissue, suggests rats may be more susceptible to the toxicity of SDZ HDL 376 compared to humans.
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PMID:In vitro metabolism of N-(5-chloro-2-methylphenyl)-N'-(2-methylpropyl)thiourea: species comparison and identification of a novel thiocarbamide-glutathione adduct. 925 Apr 6

Policosanol, a defined mixture of high molecular weight aliphatic alcohol isolated and purified from sugar cane (Saccharum officinarum, L) wax is a new cholesterol-lowering agent effective in experimental models, healthy volunteers, and patients with type II hypercholesterolemia. Also, policosanol prevents the onset of spontaneously- and experimentally-induced atherosclerotic lesions and cerebral ischemia in Mongolian gerbils. Free radicals are linked to many diseases including atherosclerosis and ischemia/ reoxidation cellular injury. Therefore, in this study the authors evaluate the antioxidant activity of policosanol on rat liver microsomes. The extent of lipid peroxidation was measured by thiobarbituric acid reactive substances (TBARS). When policosanol was administered orally (100 and 250 mg/kg) for up to 4 weeks, a partial prevention of rat in vitro microsomal lipid peroxidation was noted. The formation of TBARS in microsomes isolated from treated rats was significantly decreased by about 50%, when peroxidation was initiated by Fe3+/ADP/ NADPH, Fe2+/ascorbate and CCl4/NADPH-generating system. Also, oral administration of policosanol in rats provides a partial inhibition of lipid peroxidation, but the mechanism supporting such effect remains to be elucidated. This beneficial effect of policosanol on membrane lipid peroxidation may be useful in protecting to some extent against free radical-associated diseases.
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PMID:Effect of policosanol on in vitro and in vivo rat liver microsomal lipid peroxidation. 929 30

Recent studies in man and human apolipoprotein A-I transgenic animals emphasize the significance of apolipoprotein A-I and high density lipoprotein in antiatherogenesis. Several drugs and other compounds, e.g. phenobarbital, gemfibrozil, fenofibrate, prednisone, estrogen and alcohol, induce apolipoprotein A-I synthesis. They commonly produce serum lipoprotein patterns typical of a low risk of coronary heart disease, and many of them have been found to prevent atherogenesis, reduce coronary heart disease mortality and increase survival. These compounds act against atherosclerosis by using one or several mechanisms that include overexpression of the apolipoprotein A-I gene with an increase in serum apolipoprotein A-I and high density lipoprotein and promotion of reverse cholesterol transport, upregulation of the low density lipoprotein receptor gene with a decrease in serum apolipoprotein B and low density lipoprotein, maintenance of endothelial cell function and protection against thrombosis. They have been found to raise high density lipoprotein cholesterol and apolipoprotein A-I together with a decrease in cholesterol ester transfer protein activity, and to induce hepatic cholesterol 7 alpha-hydroxylase and cholesterol and bile acid elimination from the body. By raising the activities of apolipoprotein A-I/high density lipoprotein-associated paraoxonase and other antioxidative enzymes, the inducers have the capacity to prevent atherogenesis in arterial walls through inhibition of the oxidative modification of low density lipoprotein. Other antiatherogenic vascular actions of high density lipoprotein include interference with low density lipoprotein aggregation and uptake by endothelial cells, and competition with low density lipoprotein for endothelial-localized low density lipoprotein receptors. Apolipoprotein A-I/high density lipoprotein beneficially enhances fibrinolysis, decreases platelet aggregation, increases prostacyclin production and stabilization and prevents atherogenic immune and inflammatory responses. This gene activation or microsomal induction can prevent atherosclerosis and is a basis for tailoring effective new agents and optimal non-invasive therapy against atherosclerotic vascular disease to promote health and enhance longevity.
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PMID:Gene activation, apolipoprotein A-I/high density lipoprotein, atherosclerosis prevention and longevity. 929 1

The pyridine derivative cerivastatin is a new entirely synthetic and enantiomerically pure inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. As a sodium salt cerivastatin is present in the active, open ring form. Cerivastatin inhibited the membrane-bound (non-solubilized) HMG-CoA reductase of the native microsomal fraction isolated from rat liver with a Ki value of 1.3 x 10(-9) M. The reference compound lovastatin was 100-fold less potent and exhibited a Ki value of 150 x 10(-9) M. Cerivastatin inhibited the cholesterol synthesis in the human hepatoma cell line HepG2 cells with a similar IC50 value of 1.0 x 10(-9) M. In vivo studies reflected its high in vitro activity. In both rats and dogs, cerivastatin inhibited the hepatic [14C]cholesterol synthesis from [14C]acetate with an oral ED50 value of 0.002 mg/kg body weight, while lovastatin exhibited an oral ED50 value of 0.3 mg/kg in rats, showing again the ratio of 100 or more between cerivastatin and lovastatin. In the small intestine and testes, cerivastatin was at least 50-fold less active with oral ED50 values higher than 0.1 mg/kg, which is indicative for a high liver selectivity of cerivastatin. In cholestyramine-primed dogs cerivastatin dose-dependently lowered the serum cholesterol concentrations by up to 59% with 0.1 mg/kg after 20 days. Interestingly, the serum triglycerides were markedly reduced by 53 and 76% with 0.03 and 0.1 mg/kg, respectively. In normal chow fed dogs the low density lipoprotein (LDL) concentrations were reduced by up to 75% after 0.1 mg cerivastatin/kg. The ratio of HDL/LDL increased by 81% compared with a change of only 14% in the placebo treated control group. The antiatherogenic effect of cerivastatin was shown in rabbits fed a diet enriched with 0.2% cholesterol. After 9 weeks on diet 0.1 mg cerivastatin/kg decreased the accumulation of cholesterol ester in the arterial tissue by 73%. In summary, these data as compared to published data on other HMG-CoA reductase inhibitors demonstrate cerivastatin to be the most active compound in this class. Vastatins used in therapy are effective in mg doses, while cerivastatin offers a new low dose therapy in the microg range.
Atherosclerosis 1997 Nov
PMID:Cerivastatin: pharmacology of a novel synthetic and highly active HMG-CoA reductase inhibitor. 939 80

We investigated the effect of sitosterol on hepatic sterol 27-hydroxylase activities in subjects with sitosterolemia, a recessive inherited disease associated with accelerated atherosclerosis and increased levels of sitosterol and other plant sterols and stanols in tissues. Hepatic activities of mitochondrial sterol 27-hydroxylase, which catalyzes the first step in the conversion of cholesterol to bile acids via the acidic bile acid synthetic pathway, were measured in liver tissues and related to hepatic microsomal cholesterol 7 alpha-hydroxylase, which controls the rate of bile acid synthesis via the neutral synthetic pathway. These measurements of cholesterol catabolism were correlated to sterol concentrations and composition in plasma and liver. Sterol 27-hydroxylase activities in liver mitochondria of three homozygous sitosterolemic subjects were 68% lower than in 10 control subjects (p < .05) and were associated with increased levels of plant sterols in both plasma and liver (13% and 16% of total sterols, respectively, compared to trace amounts in controls). Analysis of Lineweaver-Burk double reciprocal plots of sterol 27-hydroxylase activities in control human liver specimens (where mitochondrial sterol 27-hydroxylase activities were measured with increasing concentrations of the cholesterol substrate, in the absence and presence of 100 microM and 300 microM sitosterol) revealed that sitosterol inhibited mitochondrial sterol 27-hydroxylase activity up to 50% by a competitive mechanism. In sitosterolemic subjects, competitive inhibition of hepatic sterol 27-hydroxylase activity by sitosterol was associated with competitively inhibited microsomal cholesterol 7 alpha-hydroxylase activity (averages from 4 sitosterolemic homozygotes and 14 controls were 12.4 +/- 1.9 and 23.6 +/- 2.5 pmol/mg/min, respectively). Furthermore, decreased cholesterol catabolism in sitosterolemic subjects was associated with significantly elevated plasma cholesterol concentrations (232 +/- 17 mg/dl, as compared to 180 +/- 13 mg/dl in controls) but with no change in hepatic cholesterol concentrations. In an animal model (rats infused intravenously with sitosterol-containing liposomes that increased sitosterol in the liver and plasma to levels similar to those found in sitosterolemic subjects), hepatic mitochondrial sterol 27-hydroxylase and microsomal cholesterol 7 alpha-hydroxylase activities also decreased significantly and were coupled to markedly elevated plasma sterol concentrations (120.7 +/- 12.5 mg/dl, as compared to 59.2 +/- 6.3 mg/dl in control animals; p < .05) but to no change in hepatic cholesterol concentrations. Thus, decreased cholesterol catabolism due to competitive inhibition of both microsomal cholesterol 7 alpha-hydroxylase and mitochondrial sterol 27-hydroxylase by elevated hepatic sitosterol concentrations contributes to hypercholesterolemia and increased risk of atherosclerosis in sitosterolemia.
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PMID:Competitive inhibition of hepatic sterol 27-hydroxylase by sitosterol: decreased activity in sitosterolemia. 946 81

There is a growing body of evidence supporting the roles of small, dense LDL and plasma triglyceride (TG), both features of the atherogenic lipoprotein phenotype, as risk factors for coronary heart disease. Although family studies and twin studies have demonstrated genetic influences on these risk factors, the specific genes involved remain to be determined definitively. The purpose of this study was to investigate genetic linkage between LDL size, TG, and related atherogenic lipoproteins and candidate genes known to be involved in lipid metabolism. The linkage analysis was based on a sample of 126 DZ women twin pairs, which avoids the potentially confounding effects of both age and gender, by use of a quantitative sib-pair linkage-analysis approach. Eight candidate genes were examined, including those for microsomal TG-transfer protein (MTP), hepatic lipase, hormone-sensitive lipase, apolipoprotein (apo) B, apo CIII, apo E, insulin receptor, and LDL receptor. The analysis suggested genetic linkage between markers for the apo B gene and LDL size, plasma levels of TG, of HDL cholesterol, and of apo B, all features of the atherogenic lipoprotein phenotype. Furthermore, evidence for linkage was maintained when the analysis was limited to women with a major LDL-subclass diameter >255 A, indicating that the apo B gene may influence LDL heterogeneity in the intermediate-to-large size range. In addition, linkage was found between the MTP gene and TG, among all the women. These findings add to the growing evidence for genetic influences on the atherogenic lipoprotein phenotype and its role in genetic susceptibility to atherosclerosis.
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PMID:Candidate-gene studies of the atherogenic lipoprotein phenotype: a sib-pair linkage analysis of DZ women twins. 946 19

The ileal Na+/bile acid cotransporter (IBAT) plays an important role in the enterohepatic circulation of bile acids. We investigated the effects of IBAT inhibition on the maintenance of serum cholesterol level by using a novel IBAT inhibitor, S-8921, in rabbits. Administration of S-8921 by its incorporation into the diet (0.01% to 0.1%) for 1 to 2 weeks in heterozygous Watanabe heritable hyperlipidemic rabbits decreased serum cholesterol by 29% to 37% and increased fecal excretion of measured bile acids by 60% to 180% compared with control rabbits. Liver microsomal cholesterol 7alpha-hydroxylase and 3-hydroxy-3-methylglutaryl coenzyme A reductase activities were increased by 75% to 84% and 84% to 89%, respectively, with S-8921 treatment. S-8921 administration (0.1% in the diet) to normal New Zealand White rabbits for 2 weeks resulted in increased hepatic low density lipoprotein receptor expression, which was assessed by Northern blot analysis. In cholesterol-fed New Zealand White rabbits, S-8921 treatment (0.003% to 0.1% in the diet) for 10 weeks dose-dependently inhibited the development of hypercholesterolemia. It also inhibited the accumulation of cholesterol in the aortic arch and reduced the severity of coronary atherosclerosis. These results indicate that IBAT inhibition by S-8921 affects serum cholesterol, liver enzymes, low density lipoprotein receptor activity, and atherosclerosis in the same manner as bile acid sequestrants. We suggest that an IBAT inhibitor such as S-8921 could be useful in the treatment of hypercholesterolemia.
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PMID:Inhibition of ileal Na+/bile acid cotransporter by S-8921 reduces serum cholesterol and prevents atherosclerosis in rabbits. 971 38

Atherogenic lipoproteins such as oxidized LDL are implicated in the pathogenesis of atherosclerosis and renal disease. Fatty acid hydroperoxides and phospholipids such as linoleyl hydroperoxide (LAox or 13-HPODE) and lysophosphatidylcholine (lyso-PC), abundant components of oxidized LDL, mediate the effects of atherogenic lipids. Oxidized LDL has been shown to induce heme oxygenase-1 (HO-1), a microsomal enzyme that is involved in heme detoxification and is a major endogenous source of carbon monoxide. HO-1 is also induced by many other stimuli that shift cellular redox. To identify the constituents and molecular mechanisms of oxidized LDL-mediated HO-1 induction, human renal epithelial cells and aortic endothelial cells were exposed to LAox and lyso-PC. Exposure to LAox (25 microM) showed an approximately 16-fold induction of HO-1 mRNA, whereas exposure to lyso-PC (25 microM) showed only an approximate 2.6-fold increase. Treatment with actinomycin-D (4 microM), a transcriptional inhibitor, as well as nuclear run-on assays, demonstrated that LAox-mediated HO-1 gene induction is dependent on de novo transcription. Cycloheximide did not affect LAox-mediated HO-1 mRNA induction, suggesting that new protein synthesis is not required for transcriptional induction. Transfection of a human HO-1 promoter-reporter gene construct showed that LAox upregulation of HO-1 occurs via mechanisms different from those of known inducers, heme and cadmium. These studies are the first demonstration that LAox induces HO-1 by transcriptional mechanisms and may have implications in the pathogenesis of cell injury in atherosclerosis and progressive renal disease.
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PMID:Linoleyl hydroperoxide transcriptionally upregulates heme oxygenase-1 gene expression in human renal epithelial and aortic endothelial cells. 980 84

Pharmacological characterization of NTE-122 (trans-1,4-bis[[1-cyclohexyl-3-(4-dimethylamino phenyl)ureido]methyl]cyclohexane), a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, was performed with both in vitro and in vivo assay systems. NTE-122 inhibited microsomal ACAT activities of various tissues (liver of rabbit and rat, small intestine of rabbit and rat, and aorta of rabbit) and cultured cells (HepG2 and CaCo-2), with IC50 values from 1.2 to 9.6 nM. The inhibition mode of NTE-122 was competitive for HepG2 ACAT. NTE-122 had no effect on other lipid metabolizing enzymes, such as 3-hydroxy-3-methylglutaryl-CoA reductase, acyl-CoA synthetase, cholesterol esterase, lecithin:cholesterol acyltransferase, acyl-CoA:sn-glycerol-3-phosphate acyltransferase and cholesterol 7alpha-hydroxylase up to 10 microM. When NTE-122 was administered to the cholesterol diet-fed rats, serum and liver cholesterol levels were markedly reduced with an ED50 of 0.12 and 0.44 mg/kg/day, respectively. In the cholesterol diet-fed rabbits, NTE-122 significantly lowered plasma and liver cholesterol levels at more than 2 mg/kg/day. These results indicate that NTE-122 is a potent, selective and competitive inhibitor of ACAT, making it a worth while therapeutic agent for hypercholesterolemia and atherosclerosis.
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PMID:Cholesterol-lowering effects of NTE-122, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on cholesterol diet-fed rats and rabbits. 986 70


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