Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:Q8NEX9 (reductase)
26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present studies, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor atorvastatin was used to test the hypothesis that inhibition of cholesterol biosynthesis in vivo with a consequent reduction in the availability of hepatic cholesterol for lipoprotein synthesis, would (1) reduce very low density lipoprotein (VLDL) apolipoprotein B (apoB) secretion into the plasma, (2) reduce the conversion of VLDL apoB to LDL apoB, and (3) reduce LDL apoB direct synthesis. ApoB kinetic studies were carried out in six control miniature pigs and in six animals after 21 days of administration of atorvastatin (3 mg/kg per day). Pigs were fed a fat- (34% of calories; polyunsaturated to monounsaturated to saturated ratio, 1:1:1) and cholesterol- (400 mg/d cholesterol; 0.1%; 0.2 mg/kcal) containing pig chow-based diet. Atorvastatin treatment significantly reduced plasma total cholesterol, LDL cholesterol, total triglyceride, and VLDL triglyceride concentrations by 16%, 31%, 19%, and 28%, respectively (P < .01). Autologous 131I-VLDL, 125I-LDL, and [3H]leucine were injected simultaneously into each pig, and apoB kinetic data were analyzed using multicompartmental analysis (SAAM II). The VLDL apoB pool size decreased by 29% (0.46 versus 0.65 mg/kg; P = .002), which was entirely due to a 34% reduction in the VLDL apoB production rate (PR) (1.43 versus 2.19 mg/kg per hour; P = .027). The fractional catabolic rate (FCR) was unchanged. The LDL apoB pool size decreased by 30% (4.74 versus 6.75 mg/kg; P = .0004), which was due to a 22% reduction in the LDL apoB PR (0.236 versus 0.301 mg/kg per hour; P = .004), since the FCR was unchanged. The reduction in LDL apoB PR was primarily due to a 34% decrease in conversion of VLDL apoB to LDL apoB; however, this reduction was not statistically significant (P = .114). Hepatic apoB mRNA abundance quantitated by RNase protection assay was decreased by 13% in the atorvastatin-treated animals (P = .003). Hepatic and intestinal LDL receptor mRNA abundances were not affected. We conclude that inhibition of hepatic HMG-CoA reductase by atorvastatin reduces both VLDL and LDL apoB concentrations, primarily by decreasing apoB secretion into the plasma and not by an increase in hepatic LDL receptor expression. This decrease in apoB secretion may, in part, be due to a reduction in apoB mRNA abundance.
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PMID:Inhibition of HMG-CoA reductase by atorvastatin decreases both VLDL and LDL apolipoprotein B production in miniature pigs. 940 31

An HMG-CoA reductase inhibition assay was developed and validated for quantitation of atorvastatin in human, dog, rat, and mouse plasma. Atorvastatin was isolated from plasma by protein precipitation. Rat-liver microsomes were used to provide the reductase enzyme. The method was validated by assaying calibration standards and quality controls in triplicate on each of the 3 days. A customized computer program was used for data calculation. Quantitation of the assay ranged from 0.36 to 16 ng/ml of atorvastatin in different plasma matrices. Assay precision and accuracy, based on the coefficient of variation and percent relative error, respectively, of quality controls were 10.4% to 14.5% and within +/- 6.25% in human; 4.89% to 10.6% (+/- 8.13%) in dog; 2.68% to 8.62% (+/- 5.00%) in rat; and 3.68% to 8.96% (+/- 5.38%) in mouse plasma. The method has been applied to pharmacokinetic studies of atorvastatin in human and toxicokinetic studies in dog, rat, and mouse after atorvastatin administration. Atorvastatin equivalent concentrations in a set of plasma samples from subjects receiving single and multiple doses of atorvastatin were determined by validated HMG-CoA reductase inhibition assays at four different laboratories. Results were compared using linear regression and concordance correlation statistical procedures. Good agreements among these data indicated that results from different laboratories with the same validated method can be used interchangeably.
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PMID:Development, validation, and interlaboratory comparison of an HMG-CoA reductase inhibition assay for quantitation of atorvastatin in plasma matrices. 948 53

The objective of this multicenter, randomized, open-label, parallel-group, 8-week study was to evaluate the comparative dose efficacy of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor atorvastatin 10, 20, 40, and 80 mg compared with simvastatin 10, 20, and 40 mg, pravastatin 10, 20, and 40 mg, lovastatin 20, 40, and 80 mg, and fluvastatin 20 and 40 mg. Investigators enrolled 534 hypercholesterolemic patients (low-density lipoprotein [LDL] cholesterol > or = 160 mg/dl [4.2 mmol/L] and triglycerides < or = 400 mg/dl [4.5 mmol/L]). The efficacy end points were mean percent change in plasma LDL cholesterol (primary), total cholesterol, triglycerides, and high-density lipoprotein cholesterol concentrations from baseline to the end of treatment (week 8). Atorvastatin 10, 20, and 40 mg produced greater (p < or = 0.01) reductions in LDL cholesterol, -38%, -46%, and -51%, respectively, than the milligram equivalent doses of simvastatin, pravastatin, lovastatin, and fluvastatin. Atorvastatin 10 mg produced LDL cholesterol reductions comparable to or greater than (p < or = 0.02) simvastatin 10, 20, and 40 mg, pravastatin 10, 20, and 40 mg, lovastatin 20 and 40 mg, and fluvastatin 20 and 40 mg. Atorvastatin 10, 20, and 40 mg produced greater (p < or = 0.01) reductions in total cholesterol than the milligram equivalent doses of simvastatin, pravastatin, lovastatin, and fluvastatin. All reductase inhibitors studied had similar tolerability. There were no incidences of persistent elevations in serum transaminases or myositis.
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PMID:Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study) 1132 75

Atorvastatin is a potent inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate and constitutes the rate-limiting step in the biosynthesis of cholesterol. Steroid hormones derived from cholesterol, as well as mevalonate and its isoprenoid derivatives, provide important contributions to the maternal animal during pregnancy and lactation, as well as to the growth and development of the offspring; these contributions may potentially be influenced by inhibition of HMG-CoA reductase. To investigate the effects of atorvastatin on various aspects of reproduction and development, female Sprague-Dawley rats received 0, 20, 100, or 225 mg/kg daily by gavage from gestation day 7 through lactation day 20. Maternal toxicity, characterized by morbidity/mortality (13%), reduced body weight gain and food consumption, and pathologic lesions in the nonglandular mucosa of the stomach, occurred at 225 mg/kg. Offspring survival at birth and during the neonatal period at 225 mg/kg was reduced relative to control by up to 45%, and 28% of litters had no viable offspring by 10 days postpartum. Additional effects on offspring included reduced body weight during the neonatal and maturation periods (100, 225 mg/kg), delayed appearance of pinnae detachment and incisor eruption (225 mg/kg), impaired rotorod performance (females only; 100, 225 mg/kg), reduced acoustic startle responding (males only; 20, 100, 225 mg/kg), and transient effects on shuttle avoidance (females only; 225 mg/kg). No treatment-related effects were observed on offspring reproduction. In a separate experiment, a single dose of 10 mg/kg atorvastatin administered to female Wistar rats on gestation day 19 or lactation day 13 provided evidence of placental transfer and excretion into the milk. Results of this study indicate that pre- and postnatal administration of atorvastatin to female rats produces developmental toxicity in their offspring via in utero and/or lactational exposure, and in the presence or absence of maternal toxicity.
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PMID:Pre- and postnatal toxicity of the HMG-CoA reductase inhibitor atorvastatin in rats. 952 Mar 44

We investigated the effects of atorvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on the biogenesis of apolipoprotein B (apoB) in intact and permeabilized HepG2 cells. Intact cells were pretreated either with single or multiple doses of atorvastatin (0.1 to 20 micromol/L) for periods of 6 to 20 hours and pulsed with [35S]methionine. In some cases the cells were permeabilized with digitonin. Experiments were performed to investigate the effects of atorvastatin on (1) the rates of lipid synthesis and secretion, (2) the synthesis and accumulation of apoB, (3) the intracellular stability of apoB, (4) the amount of apoB-containing lipoprotein particles assembled in HepG2 microsomes, and (5) the secretion and accumulation of apoB into the culture medium. ApoB synthesis, degradation, and secretion were measured by pulse-chase experiments with [35S]methionine in both intact and permeabilized HepG2 cells. Lipid synthesis was assessed by pulse-labeling experiments with [3H]acetate or [3H]oleate bound to bovine serum albumin. Comparisons were made under basal conditions and in the presence of oleate (0.36 micromol/L). Atorvastatin acutely inhibited the synthesis of cholesterol and cholesterol ester but did not have a significant effect on triglyceride or phospholipid synthesis. Atorvastatin did not affect the uptake of [35S]methionine by the cells nor did it influence the synthesis of apoB or a control protein, albumin. However, atorvastatin reduced the secretion of apoB into the culture medium, apparently by enhancing the degradation of apoB in the cell under basal and induced conditions with oleate. The stability of apoB associated with the lipoprotein particles was also significantly lowered by atorvastatin. The stimulated degradation of apoB in atorvastatin-treated cells was sensitive to MG132, a proteasome inhibitor. The net effect of atorvastatin was a reduction in the number of apoB-containing lipoprotein particles of different sizes isolated from microsomes and a reduction in apoB secretion into the culture medium. The data suggest that atorvastatin may impair the translocation of apoB into the lumen of the endoplasmic reticulum, thus increasing the amount of apoB degraded intracellularly. It is hypothesized that atorvastatin alters these parameters primarily as a result of inhibiting cholesterol synthesis and limiting the availability of cholesterol and/or cholesterol ester for the normal assembly of apoB-containing lipoprotein particles.
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PMID:Effects of atorvastatin on the intracellular stability and secretion of apolipoprotein B in HepG2 cells. 959 38

Recent evidence suggests that apoptosis may be involved in the control of vascular smooth muscle cell (VSMC) number in atherosclerotic lesions. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to induce apoptosis in a variety of tumor cell lines. To evaluate whether these agents also induce apoptosis of VSMCs, cultured rat VSMCs were treated with increasing doses of atorvastatin in the presence of FBS as a survival factor. The presence of apoptosis was evaluated by morphological criteria, annexin V binding, and DNA fragmentation and quantified as the proportion of hypodiploid cells by flow cytometry. Atorvastatin induced apoptosis in a dose-dependent manner, an effect also seen with simvastatin and lovastatin, but not with the hydrophilic drug pravastatin. The proapoptotic effect of statins was seen only when the inhibition of acetate incorporation into sterols was >95% and was fully reversed by mevalonate, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate but not by isopentenyl adenosine, ubiquinone, or squalene, suggesting a role for prenylated proteins in the regulation of VSMC apoptosis. To further assess the role of protein prenylation, VSMCs were exposed to the prenyl transferase inhibitors perillic acid and manumycin A. Both agents induced VSMC apoptosis as evaluated by the above-mentioned criteria. Finally, VSMC treatment with lipophilic statins was associated with decreased prenylation of p21-Rho B, further supporting the role of protein prenylation inhibition in statin-induced VSMC apoptosis. The present data suggest that interference with protein prenylation by HMG-CoA reductase inhibitors or other agents may provide new strategies for the prevention of neointimal thickening.
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PMID:3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. 973 71

Patients with hypercholesterolaemia are at an increased risk of coronary heart disease. Lowering elevated cholesterol levels has been shown to reduce effectively the risk of coronary events. Atorvastatin, a recently introduced statin, produces pronounced lipid-lowering via inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. For example, atorvastatin 10-80 mg.day-1 reduces low density lipoprotein cholesterol (LDL-C) from baseline by 41-61% in a dose-dependent manner. Atorvastatin also lowers triglyceride levels by 23-45% over the same dose range. While sharing a common mechanism of action with other statins, atorvastatin leads to greater decreases in LDL-C, total cholesterol, apolipoprotein B and triglyceride levels than other statins. In the CURVES study, atorvastatin 10-40 mg.day-1 produced greater reductions in LDL-C than milligram equivalent doses of comparator statins. Studies have also shown that relatively more patients treated with atorvastatin achieve LDL-C treatment goals, and at a lower overall cost, than those treated with other statins. A further advantage of this enhanced efficacy is that atorvastatin shares a safety profile similar to that of the other statins. The efficacy and safety of atorvastatin has been demonstrated in a range of patient subgroups. A comprehensive ongoing clinical programme for atorvastatin includes morbidity and mortality studies.
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PMID:Addressing the challenge. 982 Oct 14

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, interactions, and formulary considerations of atorvastatin relative to other hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are discussed. Atorvastatin calcium, a synthetic stereoisomer of a pentasubstituted pyrrole, prevents the conversion of HMG-CoA by competitive and selective inhibition of HMG-CoA reductase. This limits cholesterol formation. Atorvastatin undergoes extensive first-pass metabolism; the first-pass effect is saturable at higher doses. Time to maximum plasma concentration ranges from one to four hours. The plasma elimination half-life is considerably longer than for other statins. Like other statins, atorvastatin reduces low-density-lipoprotein cholesterol (LDL-C) and total cholesterol in patients with hypercholesterolemia. However, the reductions achieved with atorvastatin exceed those for other statins. Atorvastatin recipients are more likely to achieve LDL-C goals and to do so more quickly. Atorvastatin also moderately reduces triglyceride levels in patients with hypertriglyceridemia and may play a role in the management of familial hypercholesterolemia. Adequate lipid control with atorvastatin monotherapy may preclude the need for combination drug therapy in some patients. The adverse effects of atorvastatin include mild gastrointestinal disturbances, increased liver enzyme levels, and myalgia. Drug interactions involving atorvastatin can be expected to parallel those of other statins metabolized via CYP3A4. Atorvastatin has become a popular addition to hospital formularies, even though formal pharmacoeconomic analyses are lacking. Atorvastatin effectively reduces blood lipids and may offer some advantages over other statins, but more studies are needed to clarify its optimal role in pharmacotherapy.
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PMID:Atorvastatin: a hydroxymethylglutaryl-coenzyme A reductase inhibitor. 1055 20

The effects of atorvastatin (3 mg kg(-1)) and simvastatin (3 mg kg(-1)) on hepatic enzyme activities involved in very low density lipoprotein metabolism were studied in coconut oil/cholesterol fed rabbits. Plasma cholesterol and triglyceride levels increased 19 and 4 fold, respectively, after 7 weeks of feeding. Treatment with statins during the last 4 weeks of feeding abolished the progression of hypercholesterolaemia and reduced plasma triglyceride levels. 3-Hydroxy-3-methyl-glutaryl Coenzyme A reductase, acylcoenzyme A:cholesterol acyltransferase, phosphatidate phosphohydrolase and diacylglycerol acyltransferase activities were not affected by drug treatment. Accordingly, hepatic free cholesterol, cholesteryl ester and triglyceride content were not modified. Simvastatin treatment caused an increase (72%) in lipoprotein lipase activity without affecting hepatic lipase activity. Atorvastatin caused a reduction in hepatic phospholipid content and a compensatory increase in CTP:phosphocholine cytidylyl transferase activity. The results presented in this study suggest that, besides the inhibitory effect on 3-hydroxy-3-methyl-glutaryl Coenzyme A reductase, simvastatin and atorvastatin may have additional effects that contribute to their triglyceride-lowering ability.
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PMID:Different effect of simvastatin and atorvastatin on key enzymes involved in VLDL synthesis and catabolism in high fat/cholesterol fed rabbits. 1045 99

Cardiovascular mortality, mainly due to the rupture of unstable atherosclerotic plaques, is reduced by 3-hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors. Inflammatory cells, attracted to the vascular lesion by chemokines, have been implicated in the process of the plaque rupture. In cultured vascular smooth muscle cells (VSMC) and U937 mononuclear cells we have studied the effect of Atorvastatin (Atv) on nuclear factor kappaB (NF-kappaB) activity, an inducer of the mRNA expression of chemokines such as interferon-inducible protein 10 (IP-10) and monocyte chemoattractant protein 1 (MCP-1). Angiotensin II (Ang II) and tumor necrosis factor alpha (TNF-alpha) increased NF-kappaB activity in VSMC (2 and 5-fold, respectively). Preincubation of cells with 10(-7) mol/l Atv diminished this activation (44 and 53%). The inhibition was reversed by mevalonate, farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), but not by other isoprenoids. Coinciding with the NF-kappaB activation in VSMC, there was a diminution of cytoplasmic IkappaB levels that was recovered by pretreatment with Atv. Ang II and TNF-alpha induced the expression of IP-10 (1.5 and 3.4-fold) and MCP-1 (2.4 and 4-fold) in VSMC. Atv reduced this overexpression around 38 and 35% (IP-10), and 54 and 39% (MCP-1), respectively. Our results strongly suggest that Atv, through the inhibition of NF-kappaB activity and chemokine gene expression, could reduce the inflammation within the atherosclerotic lesion and play a role in the stabilization of the lesion.
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PMID:Atorvastatin reduces NF-kappaB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells. 1055 11


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