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Louis H. Cohen - One of the best experts on this subject based on the ideXlab platform.
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Action of lovastatin, simvastatin, and pravastatin on Sterol Synthesis and their antiproliferative effect in cultured myoblasts from human striated muscle
Biochemical Pharmacology, 1996Co-Authors: Arlène K. Van Vliet, Pascale Nègre-aminou, G.christa F Van Thiel, Piet A. Bolhuis, Louis H. CohenAbstract:Lovastatin, simvastatin, and pravastatin are fairly strong inhibitors of Sterol Synthesis in human myoblasts in culture. Lovastatin and simvastatin have IC50 values of 19 ± 6 nM and 4.0 ± 2.3 nM, respectively. Pravastatin is a weaker inhibitor of Sterol Synthesis (IC50 value of 110 ± 38 nM). Through inhibition of mevalonate production, these compounds have a distinct inhibiting effect on cell proliferation. Because proliferation of myoblasts is important in the repair of damaged skeletal muscle, experiments were performed to investigate the effect of lovastatin, simvastatin, and pravastatin on cell proliferation and cell viability. The more potent inhibitors of Sterol Synthesis, lovastatin, and simvastatin, were able to inhibit the proliferation of these cells during 3 days of incubation with drug concentrations of 1 μM for lovastatin and 0.1 μM or 1 μM for simvastatin. DNA Synthesis was decreased by more than 80% in the presence of 1 μM of lovastatin or simvastatin. In contrast, under these conditions, pravastatin had no influence on cell proliferation or DNA Synthesis, which is probably related to the lack of inhibition of Sterol Synthesis by pravastatin on extended incubation. The three 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors did not disturb cell viability because mitochondrial dehydrogenase activity and ATP content remained proportional to the number of cells in the culture at any concentration used. Chemicals/CAS: Acetic Acid, 64-19-7; Adenosine Triphosphate, 56-65-5; Anticholesteremic Agents; DNA, 9007-49-2; Enzyme Inhibitors; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin, 75330-75-5; Oxidoreductases, EC 1.-; Pravastatin, 81093-37-0; Simvastatin, 79902-63-9; Sterols
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Vastatins have a distinct effect on Sterol Synthesis and progesterone secretion in human granulosa cells in vitro.
Biochimica et Biophysica Acta, 1996Co-Authors: A.k. Van Vliet, G.c.f. Van Thiel, N. Naaktgeboren, Louis H. CohenAbstract:Lovastatin and simvastatin are strong inhibitors of choleSterol Synthesis in cultured human granulosa cells, as measured within 6 days after isolation, with IC50-values of respectively 27.0 and 18.2 nM obtained after 3.5 hours of incubation with the drugs. Pravastatin is a much weaker inhibitor of choleSterol Synthesis (IC50-value of 977.8 nM) in these cells. Under these conditions inhibition of choleSterol Synthesis had no influence on progesterone secretion into the medium which was probably due to the presence of large choleSterol pools in the cells. To deplete these pools, granulosa cells were cultured for 7 days after which the culture medium was changed into medium supplemented with 20% lipoprotein-depleted serum to deprive the cells of exogenous choleSterol. Additionally, 30 mIU of follicle-stimulating hormone and luteinizing hormone per ml were added to stimulate the progesterone production and secretion, thereby decreasing the cholesteryl ester pools. After 48 h of incubation, culture was continued without hormones for another two days. Thereafter, the cells were preincubated for 24 h without or with 1 μM of lovastatin, simvastatin or pravastatin in medium containing lipoprotein-deficient serum and the above mentioned hormones. This period is followed by incubation for another 24 h in the presence of [14C]acetate after which cells and media were collected for determination of 14C-labelled Sterols synthesized and progesterone secreted into the media. Now, lovastatin and simvastatin, which strongly inhibited Sterol Synthesis, significantly attenuated the secretion of progesterone. One μM of pravastatin had no significant effect on Sterol Synthesis nor on progesterone secretion. When the latter experiment was performed under conditions in which exogenous choleSterol was provided in the form of human low density lipoproteins, no influence of the vastatins on progesterone secretion was observed. So under conditions in which the choleSterol pools were decreased, lovastatin and simvastatin attenuated the progesterone secretion, whereas pravastatin did not. When pools were filled by exogenous choleSterol, no effect on progesterone secretion by either of the drugs was observed. Chemicals/CAS: CholeSterol, 57-88-5; Culture Media; Enzyme Inhibitors; Follicle Stimulating Hormone, 9002-68-0; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin, 75330-75-5; Luteinizing Hormone, 9002-67-9; Pravastatin, 81093-37-0; Progesterone, 57-83-0; Simvastatin, 79902-63-9
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Different effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors on Sterol Synthesis in various human cell types.
Biochimica et Biophysica Acta, 1995Co-Authors: A.k. Van Vliet, G.c.f. Van Thiel, R.h. Huisman, Han Moshage, Sing Hiem Yap, Louis H. CohenAbstract:The three vastatins examined, lovastatin, simvastatin and pravastatin, are equally strong inhibitors of the Sterol Synthesis in human hepatocytes in culture with IC50-values of 4.1, 8.0 and 2.0 nM, respectively. However, in the human extrahepatic cells: umbilical vascular endothelial cells, retinal pigment epithelial cells, cornea fibroblasts and granulosa cells, pravastatin was much less inhibiting the Sterol Synthesis than lovastatin or simvastatin. It was observed as well that longer incubation with the vastatins resulted in higher IC50-values. In order to show that the feedback regulation mechanism for 3-hydroxy-3-methylglutaryl-coenzyme A reductase was involved in this phenomena mRNA levels were measured in human vascular endothelial cells after incubation with the vastatins for 3.5 h and for 20 h. Indeed, lovastatin and simvastatin gave rise to higher levels of HMG-CoA reductase mRNA after 20 h than after 3.5 h of incubation. The differences observed in different human cell types can be explained by supposing that pravastatin is transported into the human hepatocyte via a liver-specific transporter. This was supported by the results of uptake experiments with 14C-labelled pravastatin and 14C-labelled simvastatin into human hepatocytes compared to that into human umbilical endothelial cells (as an example of an extrahepatic cell type). [14C]-Simvastatin was associated with both cell types, whereas [14C]-pravastatin was hardly associated with human endothelial cells, but to a similar extent as [14C]-simvastatin with human hepatocytes. Chemicals/CAS: mevinolin, 75330-75-5; pravastatin, 81131-74-0; simvastatin, 79902-63-9; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin, 75330-75-5; RNA, Messenger; Simvastatin, 79902-63-9; Sterols
Richard J. Cenedella - One of the best experts on this subject based on the ideXlab platform.
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HMG CoA reductase activity of lens epithelial cells: compared with true rates of Sterol Synthesis.
Current Eye Research, 2009Co-Authors: Richard J. CenedellaAbstract:The regulation of Sterol Synthesis in the lens was addressed in the present study by comparing changes in the activity of HMG CoA reductase to changes in true rates of Sterol Synthesis for bovine lens epithelial cells in culture. The lens cells possessed very high levels of reductase activity (165 to 241 units/106 cells) which doubled when the cells were grown in media depleted of lipoproteins. True rates of Sterol Synthesis were simultaneously measured from incorporation of tritiated water into digitonin-precipitable Sterols. Rates of Sterol Synthesis increased an average 37% more than the increase in reductase activity when the cells were deprived of exogenous choleSterol. Although not perfect, the results indicate a close correlation between HMG CoA reductase activity and rates of Sterol Synthesis in lens epithelial cells. We conclude that the activity of HMG CoA reductase is a major determinant of the rate of choleSterol Synthesis in the lens.
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Comparison of effects of U18666A and enantiomeric U18666A on Sterol Synthesis and induction of apoptosis
Lipids, 2005Co-Authors: Richard J. Cenedella, Patricia S. Sexton, Kathiresan Krishnan, Douglas F. CoveyAbstract:Treatment of animals or cells with the amphipathic tertiary amine U18666A {3β-[2-(diethylamino) ethoxy]androst-5-en-17-one} provides models for several human diseases (e.g., cataracts, Niemann-Pick disease, and epilepsy). Although U18666A can inhibit several enzymes in the choleSterol Synthesis pathway, we hypothesized that induction of these varied conditions was due to physical effects of the amine rather than to inhibition of specific proteins. To test this possibility we compared the capacity of U18666A and its enantiomer, ent-U18666A, to inhibit net Sterol Synthesis and induce apoptosis in cultured bovine lens epithelial cells. Nonenantiospecific actions dependent on the physical properties of these mirror image molecules would be identical, but effects dependent upon enantiospecific interactions would be different for the enantiomers. At the same concentrations, both forms of the compound equally inhibited Sterol Synthesis and induced apoptosis. These observations supported a generalized mechanism of enzyme inhibition such as perturbation of the microenvironment of endoplasmic enzymes and alteration of membrane order, perhaps of the mitochondrial membrane, to explain induction of apoptosis.
Hiroyuki Koike - One of the best experts on this subject based on the ideXlab platform.
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TISSUE-SELECTIVE INHIBITION OF Sterol Synthesis IN MICE BY PRAVASTATIN SODIUM AFTER A SINGLE OR REPEATED ORAL ADMINISTRATIONS
Lipids, 1995Co-Authors: Teiichiro Koga, Takashi Kikuchi, Atsuhiro Miyazaki, Hiroyuki KoikeAbstract:Pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, exhibits liver-selectivity in inhibiting Sterol Synthesis, when administered as a single oral dose to mice or rats, whereas lovastatin and simvastatin do not. This may be due to the fact that pravastatin is distributed intracellularly, to a large extent, in the liver and extracellularly in nonhepatic tissues. In the present study, we examined whether the difference in liver-selectivity among these three HMG-CoA reductase inhibitors observed in single-dose studies was preserved after repeated oral administrations of drugs to mice.De novo Sterol Synthesis in different tissues of mice was examinedin vivo three hours after the last dose of drug by measuring incorporation of intraperitoneally injected [14C]acetate into total Sterols. Pravastatin administered orally for 11 consecutive days at 5 and 10 mg/kg exhibited a greater liver-selectivity than lovastatin and simvastatin: Sterol Synthesis was inhibited more than 60% in the liver by all three drugs, whereas that in nonhepatic tissues was inhibited less than 10% by pravastatin and more than 30% by lovastatin and simvastatinin in most of the nonhepatic tissues examined. Pravastatin administered orallyfor 11 consecutive days at 10 mg/kg caused more selective inhibition of Sterol Synthesis in liverex vivo than two other inhibitors at the same dose. Pravastatin inhibitedde novo Sterol Synthesis from [14C]acetate into Sterol fraction in the liver slicesin vitro, but minimally in those of the spleen and testis, whereas lovastatin and simvastatin inhibited in those of all three tissues. Since the drug concentrations determined in the same tissue samples of the liver, spleen, and testis were almost comparable among the three drugs, it was suggested that the cellular distribution profiles of pravastatin observed in a single-dose study were preserved in the multiple-dose study. We conclude that the difference in tissue-selectivity between pravastatin and the other two inhibitors to inhibit Sterol Synthesis in mice is maintained, regardless of the duration of administration.
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Tissue selectivity of pravastatin sodium, lovastatin and simvastatin. The relationship between inhibition of de novo Sterol Synthesis and active drug concentrations in the liver, spleen and testis in rat.
FEBS Journal, 1992Co-Authors: Teiichiro Koga, Hiroyuki Koike, Kuniaki Fukuda, Yohko Shimada, Masaharu Fukami, Yoshio TsujitaAbstract:Tissue selectivity of pravastatin sodium (pravastatin), lovastatin and simvastatin, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors was examined by measuring inhibition of de novo Sterol Synthesis and active drug concentrations in the liver, spleen and testis in rats after a single oral administration (25 mg/kg) of these drugs. Regarding tissue drug concentrations, all three drugs were liver selective: concentrations of drugs in the liver were about ten-times higher than those in the spleen and testis. On the other hand, pravastatin was far more liver selective in inhibiting Sterol Synthesis than two other inhibitors: pravastatin inhibited de novo Sterol Synthesis in the liver but minimally in the spleen and testis, whereas lovastatin and simvastatin inhibited in all three tissues. Microautoradiographic and in vitro cellular-uptake studies demonstrated that pravastatin remained in the extracellular space in the spleen, whereas the other drugs entered the cell. We conclude that pravastatin exhibits a liver-selective inhibition of Sterol Synthesis because the agent permeates the cell membrane in the liver, but not in non-hepatic tissues.
Roger S. Newton - One of the best experts on this subject based on the ideXlab platform.
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Hepatic and nonhepatic Sterol Synthesis and tissue distribution following administration of a liver selective HMG-CoA reductase inhibitor, CI-981: comparison with selected HMG-CoA reductase inhibitors.
Biochimica et Biophysica Acta, 1992Co-Authors: Thomas M.a. Bocan, E. Ferguson, William P. Mcnally, Paul D. Uhlendorf, Sandra Bak Mueller, Peter D. Dehart, D. R. Sliskovic, Bruce D. Roth, Brian R. Krause, Roger S. NewtonAbstract:Since choleSterol bioSynthesis is an integral part of cellular metabolism, several HMG-CoA reductase inhibitors were systematically analyzed in in vitro, ex vivo and in vivo Sterol Synthesis assays using [14C]acetate incorporation into digitonin precipitable Sterols as a marker of choleSterol Synthesis. Tissue distribution of radiolabeled CI-981 and lovastatin was also performed. In vitro, CI-981 and PD134967-15 were equipotent in liver, spleen, testis and adrenal, lovastatin was more potent in extrahepatic tissues than liver and BMY21950, pravastatin and PD135023-15 were more potent in liver than peripheral tissues. In ex vivo assays, all inhibitors except lovastatin preferentially inhibited liver Sterol Synthesis; however, pravastatin and BMY22089 were strikingly less potent in the liver. CI-981 inhibited Sterol Synthesis in vivo in the liver, spleen and adrenal while not affecting the testis, kidney, muscle and brain. Lovastatin inhibited Sterol Synthesis to a greater extent than CI-981 in the spleen, adrenal and kidney while pravastatin and BMY22089 primarily affected liver and kidney. The tissue distribution of radiolabeled CI-981 and lovastatin support the changes observed in tissue Sterol Synthesis. Thus, we conclude that a spectrum of liver selective HMG-CoA reductase inhibitors exist and that categorizing agents as liver selective is highly dependent upon method of analysis.
Teiichiro Koga - One of the best experts on this subject based on the ideXlab platform.
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TISSUE-SELECTIVE INHIBITION OF Sterol Synthesis IN MICE BY PRAVASTATIN SODIUM AFTER A SINGLE OR REPEATED ORAL ADMINISTRATIONS
Lipids, 1995Co-Authors: Teiichiro Koga, Takashi Kikuchi, Atsuhiro Miyazaki, Hiroyuki KoikeAbstract:Pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, exhibits liver-selectivity in inhibiting Sterol Synthesis, when administered as a single oral dose to mice or rats, whereas lovastatin and simvastatin do not. This may be due to the fact that pravastatin is distributed intracellularly, to a large extent, in the liver and extracellularly in nonhepatic tissues. In the present study, we examined whether the difference in liver-selectivity among these three HMG-CoA reductase inhibitors observed in single-dose studies was preserved after repeated oral administrations of drugs to mice.De novo Sterol Synthesis in different tissues of mice was examinedin vivo three hours after the last dose of drug by measuring incorporation of intraperitoneally injected [14C]acetate into total Sterols. Pravastatin administered orally for 11 consecutive days at 5 and 10 mg/kg exhibited a greater liver-selectivity than lovastatin and simvastatin: Sterol Synthesis was inhibited more than 60% in the liver by all three drugs, whereas that in nonhepatic tissues was inhibited less than 10% by pravastatin and more than 30% by lovastatin and simvastatinin in most of the nonhepatic tissues examined. Pravastatin administered orallyfor 11 consecutive days at 10 mg/kg caused more selective inhibition of Sterol Synthesis in liverex vivo than two other inhibitors at the same dose. Pravastatin inhibitedde novo Sterol Synthesis from [14C]acetate into Sterol fraction in the liver slicesin vitro, but minimally in those of the spleen and testis, whereas lovastatin and simvastatin inhibited in those of all three tissues. Since the drug concentrations determined in the same tissue samples of the liver, spleen, and testis were almost comparable among the three drugs, it was suggested that the cellular distribution profiles of pravastatin observed in a single-dose study were preserved in the multiple-dose study. We conclude that the difference in tissue-selectivity between pravastatin and the other two inhibitors to inhibit Sterol Synthesis in mice is maintained, regardless of the duration of administration.
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Tissue selectivity of pravastatin sodium, lovastatin and simvastatin. The relationship between inhibition of de novo Sterol Synthesis and active drug concentrations in the liver, spleen and testis in rat.
FEBS Journal, 1992Co-Authors: Teiichiro Koga, Hiroyuki Koike, Kuniaki Fukuda, Yohko Shimada, Masaharu Fukami, Yoshio TsujitaAbstract:Tissue selectivity of pravastatin sodium (pravastatin), lovastatin and simvastatin, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors was examined by measuring inhibition of de novo Sterol Synthesis and active drug concentrations in the liver, spleen and testis in rats after a single oral administration (25 mg/kg) of these drugs. Regarding tissue drug concentrations, all three drugs were liver selective: concentrations of drugs in the liver were about ten-times higher than those in the spleen and testis. On the other hand, pravastatin was far more liver selective in inhibiting Sterol Synthesis than two other inhibitors: pravastatin inhibited de novo Sterol Synthesis in the liver but minimally in the spleen and testis, whereas lovastatin and simvastatin inhibited in all three tissues. Microautoradiographic and in vitro cellular-uptake studies demonstrated that pravastatin remained in the extracellular space in the spleen, whereas the other drugs entered the cell. We conclude that pravastatin exhibits a liver-selective inhibition of Sterol Synthesis because the agent permeates the cell membrane in the liver, but not in non-hepatic tissues.