Lack of correlation between the rate of cholesterol biosynthesis and the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase in rats and in fibroblasts treated with ML-236B

Bensch, William R.; Ingebritsen, Thomas S.; Diller, E. R.

doi:10.1016/0006-291x(78)90602-2

Cited by 54 publications

(16 citation statements)

References 17 publications

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“…Note that in these experiments the statins caused an increase in HMG‐CoA reductase activity rather than a decrease. Compensatory upregulation of the mevalonate pathway is known to occur as a result of the blockade in rodents (21, 22) …”

Section: Resultssupporting

confidence: 91%

“…However, despite inhibition of the mevalonate pathway within rabbit osteoclasts in vivo, no inhibitory effect was demonstrated on osteoclast function in PTH‐induced change in total serum calcium concentration in the TPTX rat. The apparent discrepancy between the ability to affect Rap1A prenylation in rabbit osteoclasts and the lack of an effect of statins in the rat in vivo may be explained by the well‐known compensatory response to HMG‐CoA reductase blockade in rats (21, 22) . The difference between the inhibition of bone resorption in the fetal rat long bone assay in vitro and the inability of the statins to inhibit bone resorption in the TPTX rat is puzzling.…”

Section: Discussionmentioning

confidence: 98%

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The Ability of Statins to Inhibit Bone Resorption Is Directly Related to Their Inhibitory Effect on HMG-CoA Reductase Activity

Staal

Frith

French

et al. 2003

Journal of Bone and Mineral Research

160

109

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Statins, which are inhibitors of 3-hydroxy-3-glutaryl-coenzyme A (HMG-CoA) reductase, decrease the hepatic biosynthesis of cholesterol by blocking the mevalonate pathway. Nitrogen-containing bisphosphonate drugs also inhibit the mevalonate pathway, preventing the production of the isoprenoids, which consequently results in the inhibition of osteoclast formation and osteoclast function. Therefore, we hypothesized that statins could affect bone metabolism in vivo through effects on osteoclastic bone resorption. In vitro, cerivastatin inhibited the parathyroid hormone (PTH)-stimulated bone resorption. Using a panel of 40 statin analogs, which showed variable effects on HMG-CoA reductase activity, we found that the ability of compounds to inhibit bone resorption is directly related to HMG-CoA reductase activity. However, in the thyro-parathyrodectomy (TPTX) model for bone resorption in the rat in vivo, cerivastatin did not prevent experimentally induced increases in bone resorption. The lack of effect of cerivastatin in this model is not related to a limited penetration of the target tissue (bone marrow), because a significant effect on HMG-CoA reductase activity was demonstrated in the total rat bone marrow cell extracts of rats posttreatment in vivo. Furthermore, cerivastatin inhibited protein prenylation in osteoclasts isolated from the rabbit bone marrow of rabbits after treatment in vivo. In contrast to other studies, none of the statins tested showed anabolic effects in parietal bone explant cultures. Taken

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 98%

The Ability of Statins to Inhibit Bone Resorption Is Directly Related to Their Inhibitory Effect on HMG-CoA Reductase Activity

Staal

Frith

French

et al. 2003

Journal of Bone and Mineral Research

160

109

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“…maintained in the presence of 0.25 pM mevinolin showed a significant increase in HMG-CoA reductase activity, despite the fact that isoprenoid synthesis was markedly depressed in these cells (see Table 5). This phenomenon, which has been documented in other cell lines exposed to reductase inhibitors (Brown et al, 1978;Bensch et al, 1978;Edwards et al, 1980;Sinensky and Logel, 1983) is due to a compensatory increase in the cellular content of the enzyme. The increased enzyme activity is not expressed in the intact cells, but it is detected when the cells are broken and the inhibitor is diluted in the assay medium.…”

Section: Effects Of Inhibitors Of Cell Cycling On Ace Activity and Nementioning

confidence: 84%

Differentiation of neuroblastoma cells induced by an inhibitor of mevalonate synthesis: Relation of neurite outgrowth and acetylcholinesterase activity to changes in cell proliferation and blocked isoprenoid synthesis

Maltese

Sheridan

1985

Journal Cellular Physiology

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Mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, stimulates neurite outgrowth and acetylcholinesterase (ACE) activity in C1300 (Neuro-2A) murine neuroblastoma cells. Sprouting of neurites began within 4-8 h, before changes in cell proliferation could be detected by [3H]thymidine incorporation or flow cytometry. In contrast, the increase in ACE activity was temporally correlated with suppression of DNA synthesis, which occurred after 8 h. The activity of the membrane marker enzyme phosphodiesterase I was not stimulated by mevinolin. Suppression of protein synthesis with cycloheximide blocked the induction of ACE activity but only partially inhibited neurite outgrowth in the mevinolin-treated cultures. When mevinolin was removed from the culture medium, most of the cells retracted their neurites within 2 h, but ACE activity did not decline until DNA synthesis began to return to control levels after 10 h. Similarly, retraction of neurites in differentiated cells exposed to colchicine was not accompanied by a decrease in ACE activity. DNA histograms suggested that mevinolin arrests neuroblastoma cells in both the G1 and G2/M compartments of the cell cycle. Other cytostatic drugs that arrest cells at different stages of the cell cycle did not cause Neuro-2A cells to form neurites such as those seen in the mevinolin-treated cultures. When incorporation of [3H]acetate into isoprenoid compounds was studied in cultures containing mevinolin in concentrations ranging from 0.25 microM to 25 microM, the labeling of cholesterol, dolichol, and ubiquinone was suppressed by 90% or more at all concentrations. However, significant growth arrest and cell differentiation were observed only at the highest concentrations of mevinolin. Supplementing the medium with 100 microM mevalonate prevented the cellular response to mevinolin, but additions of cholesterol, dolichol, ubiquinone, or isopentenyl adenine were generally ineffective. The cholesterol content of neuroblastoma cells incubated with 25 microM mevinolin for 24 h was not diminished, and protein glycosylation, measured by [3H]mannose incorporation, was decreased only after 24 h at high mevinolin concentration. These studies suggest that the stimulation of neurite outgrowth and the increase in ACE activity induced by mevinolin are independent phenomena. Whereas neurite outgrowth is not related directly to the effects of mevinolin on cell cycling, the induction of ACE is correlated with the inhibition of cell proliferation.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…As reported previously (31,32), the induction of hepatic HMG-CoA reductase activity by inhibition of the enzyme or bile acid sequestrant is considered to be a compensatory phenomenon caused by depletion of cholesterol. In the present study, hepatic HMG-CoA reductase activity was induced by 6.6 and 27.1-fold in groups 2 and 3 ( Fig.…”

Section: Discussionmentioning

confidence: 59%

Effects of Pravastatin Sodium Alone and in Combination with Cholestyramine on Hepatic, Intestinal and Adrenal Low Density Lipoprotein Receptors in Homozygous Watanabe Heritable Hyperlipidemic Rabbits

Kuroda

Matsumoto

Itakura

et al. 1992

Japanese Journal of Pharmacology

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Pravastatin sodium (pravastatin), a tissue-selective inhibitor of 3-hydroxy-3-methylglu taryl coenzyme A reductase, was administered alone (50 mg/kg) or in combination with cholestyramine, a bile acid sequestrant resin, at the level of 2% in the diet to homozygous Watanabe heritable hyper lipidemic (WHHL) rabbits for 4 weeks. The low density lipoprotein (LDL)-cholesterol levels were re duced by 29% and 56% with pravastatin alone and the combination treatment, respectively. Hepatic LDL receptor activity was increased by 11.2 and 13.9-fold with pravastatin alone and the combination treatment, respectively. The LDL receptor activity in the untreated homozygous WHHL rabbits was only 2.5% of that in the normal rabbits. mRNA for the LDL receptor in the liver was also increased by 2.1 and 3.4-fold with pravastatin alone and the combination treatment, respectively. On the other hand, mRNA for the LDL receptor in the adrenal gland was not affected by pravastatin and the com bination treatment, whereas the mRNA in the intestine was increased in both groups. These results suggest the following: 1) the induction of hepatic LDL receptor activity by the treatment of pravastatin alone or in combination with cholestyramine is the main cause of the reduction of serum cholesterol levels by these treatments even in LDL receptor-deficient animals.2) The induction of the mRNA for the LDL receptor in the liver and intestine, but not that in the adrenal gland, might be a reflection of the tissue-selective inhibition of cholesterol synthesis by pravastatin.

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Lack of correlation between the rate of cholesterol biosynthesis and the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase in rats and in fibroblasts treated with ML-236B

Cited by 54 publications

References 17 publications

The Ability of Statins to Inhibit Bone Resorption Is Directly Related to Their Inhibitory Effect on HMG-CoA Reductase Activity

The Ability of Statins to Inhibit Bone Resorption Is Directly Related to Their Inhibitory Effect on HMG-CoA Reductase Activity

Differentiation of neuroblastoma cells induced by an inhibitor of mevalonate synthesis: Relation of neurite outgrowth and acetylcholinesterase activity to changes in cell proliferation and blocked isoprenoid synthesis

Effects of Pravastatin Sodium Alone and in Combination with Cholestyramine on Hepatic, Intestinal and Adrenal Low Density Lipoprotein Receptors in Homozygous Watanabe Heritable Hyperlipidemic Rabbits

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