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Action of lovastatin, simvastatin, and pravastatin on sterol synthesis and their antiproliferative effect in cultured myoblasts from human striated muscle

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Author: Vliet, A.K. van · Nègre-Arrariou, P. · Thiel, G.C.F. van · Bolhuis, P.A. · Cohen, L.H.
Type:article
Date:1996
Institution: TNO Preventie en Gezondheid
Source:Biochemical Pharmacology, 9, 52, 1387-1392
Identifier: 233551
doi: doi:10.1016/S0006-2952(96)00467-4
Keywords: Biology · HMG-CoA reductase inhibitors · Human myoblasts · Sterol synthesis · Adenosine triphosphate · Hydroxymethylglutaryl coenzyme a reductase inhibitor · Mevinolin · Mitochondrial enzyme · Cell culture · Cell proliferation · Cell viability · Concentration response · Controlled study · Dna synthesis · Human cell · Human tissue · Muscle biopsy · Myoblast · Myopathy · Skeletal muscle · Acetic Acid · Adenosine Triphosphate · Anticholesteremic Agents · Cell Division · Cell Survival · Cells, Cultured · DNA · Enzyme Inhibitors · Humans · Hydroxymethylglutaryl-CoA Reductase Inhibitors · Lovastatin · Mitochondria · Muscle, Skeletal · Oxidoreductases · Pravastatin · Simvastatin · Sterols

Abstract

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