Abstract
In order to investigate the potential involvement of mitochondrial electron transport chain (ETC) dysfunction in myotoxicity associated with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) treatment, assessment was made of ETC activity and ubiquinone status in two patients experiencing myopathy following treatment with simvastatin (40 mg/day) and cyclosporin (patient 1) and simvastatin (40 mg/day) and itraconazole (patient 2). Analysis of skeletal muscle biopsies revealed a decreased ubiquinone status (77 and 132; reference range: 140-580 pmol/mg) and cytochrome oxidase (complex IV) activity (0.006 and 0.007 reference range: 0.014-0.034). To assess statin treatment in the absence of possible pharmacological interference from cyclosporin or itraconazole, primary astrocytes were cultured with lovastatin (100 microM). Lovastatin treatment resulted in a decrease in ubiquinone (97.9 +/- 14.9; control: 202.9 +/- 18.4 pmol/mg; p < 0.05), and complex IV activity (0.008 +/- 0.001; control: 0.011 +/- 0.001; p < 0.05) relative to control. These data, coupled with the patient findings, indicate a possible association between statin treatment, decreased ubiquinone status, and loss of complex IV activity.
Publication types
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Case Reports
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Animals
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Astrocytes / drug effects
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Astrocytes / enzymology
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Astrocytes / metabolism
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Cells, Cultured
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Cyclosporine / administration & dosage
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Cyclosporine / pharmacology
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Cyclosporine / therapeutic use
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Drug Interactions
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Drug Therapy, Combination
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Electron Transport Complex IV / metabolism*
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Female
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects*
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Itraconazole / administration & dosage
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Itraconazole / pharmacology
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Itraconazole / therapeutic use
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Male
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Middle Aged
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Muscle, Skeletal / drug effects*
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Muscle, Skeletal / enzymology
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Muscle, Skeletal / metabolism
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Muscle, Skeletal / pathology
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Muscular Diseases / chemically induced*
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Muscular Diseases / enzymology
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Muscular Diseases / metabolism
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Muscular Diseases / pathology
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Rats
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Rhabdomyolysis / chemically induced
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Rhabdomyolysis / enzymology
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Rhabdomyolysis / metabolism
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Rhabdomyolysis / pathology
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Simvastatin / administration & dosage
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Simvastatin / adverse effects*
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Ubiquinone / metabolism*
Substances
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Ubiquinone
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Itraconazole
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Cyclosporine
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Simvastatin
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Electron Transport Complex IV