Decreased ubiquinone availability and impaired mitochondrial cytochrome oxidase activity associated with statin treatment.
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.
Duncan
Andrew J
AJ
Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 1BG, UK.
Hargreaves
Iain P
IP
Damian
Maxwell S
MS
Land
John M
JM
Heales
Simon J R
SJ
D000368:Aged; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D003576:Electron Transport Complex IV / Q000378:metabolism*; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D017964:Itraconazole / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D012206:Rhabdomyolysis / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects*; D014451:Ubiquinone / Q000378:metabolism*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014451:Ubiquinone; D017964:Itraconazole; D016572:Cyclosporine; D019821:Simvastatin; D003576:Electron Transport Complex IV