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 patien...
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| Veröffentlicht in: | Toxicology mechanisms and methods 2009-01, Vol.19 (1), p.44-50 |
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| creator | Duncan, Andrew J. Hargreaves, Iain P. Damian, Maxwell S. Land, John M. Heales, Simon J. R. |
| description | 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 μM). 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. |
| doi_str_mv | 10.1080/15376510802305047 |
| format | Article |
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R.</creator><creatorcontrib>Duncan, Andrew J. ; Hargreaves, Iain P. ; Damian, Maxwell S. ; Land, John M. ; Heales, Simon J. R.</creatorcontrib><description>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 μM). 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.</description><identifier>ISSN: 1537-6516</identifier><identifier>EISSN: 1537-6524</identifier><identifier>DOI: 10.1080/15376510802305047</identifier><identifier>PMID: 19778232</identifier><language>eng</language><publisher>England: Informa UK Ltd</publisher><subject>Aged ; Animals ; Astrocytes - drug effects ; Astrocytes - enzymology ; Astrocytes - metabolism ; Cells, Cultured ; Cyclosporine - administration & dosage ; Cyclosporine - pharmacology ; Cyclosporine - therapeutic use ; Cytochrome oxidase ; Drug Interactions ; Drug Therapy, Combination ; Electron transport chain ; Electron Transport Complex IV - metabolism ; Female ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects ; Itraconazole - administration & dosage ; Itraconazole - pharmacology ; Itraconazole - therapeutic use ; Male ; Middle Aged ; Muscle, Skeletal - drug effects ; Muscle, Skeletal - enzymology ; Muscle, Skeletal - metabolism ; Muscle, Skeletal - pathology ; Muscular Diseases - chemically induced ; Muscular Diseases - enzymology ; Muscular Diseases - metabolism ; Muscular Diseases - pathology ; Rats ; Rhabdomyolysis - chemically induced ; Rhabdomyolysis - enzymology ; Rhabdomyolysis - metabolism ; Rhabdomyolysis - pathology ; Simvastatin - administration & dosage ; Simvastatin - adverse effects ; Statin ; Ubiquinone ; Ubiquinone - metabolism</subject><ispartof>Toxicology mechanisms and methods, 2009-01, Vol.19 (1), p.44-50</ispartof><rights>2009 Informa UK Ltd 2009</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c499t-a34ac49c9c1b3d558d2071ade5f9c3d706bce3e65a8ae19f3acc37cd9e0072bf3</citedby><cites>FETCH-LOGICAL-c499t-a34ac49c9c1b3d558d2071ade5f9c3d706bce3e65a8ae19f3acc37cd9e0072bf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.tandfonline.com/doi/pdf/10.1080/15376510802305047$$EPDF$$P50$$Ginformaworld$$H</linktopdf><linktohtml>$$Uhttps://www.tandfonline.com/doi/full/10.1080/15376510802305047$$EHTML$$P50$$Ginformaworld$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,59647,59753,60436,60542,61221,61256,61402,61437</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19778232$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Duncan, Andrew J.</creatorcontrib><creatorcontrib>Hargreaves, Iain P.</creatorcontrib><creatorcontrib>Damian, Maxwell S.</creatorcontrib><creatorcontrib>Land, John M.</creatorcontrib><creatorcontrib>Heales, Simon J. R.</creatorcontrib><title>Decreased Ubiquinone Availability and Impaired Mitochondrial Cytochrome Oxidase Activity Associated With Statin Treatment</title><title>Toxicology mechanisms and methods</title><addtitle>Toxicol Mech Methods</addtitle><description>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 μM). 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.</description><subject>Aged</subject><subject>Animals</subject><subject>Astrocytes - drug effects</subject><subject>Astrocytes - enzymology</subject><subject>Astrocytes - metabolism</subject><subject>Cells, Cultured</subject><subject>Cyclosporine - administration & dosage</subject><subject>Cyclosporine - pharmacology</subject><subject>Cyclosporine - therapeutic use</subject><subject>Cytochrome oxidase</subject><subject>Drug Interactions</subject><subject>Drug Therapy, Combination</subject><subject>Electron transport chain</subject><subject>Electron Transport Complex IV - metabolism</subject><subject>Female</subject><subject>Humans</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects</subject><subject>Itraconazole - administration & dosage</subject><subject>Itraconazole - pharmacology</subject><subject>Itraconazole - therapeutic use</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Muscle, Skeletal - drug effects</subject><subject>Muscle, Skeletal - enzymology</subject><subject>Muscle, Skeletal - metabolism</subject><subject>Muscle, Skeletal - pathology</subject><subject>Muscular Diseases - chemically induced</subject><subject>Muscular Diseases - enzymology</subject><subject>Muscular Diseases - metabolism</subject><subject>Muscular Diseases - pathology</subject><subject>Rats</subject><subject>Rhabdomyolysis - chemically induced</subject><subject>Rhabdomyolysis - enzymology</subject><subject>Rhabdomyolysis - metabolism</subject><subject>Rhabdomyolysis - pathology</subject><subject>Simvastatin - administration & dosage</subject><subject>Simvastatin - adverse effects</subject><subject>Statin</subject><subject>Ubiquinone</subject><subject>Ubiquinone - metabolism</subject><issn>1537-6516</issn><issn>1537-6524</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUFv1DAQhSMEoqXwA7ggn-C0YMdxHAsuq6VApaIeaMUxmtgTravE3tpOIf--jnYFQkgLJz9b33sz8iuKl4y-ZbSh75jgshaLLDkVtJKPitPlbVWLsnr8S7P6pHgW4y2lrGEVe1qcMCVlU_LytJg_og4IEQ256ezdZJ13SNb3YAfo7GDTTMAZcjHuwIYMfbXJ6613JlgYyGZebsGPSK5-WpNjyFone7_Y1jF6bSFl03ebtuRbgmQduc7T0oguPS-e9DBEfHE4z4qbT-fXmy-ry6vPF5v15UpXSqUV8Aqy0kqzjhshGlNSycCg6JXmRtK608ixFtAAMtVz0JpLbRRSKsuu52fFm33uLvi7CWNqRxs1DgM49FNsG1mxRuX_-ycpOVdc0Jpl8vVRsqRVSbmq_gMsRa5wmc32oA4-xoB9uwt2hDC3jLZLw-1fZWfPq0P41I1ofjsO7Wbgwx6wrvdhhB8-DKZNMA8-9AGctrHlx_Lf_2HfIgxpqyFge-un4HJrR7Z7AOiwy6A</recordid><startdate>20090101</startdate><enddate>20090101</enddate><creator>Duncan, Andrew J.</creator><creator>Hargreaves, Iain P.</creator><creator>Damian, Maxwell S.</creator><creator>Land, John M.</creator><creator>Heales, Simon J. 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R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c499t-a34ac49c9c1b3d558d2071ade5f9c3d706bce3e65a8ae19f3acc37cd9e0072bf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Aged</topic><topic>Animals</topic><topic>Astrocytes - drug effects</topic><topic>Astrocytes - enzymology</topic><topic>Astrocytes - metabolism</topic><topic>Cells, Cultured</topic><topic>Cyclosporine - administration & dosage</topic><topic>Cyclosporine - pharmacology</topic><topic>Cyclosporine - therapeutic use</topic><topic>Cytochrome oxidase</topic><topic>Drug Interactions</topic><topic>Drug Therapy, Combination</topic><topic>Electron transport chain</topic><topic>Electron Transport Complex IV - metabolism</topic><topic>Female</topic><topic>Humans</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects</topic><topic>Itraconazole - administration & dosage</topic><topic>Itraconazole - pharmacology</topic><topic>Itraconazole - therapeutic use</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Muscle, Skeletal - drug effects</topic><topic>Muscle, Skeletal - enzymology</topic><topic>Muscle, Skeletal - metabolism</topic><topic>Muscle, Skeletal - pathology</topic><topic>Muscular Diseases - chemically induced</topic><topic>Muscular Diseases - enzymology</topic><topic>Muscular Diseases - metabolism</topic><topic>Muscular Diseases - pathology</topic><topic>Rats</topic><topic>Rhabdomyolysis - chemically induced</topic><topic>Rhabdomyolysis - enzymology</topic><topic>Rhabdomyolysis - metabolism</topic><topic>Rhabdomyolysis - pathology</topic><topic>Simvastatin - administration & dosage</topic><topic>Simvastatin - adverse effects</topic><topic>Statin</topic><topic>Ubiquinone</topic><topic>Ubiquinone - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Duncan, Andrew J.</creatorcontrib><creatorcontrib>Hargreaves, Iain P.</creatorcontrib><creatorcontrib>Damian, Maxwell S.</creatorcontrib><creatorcontrib>Land, John M.</creatorcontrib><creatorcontrib>Heales, Simon J. R.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>MEDLINE - Academic</collection><jtitle>Toxicology mechanisms and methods</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Duncan, Andrew J.</au><au>Hargreaves, Iain P.</au><au>Damian, Maxwell S.</au><au>Land, John M.</au><au>Heales, Simon J. R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Decreased Ubiquinone Availability and Impaired Mitochondrial Cytochrome Oxidase Activity Associated With Statin Treatment</atitle><jtitle>Toxicology mechanisms and methods</jtitle><addtitle>Toxicol Mech Methods</addtitle><date>2009-01-01</date><risdate>2009</risdate><volume>19</volume><issue>1</issue><spage>44</spage><epage>50</epage><pages>44-50</pages><issn>1537-6516</issn><eissn>1537-6524</eissn><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 μM). 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.</abstract><cop>England</cop><pub>Informa UK Ltd</pub><pmid>19778232</pmid><doi>10.1080/15376510802305047</doi><tpages>7</tpages></addata></record> |
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| source | MEDLINE; Taylor & Francis:Master (3349 titles); Taylor & Francis Medical Library - CRKN |
| subjects | Aged Animals Astrocytes - drug effects Astrocytes - enzymology Astrocytes - metabolism Cells, Cultured Cyclosporine - administration & dosage Cyclosporine - pharmacology Cyclosporine - therapeutic use Cytochrome oxidase Drug Interactions Drug Therapy, Combination Electron transport chain Electron Transport Complex IV - metabolism Female Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects Itraconazole - administration & dosage Itraconazole - pharmacology Itraconazole - therapeutic use Male Middle Aged Muscle, Skeletal - drug effects Muscle, Skeletal - enzymology Muscle, Skeletal - metabolism Muscle, Skeletal - pathology Muscular Diseases - chemically induced Muscular Diseases - enzymology Muscular Diseases - metabolism Muscular Diseases - pathology Rats Rhabdomyolysis - chemically induced Rhabdomyolysis - enzymology Rhabdomyolysis - metabolism Rhabdomyolysis - pathology Simvastatin - administration & dosage Simvastatin - adverse effects Statin Ubiquinone Ubiquinone - metabolism |
| title | Decreased Ubiquinone Availability and Impaired Mitochondrial Cytochrome Oxidase Activity Associated With Statin Treatment |
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