Influence of 3-hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors on Ubiquinone Levels in Rat Skeletal Muscle and Heart: Relationship to Cytotoxicity and Inhibitory Activity for Cholesterol Synthesis in Human Skeletal Muscle Cells
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Accession number;07A0040469
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| Title;Influence of 3-hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors on Ubiquinone Levels in Rat Skeletal Muscle and Heart: Relationship to Cytotoxicity and Inhibitory Activity for Cholesterol Synthesis in Human Skeletal Muscle Cells |
| Author;
YAMAZAKI HIROYUKI
(Tokyo New Drug Research Laboratories I, Pharmaceutical Division, Kowa, Co. Ltd.)
SUZUKI MAHOMI
(Tokyo New Drug Research Laboratories I, Pharmaceutical Division, Kowa, Co. Ltd.)
AOKI TARO
(Tokyo New Drug Research Laboratories I, Pharmaceutical Division, Kowa, Co. Ltd.)
MORIKAWA SHIGERU
(Tokyo New Drug Research Laboratories I, Pharmaceutical Division, Kowa, Co. Ltd.)
MAEJIMA TAKASHI
(Tokyo New Drug Research Laboratories I, Pharmaceutical Division, Kowa, Co. Ltd.)
SATO FUMIYASU
(Tokyo New Drug Research Laboratories I, Pharmaceutical Division, Kowa, Co. Ltd.)
SAWANOBORI KIMIO
(Tokyo New Drug Research Laboratories I, Pharmaceutical Division, Kowa, Co. Ltd.)
KITAHARA MASAKI
(Shiraoka Research Station of Biological Science, Nissan Chemical Industries, Ltd., Shiraoka.)
KODAMA TATSUHIKO
(Laboratory for System Biology and Medicine, RCAST, The University of Tokyo.)
SAITO YASUSHI
(Department of Clinical Cell Biology (F5), Graduate School of Medicine, Chiba University)
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Journal Title;J Atheroscler Thromb
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Journal Code:L2187A
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ISSN:1340-3478
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VOL.13;NO.6;PAGE.295-307 (J-STAGE)(2006)
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| Figure&Table&Reference;FIG.7, TBL.2, REF.51 |
| Pub. Country;Japan |
| Language;English |
| Abstract;Although statins are prescribed as relatively safe and effective drugs for hypercholesterolemic patients, it has been reported that a significant side effect, myopathy, occurs infrequently during medication. Moreover, because statins decrease cardiac ubiquinone levels, the risk of cardiac dysfunction has been suggested. This study sought to evaluate and compare the cytotoxicity of statins (cerivastatin, pitavastatin, fluvastatin, simvastatin, atorvastatin and pravastatin) in cultured human skeletal muscle cells (HSkMCs) and the effects on ubiquinone levels in statin-treated rat skeletal muscle and heart. Cerivastatin, the most potent inhibitor of HMG-CoA reductase, showed the strongest cytotoxicity (over 10-fold) among the statins examined, while the effects of the others were in a similar range. In rat experiments, neither pitavastatin nor cerivastatin decreased ubiquinone levels in skeletal muscle, but both dose-dependently lowered ubiquinone levels in the heart. As the rates of reduction by pitavastatin (9.6% at 30 mg/kg) and cerivastatin (9.7% at 0.3 mg/kg) were almost equal, it was estimated that cerivastatin reduced ubiquinone levels in the rat heart approximately 100-fold more strongly than pitavastatin, based on the effective doses. We found that cerivastatin showed the most potent cytotoxicity in HSkMCs and strongly lowered ubiquinone levels in the rat heart. (Author abst.) |
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