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.
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.
Yamazaki
Hiroyuki
H
Tokyo New Drug Research Laboratories I, Pharmaceutical Division, Kowa, Co. Ltd, Japan. hyamazk@kowa.co.jp
Suzuki
Mahomi
M
Aoki
Taro
T
Morikawa
Shigeru
S
Maejima
Takashi
T
Sato
Fumiyasu
F
Sawanobori
Kimio
K
Kitahara
Masaki
M
Kodama
Tatsuhiko
T
Saito
Yasushi
Y
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis* / Q000378:metabolism; D004798:Enzymes / Q000097:blood / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids / Q000097:blood; D008297:Male; D009124:Muscle Proteins / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014451:Ubiquinone / Q000378:metabolism*
D004798:Enzymes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D009124:Muscle Proteins; D014451:Ubiquinone; D002784:Cholesterol