The effect of Simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and ubiquinone in skeletal muscle

Laaksonen, Reijo; Jokelainen, Kalle; Laakso, Juha; Sahi, Timo; Härkönen, Matti; Tikkanen, Matti J.; Himberg, Jaakko‐Juhani

doi:10.1016/s0002-9149(97)89180-1

Cited by 153 publications

(84 citation statements)

References 18 publications

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“…In skeletal muscle, as the decrease of ubiquinone levels is thought to be one of the causative phenomena of muscle disorders, evaluation of the effect of statins on ubiquinone levels in skeletal muscle is considered useful to predict the possibility that statins will cause the development of myopathy. In humans, simvastatin at low doses (20 mg/d) did not decrease skeletal muscle ubiquinone 35,36) , but highdose treatment with simvastatin (80 mg/d) decreased ubiquinone levels in human skeletal muscle and decreased respiratory chain enzyme activity in a minority of patients with a substantial reduction in the muscle ubiquinone level 13) . In that study, simvastatin and atorvastatin similarly reduced cholesterol and ubiquinone levels in serum, but only simvastatin treatment reduced skeletal muscle ubiquinone levels.…”

Section: Discussionmentioning

confidence: 91%

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

Yamazaki¹,

Suzuki²,

Aoki³

et al. 2006

J Atheroscler Thromb

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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. J Atheroscler Thromb, 2006; 13:295-307.

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Section: Discussionmentioning

confidence: 91%

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

Yamazaki¹,

Suzuki²,

Aoki³

et al. 2006

J Atheroscler Thromb

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“…Despite in-vitro support for this concept, 32,33 a human study of six months of simvastatin treatment (20 mg per day) on skeletal muscle concentrations of high-energy phosphates and ubiquinone demonstrated that the muscle high-energy phosphate and ubiquinone concentrations assayed after simvastatin treatment were similar to those observed at baseline and did not differ from values in control subjects. 34 No clinical study has yet provided support for the hypothesis of diminished isoprenoid synthesis or energy generation in muscle cells during statin therapy. Some have proposed that statin interaction with the cytochrome P-450 hepatic enzyme system might be related to myopathy.…”

Section: Mechanism Of Myopathymentioning

confidence: 99%

ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins

Pasternak¹,

Smith²,

Merz³

et al. 2002

Circulation

649

233

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“…How the intracellular Q10 levels are affected during statin treatment in human beings is not thoroughly investigated, although a small study in 19 simvastatin-treated individuals indicated that there was no change in Q10 levels in skeletal muscle tissue during statin treatment [25].…”

Section: Discussionmentioning

confidence: 99%

Statin‐induced Myopathy and Ubiquinone Levels in Serum – Results from a Prospective, Observational Study

Skilving

Ačimovič

Rane

et al. 2015

Basic Clin Pharma Tox

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It has been suggested that an impaired ubiquinone (Q10) synthesis may be responsible for muscular side effects caused by statins. The primary aim of this study was to investigate whether low Q10 levels in serum could be used as a marker to predict the risk of developing statin-induced myopathy. The secondary aim was to compare the change in Q10 levels during statin treatment and differences between men and women. Serum samples from a prospective, observational study in statin-treated patients who were thoroughly followed regarding muscular symptoms were used. In this cohort, 16 developed myopathy and 126 had no muscular symptoms related to statin treatment. Q10 levels were measured with a novel LC-MS method at baseline and after 2 months of statin treatment. Q10 levels showed no correlation with the risk of developing statin-induced myopathy. Individuals with low levels, Q10 < 200 ng/ml, at baseline had no increased risk of developing myopathy. In consistence with earlier reports, we showed that Q10 levels were reduced by 30% during statin treatment. There was no significant difference in the reduction between patients with or without myopathy. Women had approximately 30% lower Q10 levels compared to men both before and after treatment. In this study, there was no association between Q10 levels at baseline and statin-induced muscular side effects during a 2-month follow-up period, and our results indicate that Q10 levels in serum is not a useful marker to predict statin-induced myopathy.Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are used for treatment of hypercholesterolaemia and have a pronounced, preventive effect on serious cardiovascular events and mortality [1,2]. Today, statins are some of the most prescribed drugs in the Western world, and the consumption is steadily increasing [3]. However, several reports have demonstrated that statin-induced muscular side effects such as myalgia are more common than first demonstrated in clinical trials. In fact, 10-15% of patients prescribed statins may experience muscle symptoms [4][5][6]. The statin-induced myopathy is considered to be dose dependent [7] but independent of the cholesterol-lowering effect [8].Statins affect not only the synthesis of cholesterol but also all products in the cholesterol biosynthesis pathway.Ubiquinone (Q10) is one of these products. The major part of the intracellular Q10 is present in the inner mitochondrial membrane as an essential part of the electron transport chain [9,10]. A smaller fraction is present in the cytosol where it has antioxidative functions [9,11]. Q10 is also present in the blood and is mainly bound to low-density lipoprotein (LDL) and also, to some extent, to high density lipoprotein (HDL) and very low-density lipoprotein (VLDL) [12].It has been suggested that the decreased synthesis of Q10 may be involved in statin-induced myopathy [13,14]. In particular, the reduction of mitochondrial Q10 has been suggested to cause myopathy, and statin treatments have been shown to negatively a...

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The effect of Simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and ubiquinone in skeletal muscle

Cited by 153 publications

References 18 publications

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

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

ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins

Statin‐induced Myopathy and Ubiquinone Levels in Serum – Results from a Prospective, Observational Study

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