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

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

HMG-CoA reductase inhibitors induce apoptosis of lymphoma cells by promoting ROS generation and regulating Akt, Erk and p38 signals via suppression of mevalonate pathway

“…11, 13, 15, 17, 26 These previous data are consistent with our results showing that statins, especially fluvastatin, induced significant inhibition of the viability of lymphoma cells. We next documented that apoptosis was responsible for fluvastatin-induced cytotoxicity towards A20 cells using flow cytometry, HO/PI double staining, TEM, DNA fragmentation and annexin V-FITC staining, indicating that fluvastatin treatment directly induced an apoptotic death in lymphoma cells.…”

Possible Mechanisms Underlying Statin-Induced Skeletal Muscle Toxicity in L6 Fibroblasts and in Rats

“…However, the mechanism of statin-induced myopathy is not yet fully understood. Several hypotheses have been proposed to explain statin-induced myotoxicity, including the lowering of ubiquinone levels (5,6), alterations of chloride channel conductance within myocytes (7), and apoptosis induction (8 -10). HMG-CoA reductase, which converts HMG-CoA to mevalonate, is a rate-limiting enzyme of the mevalonate cascade (11).…”

Uremic Toxins Enhance Statin-Induced Cytotoxicity in Differentiated Human Rhabdomyosarcoma Cells

“…It has been reported that CoQ 10 is involved in mitochondrial electron transport and oxidative phosphorylation [19], but that it cannot suppress statin-induced skeletal muscle toxicity [24]. Therefore, these results suggest that mitochondrial electron transport and oxidative phosphorylation and CoQ 10 are not involved in the acceleration of statin-induced apoptosis and cytotoxicity by uremic toxins on RD cells.…”

“…Subsequently, statins decrease activity of small G proteins such as Ras and Rho, which are associated with apoptotic signals [18]. Reduced biosynthesis of coenzymeQ-10 (CoQ 10 ) results in abnormal oxidative phosphorylation in the mitochondrial electron transport chain, which damages cellular homeostasis [19]. Furthermore, interleukin-(IL)-1β- and IL-6-induced oxidative stress promotes hepatic cholesterol synthesis [20].…”