Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona.
Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson, Arizona.
J Biochem Mol Toxicol. 2020 Jun;34(6):e22484. doi: 10.1002/jbt.22484. Epub 2020 Mar 20.
Statins are among the most commonly prescribed drugs for the treatment of high blood cholesterol. Myotoxicity of statins in certain individuals is often a severe side effect leading to withdrawal. Using C2C12 and H9c2 cells, both exhibiting characteristics of skeletal muscle cells, we addressed whether resveratrol (RSV) can prevent statin toxicity. Statins decreased cell viability in a dose and time-dependent manner. Among the five statins tested, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin, simvastatin is the most toxic one. Simvastatin at 10 µM caused about 65% loss of metabolic activity as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays in C2C12 cells or H9c2 cells. Inhibition of metabolic activity correlates with an increase in caspase activity. RSV was found to protect H9c2 cells from simvastatin-induced activation of caspase-3/7. However, such protection was not found in C2C12 cells. This cell type-dependent effect of RSV adds to the complexity in muscle cell toxicity of statins.
他汀类药物是治疗高胆固醇血症最常用的药物之一。他汀类药物在某些个体中的肌毒性常常是导致停药的严重副作用。我们使用同时具有骨骼肌细胞特征的 C2C12 和 H9c2 细胞，研究白藜芦醇（RSV）是否可以预防他汀类药物毒性。他汀类药物以剂量和时间依赖的方式降低细胞活力。在所测试的五种他汀类药物中，阿托伐他汀、辛伐他汀、洛伐他汀、普伐他汀和氟伐他汀，辛伐他汀的毒性最大。辛伐他汀在 10μM 时，通过 C2C12 细胞或 H9c2 细胞中的 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐测定法，导致约 65%的代谢活性丧失。代谢活性的抑制与半胱天冬酶活性的增加相关。发现 RSV 可保护 H9c2 细胞免受辛伐他汀诱导的 caspase-3/7 激活。然而，在 C2C12 细胞中未发现这种保护作用。RSV 的这种细胞类型依赖性作用增加了他汀类药物对肌肉细胞毒性的复杂性。
