Itagaki Mai, Takaguri Akira, Kano Seiichiro, Kaneta Shigeru, Ichihara Kazuo, Satoh Kumi
Division of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, Otaru, Japan.
J Pharmacol Sci. 2009 Jan;109(1):94-101. doi: 10.1254/jphs.08238fp. Epub 2009 Jan 8.
3-Hydroxy-3-methylglutaryl CoA reductase inhibitors (statins) are safe and well-tolerated therapeutic drugs. However, they occasionally induce myotoxicity such as myopathy and rhabdomyolysis. Here, we investigated the mechanism of statin-induced myotoxicity in L6 fibroblasts and in rats in vivo. L6 fibroblasts were differentiated and then treated with pravastatin, simvastatin, or fluvastatin for 72 h. Hydrophobic simvastatin and fluvastatin decreased cell viability in a dose-dependent manner via apoptosis characterized by typical nuclear fragmentation and condensation and caspase-3 activation. Both hydrophobic statins transferred RhoA localization from the cell membrane to the cytosol. These changes induced by both hydrophobic statins were completely abolished by the co-application of geranylgeranylpyrophosphate (GGPP). Y27632, a Rho-kinase inhibitor, mimicked the hydrophobic statin-induced apoptosis. Hydrophilic pravastatin did not affect the viability of the cells. Fluvastatin was continuously infused (2.08 mg/kg at an infusion rate of 0.5 mL/h) into the right internal jugular vein of the rats in vivo for 72 h. Fluvastatin infusion significantly elevated the plasma CPK level and transferred RhoA localization in the skeletal muscle from the cell membrane to the cytosol. In conclusion, RhoA dysfunction due to loss of lipid modification with GGPP is involved in the mechanisms of statin-induced skeletal muscle toxicity.
3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）是安全且耐受性良好的治疗药物。然而，它们偶尔会诱发肌毒性，如肌病和横纹肌溶解。在此，我们研究了他汀类药物在L6成纤维细胞和体内大鼠中诱发肌毒性的机制。将L6成纤维细胞分化后，用普伐他汀、辛伐他汀或氟伐他汀处理72小时。疏水性的辛伐他汀和氟伐他汀通过典型的核碎片化、凝聚和半胱天冬酶-3激活所表征的凋亡，以剂量依赖性方式降低细胞活力。两种疏水性他汀均使RhoA定位从细胞膜转移至胞质溶胶。香叶基香叶基焦磷酸（GGPP）共同应用可完全消除这两种疏水性他汀所诱导的这些变化。Rho激酶抑制剂Y27632模拟了疏水性他汀诱导的凋亡。亲水性的普伐他汀不影响细胞活力。在体内将氟伐他汀以0.5 mL/h的输注速率连续输注（2.08 mg/kg）到大鼠的右颈内静脉中72小时。氟伐他汀输注显著提高血浆肌酸磷酸激酶（CPK）水平，并使骨骼肌中的RhoA定位从细胞膜转移至胞质溶胶。总之，由于GGPP脂质修饰缺失导致的RhoA功能障碍参与了他汀类药物诱导的骨骼肌毒性机制。
