Schaefer William H, Lawrence Jeffery W, Loughlin Amy F, Stoffregen Dana A, Mixson Lori A, Dean Dennis C, Raab Conrad E, Yu Nathan X, Lankas George R, Frederick Clay B
Department of Safety Assessment, Merck Research Laboratories, West Point, PA, 19486, USA.
Toxicol Appl Pharmacol. 2004 Jan 1;194(1):10-23. doi: 10.1016/j.taap.2003.08.013.
As a class, hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors can potentially cause skeletal myopathy. One statin, cerivastatin, has recently been withdrawn from the market due to an unacceptably high incidence of rhabdomyolysis. The mechanism underlying statin-induced myopathy is unknown. This paper sought to investigate the relationship among statin-induced myopathy, mitochondrial function, and muscle ubiquinone levels. Rats were administered cerivastatin at 0.1, 0.5, and 1.0 (mg/kg)/day or dose vehicle (controls) by oral gavage for 15 days. Samples of type I-predominant skeletal muscle (soleus) and type II-predominant skeletal muscle [quadriceps and extensor digitorum longus (EDL)], and blood were collected on study days 5, 10, and 15 for morphological evaluation, clinical chemistry, mitochondrial function tests, and analysis of ubiquinone levels. No histological changes were observed in any of the animals on study days 5 or 10, but on study day 15, mid- and high-dose animals had necrosis and inflammation in type II skeletal muscle. Elevated creatine kinase (CK) levels in blood (a clinical marker of myopathy) correlated with the histopathological diagnosis of myopathy. Ultrastructural characterization of skeletal muscle revealed disruption of the sarcomere and altered mitochondria only in myofibers with degeneration, while adjacent myofibers were unaffected and had normal mitochondria. Thus, mitochondrial effects appeared not to precede myofiber degeneration. Mean coenzyme Q9 (CoQ9) levels in all dose groups were slightly decreased relative to controls in type II skeletal muscle, although the difference was not significantly different in most cases. Mitochondrial function in skeletal muscle was not affected by the changes in ubiquinone levels. The ubiquinone levels in high-dose-treated animals exhibiting myopathy were not significantly different from low-dose animals with no observable toxic effects. Furthermore, ubiquinone levels did not correlate with circulating CK levels in treated animals. The results of this study suggest that neither mitochondrial injury, nor a decrease in muscle ubiquinone levels, is the primary cause of skeletal myopathy in cerivastatin-dosed rats.
作为一类药物，羟甲基戊二酰辅酶A（HMG - CoA）还原酶抑制剂可能会引发骨骼肌病。一种他汀类药物西立伐他汀，由于横纹肌溶解发生率高得令人无法接受，最近已退出市场。他汀类药物所致肌病的潜在机制尚不清楚。本文旨在研究他汀类药物所致肌病、线粒体功能和肌肉泛醌水平之间的关系。通过口服灌胃法，给大鼠分别施用0.1、0.5和1.0（毫克/千克）/天的西立伐他汀或赋形剂（对照组），持续15天。在研究的第5、10和15天，采集以I型为主的骨骼肌（比目鱼肌）和以II型为主的骨骼肌[股四头肌和趾长伸肌（EDL）]样本以及血液，用于形态学评估、临床化学分析、线粒体功能测试和泛醌水平分析。在研究的第5天或第10天，未在任何动物身上观察到组织学变化，但在研究的第15天，中、高剂量组动物的II型骨骼肌出现坏死和炎症。血液中肌酸激酶（CK）水平升高（肌病的临床标志物）与肌病的组织病理学诊断相关。骨骼肌的超微结构特征显示，仅在发生变性的肌纤维中，肌节遭到破坏且线粒体发生改变，而相邻的肌纤维未受影响且线粒体正常。因此，线粒体效应似乎并非先于肌纤维变性出现。相对于对照组，所有剂量组II型骨骼肌中的辅酶Q9（CoQ9）平均水平略有下降，尽管在大多数情况下差异并不显著。骨骼肌中的线粒体功能并未受到泛醌水平变化的影响。出现肌病的高剂量治疗组动物的泛醌水平与未观察到毒性作用的低剂量组动物并无显著差异。此外，在接受治疗的动物中，泛醌水平与循环CK水平之间并无关联。本研究结果表明，线粒体损伤和肌肉泛醌水平降低均不是西立伐他汀给药大鼠骨骼肌病的主要原因。
