Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 1BG, UK.
Toxicol Mech Methods. 2009 Jan;19(1):44-50. doi: 10.1080/15376510802305047.
In order to investigate the potential involvement of mitochondrial electron transport chain (ETC) dysfunction in myotoxicity associated with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) treatment, assessment was made of ETC activity and ubiquinone status in two patients experiencing myopathy following treatment with simvastatin (40 mg/day) and cyclosporin (patient 1) and simvastatin (40 mg/day) and itraconazole (patient 2). Analysis of skeletal muscle biopsies revealed a decreased ubiquinone status (77 and 132; reference range: 140-580 pmol/mg) and cytochrome oxidase (complex IV) activity (0.006 and 0.007 reference range: 0.014-0.034). To assess statin treatment in the absence of possible pharmacological interference from cyclosporin or itraconazole, primary astrocytes were cultured with lovastatin (100 microM). Lovastatin treatment resulted in a decrease in ubiquinone (97.9 +/- 14.9; control: 202.9 +/- 18.4 pmol/mg; p < 0.05), and complex IV activity (0.008 +/- 0.001; control: 0.011 +/- 0.001; p < 0.05) relative to control. These data, coupled with the patient findings, indicate a possible association between statin treatment, decreased ubiquinone status, and loss of complex IV activity.
为了研究线粒体电子传递链（ETC）功能障碍是否与 3-羟基-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶抑制剂（他汀类药物）治疗相关的肌毒性有关，我们评估了两名因使用辛伐他汀（40mg/天）和环孢菌素（患者 1）以及辛伐他汀（40mg/天）和伊曲康唑（患者 2）治疗后出现肌病的患者的 ETC 活性和泛醌状态。骨骼肌活检分析显示泛醌状态降低（77 和 132；参考范围：140-580 pmol/mg）和细胞色素氧化酶（复合物 IV）活性降低（0.006 和 0.007 参考范围：0.014-0.034）。为了在没有环孢菌素或伊曲康唑可能的药理学干扰的情况下评估他汀类药物治疗，我们用洛伐他汀（100μM）培养原代星形胶质细胞。洛伐他汀处理导致泛醌减少（97.9±14.9；对照：202.9±18.4 pmol/mg；p<0.05）和复合物 IV 活性降低（0.008±0.001；对照：0.011±0.001；p<0.05）相对于对照。这些数据与患者的发现相结合，表明他汀类药物治疗、泛醌状态降低和复合物 IV 活性丧失之间可能存在关联。
