Department of Nutrition and Food, Harbin Medical University, Heilongjiang, China.
Toxicol In Vitro. 2010 Feb;24(1):154-9. doi: 10.1016/j.tiv.2009.08.001. Epub 2009 Aug 13.
Fibrates, the ligands of peroxisome proliferator-activated receptor alpha (PPARalpha), are used as a class of lipid-lowering drugs in clinical practice for the treatment of dyslipidemia. Fibrates are well tolerated in most cases concomitantly with occasional adverse reactions including muscular toxicity, which is enhanced by the combination with statins. This study was designed to investigate the effects of bezafibrate as a PPARalpha agonist on human embryo rhabdomyosarcoma (RD) cells and possible mechanisms responsible for bezafibrate-mediated myopathy. The results revealed that bezafibrate caused a dose-dependent decrease in cell viability, which was fortified in association with atorvastatin at a pharmacological dose. Bezafibrate at toxic doses of 300 and 1000microM upregulated PPARalpha at the mRNA level, counteracted by a PPARalpha antagonist (MK886). Bezafibrate at a toxic dose induced typical apoptotic characteristics related to the inhibition of phosphorylation of Akt which was blocked by PPARalpha antagonist. Toxic doses of bezafibrate initiated a significant increase in pyruvate dehydrogenase kinase 4 mRNA and protein levels, compromised by MK886. These results suggest the critical roles of PPARalpha signaling in bezafibrate-induced myotoxicity and the involvement of apoptosis through Akt pathway.
贝特类药物，过氧化物酶体增殖物激活受体α（PPARα）的配体，在临床上被用作一类降脂药物，用于治疗血脂异常。贝特类药物在大多数情况下耐受性良好，但偶尔会出现不良反应，包括肌肉毒性，与他汀类药物联合使用时会增强这种毒性。本研究旨在探讨作为 PPARα激动剂的苯扎贝特对人胚横纹肌肉瘤（RD）细胞的影响及其介导肌病的可能机制。结果表明，苯扎贝特可导致细胞活力呈剂量依赖性下降，与阿托伐他汀在药理剂量下联合使用时可增强这种下降。苯扎贝特在毒性剂量 300 和 1000μM 时可上调 PPARα 的 mRNA 水平，这种上调可被 PPARα 拮抗剂（MK886）拮抗。苯扎贝特在毒性剂量下诱导与 Akt 磷酸化抑制相关的典型凋亡特征，这种抑制可被 PPARα 拮抗剂阻断。苯扎贝特的毒性剂量可引发丙酮酸脱氢酶激酶 4（PDK4）mRNA 和蛋白水平的显著增加，MK886 可减轻这种增加。这些结果表明，PPARα 信号在苯扎贝特诱导的肌毒性中起着关键作用，并且通过 Akt 途径参与了细胞凋亡。
