Pettersen John C, Pruimboom-Brees Ingrid, Francone Omar L, Amacher David E, Boldt Sherri E, Kerlin Roy L, Ballinger William E
Pfizer Worldwide Research and Development, Groton Laboratory, Pfizer, Inc., Groton, Connecticut 06340, USA.
Toxicol Pathol. 2012 Apr;40(3):435-47. doi: 10.1177/0192623311431945. Epub 2012 Feb 1.
Weak peroxisome proliferator-activated receptor (PPAR) α agonists (fibrates) are used to treat dyslipidemia. This study compared the effects of the potent and selective PPARα agonist CP-778875 on peroxisomal β-oxidation and cardiac and/or skeletal muscle injury with those of the weak PPARα agonist fenofibrate. We hypothesized that these muscle effects are mediated through the PPARα receptor, leading to increased β-oxidation and consequent oxidative stress. CP-778875 (5 or 500 mg/kg) and fenofibrate (600 or 2,000→1,200 mg/kg, dose lowered because of intolerance) were administered to rats for six weeks. Standard end points, serum troponin I, heart and skeletal muscle β-oxidation of palmitoyl-CoA, and acyl co-oxidase (AOX) mRNA were assessed. Both compounds dose-dependently increased the incidence and/or severity of cardiomyocyte degeneration and necrosis, heart weight, troponin I, and skeletal muscle degeneration. Mean heart β-oxidation (3.4- to 5.1-fold control) and AOX mRNA (2.4- to 3.2-fold control) were increased with CP-778875 500 mg/kg and both doses of fenofibrate. β-Oxidation of skeletal muscle was not affected by either compound; however, a significant increase in AOX mRNA (1.6- to 2.1-fold control) was observed with CP-778875 500 mg/kg and both doses of fenofibrate. Taken together, these findings were consistent with PPARα agonism and support the link between increased cardiac and skeletal muscle β-oxidation and resultant muscle injury in the rat.
弱过氧化物酶体增殖物激活受体（PPAR）α激动剂（贝特类药物）用于治疗血脂异常。本研究比较了强效选择性PPARα激动剂CP - 778875与弱PPARα激动剂非诺贝特对过氧化物酶体β氧化以及心脏和/或骨骼肌损伤的影响。我们假设这些肌肉效应是通过PPARα受体介导的，导致β氧化增加并随之产生氧化应激。将CP - 778875（5或500 mg/kg）和非诺贝特（600或2000→1200 mg/kg，因不耐受降低剂量）给予大鼠六周。评估了标准终点、血清肌钙蛋白I、心脏和骨骼肌中棕榈酰辅酶A的β氧化以及酰基辅酶氧化酶（AOX）mRNA。两种化合物均剂量依赖性地增加了心肌细胞变性和坏死的发生率和/或严重程度、心脏重量、肌钙蛋白I以及骨骼肌变性。CP - 778875 500 mg/kg和两种剂量的非诺贝特均使心脏平均β氧化（对照的3.4至5.1倍）和AOX mRNA（对照的2.4至3.2倍）增加。两种化合物均未影响骨骼肌的β氧化；然而，CP - 778875 500 mg/kg和两种剂量的非诺贝特均观察到AOX mRNA显著增加（对照的1.6至2.1倍）。综上所述，这些发现与PPARα激动作用一致，并支持大鼠心脏和骨骼肌β氧化增加与由此导致的肌肉损伤之间的联系。
