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The PPARα agonists fenofibrate and CP-778875 cause increased ß-oxidation, leading to oxidative injury in skeletal and cardiac muscle in the rat.
Pettersen, John C; Pruimboom-Brees, Ingrid; Francone, Omar L; Amacher, David E; Boldt, Sherri E; Kerlin, Roy L; Ballinger, William E.
Affiliation
  • Pettersen JC; Pfizer Worldwide Research and Development, Groton Laboratory, Pfizer, Inc., Groton, Connecticut 06340, USA. john.c.pettersen@pfizer.com
Toxicol Pathol ; 40(3): 435-47, 2012 Apr.
Article in En | MEDLINE | ID: mdl-22301950
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 ß-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 ß-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 ß-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 ß-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. ß-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 ß-oxidation and resultant muscle injury in the rat.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Fenofibrate / Oxidative Stress / Muscle, Skeletal / PPAR alpha / Heart Limits: Animals Language: En Journal: Toxicol Pathol Year: 2012 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Fenofibrate / Oxidative Stress / Muscle, Skeletal / PPAR alpha / Heart Limits: Animals Language: En Journal: Toxicol Pathol Year: 2012 Document type: Article Affiliation country: Country of publication: