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Toxicologic Pathology
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Articles

Fenofibrate-Induced Muscular Toxicity Is Associated with a Metabolic Shift Limited to Type-1 Muscles in Rats

Miyoko Okada1, Fumiko Sano1, Itsuko Ikeda1, Jiro Sugimoto1, Shiro Takagi1, Hiroki Sakai2 and Tokuma Yanai2

1 Safety Research Laboratory, Mitsubishi Tanabe Pharma Corporation, 1-1-1, Kazusakamatari, Kisarazu, Chiba 292-0818, Japan
2 Laboratory of Veterinary Pathology, Faculty of Applied Biological Sciences, Gifu University 1-1, Yanagido, Gifu, 501-1193, Japan

Correspondence: Miyoko Okada, Mitsubishi Tanabe Pharma Corporation, 1-1-1, Kazusakamatari, Kisarazu, Chiba 292-0818, Japan; e-mail:Okada.Miyoko{at}mg.mt-pharma.co.jp.

Morphological changes and mRNA expression levels in type-1 predominant soleus and type-2 predominant tensor fasciae latae muscles of rats treated with fenofibrate were investigated. After fenofibrate by oral gavage at 300 mg/kg/day for 28 days, degeneration/necrosis and regeneration of muscle fibers, cellular infiltration, and fibrosis were seen in soleus muscle. Additionally, expression of PDK4, CPT1-M, CPT2, and FACO mRNAs was increased. In contrast, no morphological changes or mRNA induction were apparent in tensor fasciae latae muscle. These data suggest that sensitivity to fenofibrate-induced muscle toxicity differs among muscles, with only type-1 fibers being susceptible. The up-regulation of PDK4, CPTs and FACO mRNA expression in soleus muscle indicates that the energy source is switched from glucose to fatty acids, and this might be related to the observed fenofibrate-induced muscular toxicity.

Key Words: fenofibrate • rat • myopathy • PDK4 • CPT

Abbreviations: CPT, carnitine palmitoyltransferase; • FACO, peroxisomal fatty acyl CoA oxidase; • PDH, pyruvate dehydrogenase; • PPAR{alpha}, peroxisome proliferator-activated receptor-{alpha}.

This version was published on June 1, 2009

Toxicologic Pathology, Vol. 37, No. 4, 517-520 (2009)
DOI: 10.1177/0192623309336151
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