ToxSci Advance Access originally published online on February 27, 2008
Toxicological Sciences 2008 103(2):382-396; doi:10.1093/toxsci/kfn042
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Fabp3 as a Biomarker of Skeletal Muscle Toxicity in the Rat: Comparison with Conventional Biomarkers
Investigative Toxicology, Lilly Research Laboratories, Greenfield, Indiana 46140
1 To whom correspondence should be addressed at Eli Lilly and Company, 2001 W. Main St., Greenfield, IN 46140. Fax: (317) 277-5002. E-mail: davewatson{at}lilly.com.
Received December 14, 2007; accepted February 20, 2008
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Abstract |
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Fatty acid binding protein 3 (Fabp3) has been used as a serological biomarker of cardiac injury, but its utility as a preclinical biomarker of injury to skeletal muscle is not well described. Fabp3 concentrations were determined for tissues from Sprague–Dawley rats and found to occur at highest concentrations in cardiac muscle and in skeletal muscles containing an abundance of type I fibers, such as the soleus muscle. Soleus is also a primary site of skeletal muscle (SKM) injury caused by lipid-lowering peroxisome proliferator–activated receptor alpha (PPAR-
) agonists. In rats administered repeat doses of a PPAR- agonist, the kinetics and amplitude of plasma concentrations of Fabp3 were consistent with plasma compound concentrations and histopathology findings of swollen, hyalinized, and fragmented muscle fibers with macrophage infiltration. Immunohistochemical detection of Fabp3 revealed focal depletion of Fabp3 protein from injured SKM fibers which is consistent with increased serum Fabp3 concentrations in treated rats. We then assessed the predictivity of serological Fabp3 for SKM necrosis in short duration toxicology studies. Rats were treated with various doses of 27 different compounds, and the predictivity of serological biomarkers was assessed relative to histology in individual rats and in treatment groups. Under these study conditions, Fabp3 was the most useful individual biomarker based on concordance, sensitivity, positive and negative predictive values, and false negative rate. In addition, the combination of Fabp3 and aspartate aminotransferase (AST) had greater diagnostic value than the conventional combination of creatine kinase-MM isoenzyme (CK) and AST.
Key Words: biomarker; skeletal muscle; necrosis; predictivity; rat; tissue distribution.
Structures of some proprietary compounds have not been provided in the present work with Editorial approval.
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