title: Biomarker evaluation of skeletal muscle toxicity following clofibrate administration in rats.
abstract: The use of sensitive biomarkers to monitor skeletal muscle toxicity in preclinical toxicity studies is important for the risk assessment in humans during the development of a novel compound. Skeletal muscle toxicity in Sprague Dawley Rats was induced with clofibrate at different dose levels for 7 days to compare standard clinical pathology assays with novel skeletal muscle and cardiac muscle biomarkers, gene expression and histopathological changes. The standard clinical pathology assays aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) enzyme activity were compared to novel biomarkers fatty acid binding protein 3 (Fabp3), myosin light chain 3 (Myl3), muscular isoform of CK immunoreactivity (three isoforms CKBB, CKMM, CKMB), parvalbumin (Prv), skeletal troponin I (sTnI), cardiac troponin T (cTnT), cardiac troponin I (cTnI), CKMM, and myoglobin (Myo). The biomarker elevations were correlated to histopathological findings detected in several muscles and gene expression changes. Clofibrate predominantly induced skeletal muscle toxicity of type I fibers of low magnitude. Useful biomarkers for skeletal muscle toxicity were AST, Fabp3, Myl3, (CKMB) and sTnI. Measurements of CK enzyme activity by a standard clinical assay were not useful for monitoring clofibrate-induced skeletal muscle toxicity in the rat at the doses used in this study.
authors.affiliation: Abbvie Deutschland GmbH & Co. KG, Preclinical Safety, D-67061 Ludwigshafen, Germany. Electronic address: karen.bodie@abbvie.com.
authors.forename: Karen
authors.initials: K
authors.lastname: Bodié
authors.affiliation: Abbvie Inc., Discovery, Abbott Park, IL 60064, USA.
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Buck
authors.affiliation: Abbvie Deutschland GmbH & Co. KG, Preclinical Safety, D-67061 Ludwigshafen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Pieh
authors.affiliation: Abbvie Inc., Discovery, Abbott Park, IL 60064, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Liguori
authors.affiliation: Abbvie Deutschland GmbH & Co. KG, Preclinical Safety, D-67061 Ludwigshafen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Popp
mesh_terms: D000410:Alanine Transaminase / Q000097:blood / Q000652:urine; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood / Q000652:urine; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002994:Clofibrate / Q000633:toxicity*; D003402:Creatine Kinase / Q000097:blood / Q000652:urine; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins / Q000097:blood / Q000652:urine; D020869:Gene Expression Profiling; D006321:Heart / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000633:toxicity*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D009211:Myoglobin / Q000097:blood; D018994:Myosin Light Chains / Q000097:blood / Q000652:urine; D010320:Parvalbumins / Q000097:blood / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D019209:Troponin C / Q000097:blood / Q000652:urine; D019210:Troponin I / Q000097:blood / Q000652:urine
chemical_list: D015415:Biomarkers; C509948:FABP3 protein, rat; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins; D000960:Hypolipidemic Agents; D009211:Myoglobin; D018994:Myosin Light Chains; D010320:Parvalbumins; D019209:Troponin C; D019210:Troponin I; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003402:Creatine Kinase; D002994:Clofibrate
keywords: Clofibrate; Gene expression; Rat; Skeletal muscle biomarker