Assessment of Preclinical Liver and Skeletal Muscle Biomarkers Following Clofibrate Administration in Wistar Rats.
Clofibrate is a known rodent hepatotoxicant classically associated with hepatocellular hypertrophy and increased serum activities of cellular alanine aminotransferase/aspartate aminotransferase (ALT/AST) in the absence of microscopic hepatocellular degeneration. At toxic dose, clofibrate induces liver and skeletal muscle injury. The objective of this study was to assess novel liver and skeletal muscle biomarkers following clofibrate administration in Wistar rats at different dose levels for 7 days. In addition to classical biomarkers, liver injury was assessed by cytokeratin 18 (CK18) cleaved form, high-mobility group box 1, arginase 1 (ARG1), microRNA 122 (miR-122), and glutamate dehydrogenase. Skeletal muscle injury was evaluated with fatty acid binding protein 3 (Fabp3) and myosin light chain 3 (Myl3). Clofibrate-induced hepatocellular hypertrophy and skeletal muscle degeneration (type I rich muscles) were noted microscopically. CK, Fabp3, and Myl3 elevations correlated to myofiber degeneration. Fabp3 and Myl3 outperformed CK for detection of myofiber degeneration of minimal severity. miR-122 and ARG1 results were significantly correlated and indicated the absence of liver toxicity at low doses of clofibrate, despite increased ALT/AST activities. Moreover, combining classical and novel biomarkers (Fabp3, Myl3, ARG1, and miR-122) can be considered a valuable strategy for differentiating increased transaminases due to liver toxicity from skeletal muscle toxicity.
['Maliver|Pierre|P|', 'Festag|Matthias|M|', 'Bennecke|Moritz|M|', 'Christen|Francois|F|', 'Bánfai|Balázs|B|', 'Lenz|Barbara|B|', 'Winter|Michael|M|']
D000410:Alanine Transaminase D000469:Alkaline Phosphatase D000818:Animals D000924:Anticholesteremic Agents D001119:Arginase D001219:Aspartate Aminotransferases D001663:Bilirubin D015415:Biomarkers D056486:Chemical and Drug Induced Liver Injury D002784:Cholesterol D002802:Cholinesterases D002994:Clofibrate D003404:Creatinine D004305:Dose-Response Relationship, Drug D000074026:Fatty Acid Binding Protein 3 D005969:Glutamate Dehydrogenase D053538:Keratin-18 D008099:Liver D008297:Male D035683:MicroRNAs D018482:Muscle, Skeletal D018994:Myosin Light Chains D051381:Rats D017208:Rats, Wistar D014280:Triglycerides
biomarkers clofibrate Wistar rats skeletal muscle degeneration ALT/AST activity hepatoxicity