title: Biomarker panel of cardiac and skeletal muscle troponins, fatty acid binding protein 3 and myosin light chain 3 for the accurate diagnosis of cardiotoxicity and musculoskeletal toxicity in rats.
abstract: Cardiotoxicity and musculoskeletal toxicity can be life-threatening, and thus have strong impact on both the development and marketing of drugs. Because the conventional biomarkers such as aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine kinase (CK) have low detection power, there has been increasing interest in developing biomarkers with higher detection power. The current study examined the usefulness of several promising biomarkers, cardiac and skeletal muscle troponins (cTnI, cTnT and sTnI), fatty acid binding protein 3 (FABP3) and myosin light chain 3 (MYL3), and compared the obtained data to AST, LDH and CK in rat models treated with various myotoxic and non-myotoxic compounds (isoproterenol, metaproterenol, doxorubicin, mitoxantrone, allylamine, cyclosporine A, cyclophosphamide, aminoglutethimide, acetaminophen, methapyrilene, allylalcohol and α-naphthylisothiocyanate). These promising biomarkers were found to be superior to the conventional biomarkers, as they had a specific and abundant distribution within the heart and/or skeletal muscles; exhibited a positive correlation between the amplitude of increases and the degree of pathological alterations; had higher diagnostic accuracy for detecting pathological alterations; and had the additive effect of improving the diagnostic accuracy of conventional biomarkers. However, these promising biomarkers have several drawbacks including a rapid clearance, the fact that they are affected by renal dysfunction, and different reactivity to the mode of action of individual myotoxicants. In conclusion, the promising biomarkers cTnI, cTnT, FABP3, MYL3, and sTnI demonstrated sensitivity and specificity for cardiac and skeletal myotoxicity that was superior to those of conventional biomarkers, while we should pay attention to the drawbacks of these biomarkers when used in toxicity studies.
authors.affiliation: Drug Safety Evaluation, Drug Developmental Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan. yutaka.tonomura@shionogi.co.jp
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tonomura
authors.forename: Shuuichi
authors.initials: S
authors.lastname: Matsushima
authors.forename: Emi
authors.initials: E
authors.lastname: Kashiwagi
authors.forename: Kae
authors.initials: K
authors.lastname: Fujisawa
authors.forename: Shingo
authors.initials: S
authors.lastname: Takagi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Ryou
authors.initials: R
authors.lastname: Fukushima
authors.forename: Mikinori
authors.initials: M
authors.lastname: Torii
authors.forename: Mitsunobu
authors.initials: M
authors.lastname: Matsubara
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D006331:Heart Diseases / Q000175:diagnosis*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D009135:Muscular Diseases / Q000175:diagnosis*; D009206:Myocardium / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D014336:Troponin / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C509948:FABP3 protein, rat; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins; D018994:Myosin Light Chains; D014336:Troponin; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D003402:Creatine Kinase