Role of oxidative stress in clofazimine-induced cardiac dysfunction in a zebrafish model

• Published in: Biomedicine & pharmacotherapy 2020-12, Vol.132, p.110749, Article 110749
• Main Authors: Ng, Phoebe C.I., Chan, Judy Y.W., Leung, Ross K.K., Li, J., Ren, Z., Chan, Anthony W.H., Xu, Y., Lee, S.S., Wang, R., Ji, Xia, Zheng, Jun, Chan, Denise P.C., Yew, W.W., Lee, Simon M.Y.
• Format: Article
• Language: English
• Subjects: Acetylcysteine - pharmacology; Animals; Antitubercular Agents - toxicity; Cardiac dysfunction; Clofazimine; Clofazimine - toxicity; Disease Models, Animal; Gene Expression Profiling; Heart Diseases - chemically induced; Heart Diseases - physiopathology; Heart Diseases - prevention & control; Oxidative stress; Oxidative Stress - drug effects; Zebrafish
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2020.110749

[Display omitted] •Exposure of 2 dpf zebrafish to 4 mg/L clofazimine for 2 days, adversely affected cardiac functions.•Clofazimine significantly up-regulated genes involved in antioxidant response.•Oxidative stress is a major mechanism underlying clofazimine-induced cardiac dysfunction. Clofazimine (CFZ), a riminophenazine, is now commonly used in the treatment of multidrug-resistant tuberculosis. However, its use may be potentially associated with cardiac dysfunction in some individuals. In this study, the zebrafish heart, by merit of its developmental and genetic characteristics being in homology with that of human, was chosen as an animal model for evaluation of such dysfunction. Morphological and physiological parameters were used to assess cardiac dysfunction. Transcriptome analysis was performed, followed by validation with real-time quantitative PCR, for delineation of the relevant genomics. Exposure of 2 dpf zebrafish to 4 mg/L CFZ for 2 days, adversely affected cardiac functions including significant decreases in HR, SV, CO, and FS, with observable pathophysiological developments of pericardial effusion and blood accumulation in the heart, in comparison with the control group. In addition, genes which respond to xenobiotic stimulus, related to oxygen transport, glutathione metabolism and extracellular matrix -receptor interactions, were significantly enriched among the differentially up-regulated genes. Antioxidant response element motif was enriched in the 5000 base pair upstream regions of the differentially expressed genes. Co-administration of N-acetylcysteine was shown to protect zebrafish against the development of CFZ-induced cardiac dysfunction. This study suggests an important role of oxidative stress as a major pathogenetic mechanism of riminophenazine-induced cardiac dysfunction.