Journal Article

Antifungal Miconazole Induces Cardiotoxicity Via Inhibition of APE/Ref-1-Related Pathway in Rat Neonatal Cardiomyocytes

Kyung-Jong Won, Hai Yue Lin, Soohyun Jung, Soo Min Cho, Ho-Chul Shin, Young Min Bae, Seung Hyun Lee, Hyun-Jung Kim, Byeong Hwa Jeon and Bokyung Kim

in Toxicological Sciences

Volume 126, issue 2, pages 298-305
Published in print April 2012 | ISSN: 1096-6080
Published online January 2012 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfr347
Antifungal Miconazole Induces Cardiotoxicity Via Inhibition of APE/Ref-1-Related Pathway in Rat Neonatal Cardiomyocytes

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Effects of miconazole, an azole antifungal, have not been fully determined in cardiomyocytes. We therefore identified the transcriptome in neonatal rat cardiomyocytes responding to miconazole using DNA microarray analysis and selected a gene and investigated its role in cardiomyocytes. Miconazole dose-dependently increased the levels of superoxide (O2) and apoptosis in cardiomyocytes; these increases were inhibited by treatment with antioxidants. The DNA microarray revealed that 4163 genes were upregulated and 4829 genes downregulated by more than threefold in miconazole-treated cardiomyocytes compared with the vehicle-treated control. Moreover, redox homeostasis–, oxidative stress–, and reactive oxygen species (ROS)–related categories of genes were strongly affected by miconazole treatment. Among genes overlapped in all these categories, apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1), a redox-related gene, was prominent and was diminished in the miconazole-treated group. Changes in the O2 production and apoptosis induction in response to miconazole were inhibited in cardiomyocytes transfected with adenoviral APE/Ref-1. Overexpression of APE/Ref-1 reversed the reduction in beating frequency induced by miconazole. Our results demonstrate that miconazole may induce rat cardiotoxicity via a ROS-mediated pathway, which is initiated by the inhibition of APE/Ref-1 expression. This possible new adverse event in cardiomyocyte function caused by miconazole may provide a basis for the development of novel antifungal agents.

Keywords: DNA microarray; APE/Ref-1; antifungal miconazole; cardiotoxicity

Journal Article.  4534 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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