title: Antifungal miconazole induces cardiotoxicity via inhibition of APE/Ref-1-related pathway in rat neonatal cardiomyocytes.
abstract: 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 (O(2)(-)) 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 O(2)(-) 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.
authors.affiliation: Department of Medical Science, Institute of Functional Genomics, School of Medicine, Konkuk University, Choongju 380-701, Korea.
authors.forename: Kyung-Jong
authors.initials: KJ
authors.lastname: Won
authors.forename: Hai Yue
authors.initials: HY
authors.lastname: Lin
authors.forename: Soohyun
authors.initials: S
authors.lastname: Jung
authors.forename: Soo Min
authors.initials: SM
authors.lastname: Cho
authors.forename: Ho-Chul
authors.initials: HC
authors.lastname: Shin
authors.forename: Young Min
authors.initials: YM
authors.lastname: Bae
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Lee
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Byeong Hwa
authors.initials: BH
authors.lastname: Jeon
authors.forename: Bokyung
authors.initials: B
authors.lastname: Kim
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000935:Antifungal Agents / Q000633:toxicity*; D017209:Apoptosis; D002478:Cells, Cultured; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006321:Heart / Q000187:drug effects*; D008825:Miconazole / Q000633:toxicity*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D013481:Superoxides; D008825:Miconazole; C470319:Apex1 protein, rat; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase