Role of oxidative stress in the chemical structure-related genotoxicity of nitrofurantoin in <i>Nrf2</i>-deficient <i>gpt</i> delta mice

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Author(s)

    • TSUCHIYA Takuma
    • Division of Pathology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-9501, Japan|Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1193, Japan
    • KIJIMA Aki
    • Division of Pathology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-9501, Japan
    • ISHII Yuji
    • Division of Pathology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-9501, Japan
    • TAKASU Shinji
    • Division of Pathology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-9501, Japan
    • YOKOO Yuh
    • Division of Pathology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-9501, Japan
    • NISHIKAWA Akiyoshi
    • Division of Pathology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-9501, Japan
    • YANAI Tokuma
    • Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1193, Japan
    • UMEMURA Takashi
    • Division of Pathology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-9501, Japan|Department of Animal Nursing, Yamazaki Gakuen University, 4-7-2 Minamiosawa, Hachioji, Tokyo 192-0364, Japan

Abstract

<p>Despite its antimicrobial activity, nitrofurantoin (NFT) is a renal carcinogen in rats. Oxidative stress induced by reduction of the nitro group of NFT may contribute to its genotoxicity. This is supported by our recent results indicating that the structure of the nitrofuran plays a key role in NFT-induced genotoxicity, and oxidative DNA damage is involved in renal carcinogenesis. Nuclear factor erythroid 2-related factor 2 (NRF2) regulates cellular responses to oxidative stress. To clarify the role of oxidative stress in the chemical structure-related genotoxic mechanism of NFT, we performed reporter gene mutation assays for NFT and 5-nitro-2-furaldehyde (NFA) using <i>Nrf2</i>-proficient and <i>Nrf2</i>-deficient <i>gpt</i> delta mice. NFT administration for 13 weeks resulted in a significant increase in 8-hydroxydeoxyguanosine (8-OHdG; a marker of oxidative stress) and <i>gpt</i> mutant frequency only in the kidneys of <i>Nrf2</i><sup>-/-</sup> mice. The mutation spectrum, characterized by increased substitutions at guanine bases, suggested that oxidative stress is involved in NFT-induced genotoxicity. However, NFA did not increase the mutation frequency in the kidneys, despite the increased 8-OHdG in NFA-treated <i>Nrf2</i><sup>-/-</sup> mice. Thus, it is unlikely that oxidative stress is involved in the genotoxic mechanism of NFA. These results imply that nitro reduction plays a key role in the genotoxicity of NFT, but the lack of a role of oxidative stress in the genotoxicity of NFA indicates a potential role of side chain interactions in oxidative stress caused by nitro reduction. These findings provide a basis for the development of safe nitrofurans.</p>

Journal

  • Journal of Toxicologic Pathology

    Journal of Toxicologic Pathology, 2018

    JAPANESE SOCIETY OF TOXICOLOGIC PATHOLOGY

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