Oral Azathioprine Leads to Higher Incorporation of 6-Thioguanine in DNA of Skin than Liver: The Protective Role of the Keap1/Nrf2/ARE Pathway

DOI HANDLE PDF PubMed 被引用文献1件 参考文献48件 オープンアクセス
  • Sukirti Kalra
    Authors' Affiliations: 1Biomedical Research Institute, University of Dundee, Dundee, Scotland, United Kingdom; 2Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; and Departments of 3Medicine and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • Ying Zhang
    Authors' Affiliations: 1Biomedical Research Institute, University of Dundee, Dundee, Scotland, United Kingdom; 2Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; and Departments of 3Medicine and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • Elena V. Knatko
    Authors' Affiliations: 1Biomedical Research Institute, University of Dundee, Dundee, Scotland, United Kingdom; 2Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; and Departments of 3Medicine and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • Stewart Finlayson
    Authors' Affiliations: 1Biomedical Research Institute, University of Dundee, Dundee, Scotland, United Kingdom; 2Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; and Departments of 3Medicine and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • Masayuki Yamamoto
    Authors' Affiliations: 1Biomedical Research Institute, University of Dundee, Dundee, Scotland, United Kingdom; 2Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; and Departments of 3Medicine and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • Albena T. Dinkova-Kostova
    Authors' Affiliations: 1Biomedical Research Institute, University of Dundee, Dundee, Scotland, United Kingdom; 2Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; and Departments of 3Medicine and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland

書誌事項

公開日
2011-10-01
資源種別
journal article
DOI
  • 10.1158/1940-6207.capr-11-0137
公開者
American Association for Cancer Research (AACR)

この論文をさがす

説明

<jats:title>Abstract</jats:title><jats:p>Azathioprine is a widely used anti-inflammatory, immunosuppressive, and anticancer agent. However, chronic treatment with this drug is associated with a profoundly increased risk (in certain cases by more than 100-fold) of developing squamous cell carcinoma of the skin. Incorporation of its ultimate metabolite, thio-dGTP, in DNA results in partial substitution of guanine with 6-thioguanine which, combined with exposure to UVA radiation, creates a source of synergistic mutagenic damage to DNA. We now report that oral treatment with azathioprine leads to a much greater incorporation of 6-thioguanine in DNA of mouse skin than liver. These higher levels of 6-thioguanine, together with the fact that the skin is constantly exposed to UV radiation from the sun, may be responsible, at least in part, for the increased susceptibility of this organ to tumor development. Genetic upregulation of the Keap1/Nrf2/ARE pathway, a major cellular regulator of the expression of a network of cytoprotective genes, reduces the incorporation of 6-thioguanine in DNA of both skin and liver following treatment with azathioprine. Similarly, pharmacologic activation of the pathway by the potent inducer sulforaphane results in lower 6-thioguanine incorporation in DNA and protects 6-thioguanine–treated cells against oxidative stress following exposure to UVA radiation. Protection is accompanied by increased levels of glutathione and induction of multidrug resistance-associated protein 4, an organic anion efflux pump that also exports nucleoside monophosphate analogues. Our findings suggest that activation of the Keap1/Nrf2/ARE pathway could reduce the risk for skin cancer in patients receiving long-term azathioprine therapy. Cancer Prev Res; 4(10); 1665–74. ©2011 AACR.</jats:p>

収録刊行物

  • Cancer Prevention Research

    Cancer Prevention Research 4 (10), 1665-1674, 2011-10-01

    American Association for Cancer Research (AACR)

被引用文献 (1)*注記

もっと見る

参考文献 (48)*注記

もっと見る

関連プロジェクト

もっと見る

キーワード

詳細情報 詳細情報について

問題の指摘

ページトップへ