Zinc diethyldithiocarbamate as an inducer of metallothionein in cultured vascular endothelial cells

  • Fujie Tomoya
    Department of Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science
  • Segawa Yukino
    Department of Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science
  • Uehara Akane
    Department of Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science
  • Nakamura Takehiro
    Department of Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science
  • Kimura Tomoki
    Department of Life Science, Faculty of Science and Engineering, Setsunan University
  • Yoshida Eiko
    Department of Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science
  • Yamamoto Chika
    Department of Environmental Health, Faculty of Pharmaceutical Sciences, Toho University
  • Uchiyama Masanobu
    Graduate School of Pharmaceutical Sciences, University of Tokyo
  • Naka Hiroshi
    Graduate School of Science and Research Center for Materials Science, Nagoya University
  • Kaji Toshiyuki
    Department of Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science

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Vascular endothelial cells are in direct contact with blood. Inorganic zinc is thought to be incapable of inducing metallothionein, which protects cells from heavy metal toxicity and oxidative stress, in vascular endothelial cells. Here, we aimed to further characterize the induction of metallothionein in vascular endothelial cells. Our results confirmed that inorganic zinc could not induce metallothionein in vascular endothelial cells. Moreover, ZnSO4 could not activate both the metal response element (MRE) transcription factor 1 (MTF-1)/MRE and Nrf2/antioxidant response element (ARE) pathways and was incapable of inducing metallothionein. In addition, bis(L-cysteinato)zincate(II), a zinc complex that activates the MTF-1/MRE pathway, increased MRE promoter activity but failed to induce metallothionein, suggesting that vascular endothelial metallothionein was not induced only by activation of the MTF-1/MRE pathway. Further analysis of a library of zinc complexes showed that zinc(II) bis(diethyldithiocarbamate) activated the MTF-1/MRE pathway but not the Nrf2/ARE pathway, increased MT-1A, MT-1E, and MT-2A mRNA levels, and induced metallothionein proteins. These data indicated that zinc complexes may be excellent tools to analyze metallothionein induction in vascular endothelial cells.

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