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Metal-mediated oxidative DNA damage induced by methylene blue

Yusuke Hiraku1, Hiroyuki Goto1, Masaki Kohno1

  • 1Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.

Biochimica Et Biophysica Acta
|May 6, 2014
PubMed
Abstract

Insights

Methylene blue (MB) causes DNA damage through a metal-mediated mechanism involving NADH and hydrogen peroxide. This explains how MB may lead to cancer, informing its clinical safety.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Toxicology

Background:

  • Methylene blue (MB) is clinically utilized for chromoendoscopy and methemoglobinemia treatment.
  • MB has been shown to induce tumors in experimental animals, suggesting light-independent carcinogenic mechanisms.
  • Understanding MB's DNA damaging potential is crucial for assessing its clinical safety.

Purpose of the Study:

  • To elucidate the mechanism of Methylene blue-induced DNA damage.
  • To investigate the role of redox reactions and metal ions in MB's genotoxicity.
  • To provide insights into MB-mediated carcinogenesis for clinical safety assurance.

Main Methods:

  • Utilized (32)P-5'-end-labeled DNA fragments of human tumor-relevant genes to assess DNA damage.
  • Employed UV-visible spectrometry to investigate the redox reactions of Methylene blue.
  • Assessed the role of reactive oxygen species and metal ions in DNA damage induction.

Main Results:

  • Methylene blue induced DNA damage at the 5'-ACG-3' sequence in the presence of NADH and Cu(II), inhibited by catalase and a Cu(I) chelator.
  • DNA damage occurred at all nucleotide positions with NADH and Fe(III)-EDTA, inhibited by OH scavengers and catalase.
  • MB significantly increased 8-oxo-7,8-dihydro-2'-deoxyguanosine formation, indicating oxidative DNA lesions, in the presence of NADH and metal ions.
  • UV-visible spectrometry showed NADH-dependent reduction of MB, with metal ions influencing reoxidation and spectral changes.

Conclusions:

  • Methylene blue undergoes NADH-dependent reduction and metal ion-mediated reoxidation.
  • Reduced metal ions (Cu(I), Fe(II)) interact with H2O2 to generate reactive species (Cu(I)OOH, OH) that cause DNA damage.
  • Metal-mediated DNA damage is a key contributor to Methylene blue-induced carcinogenesis, informing its clinical safety.
Keywords:
CarcinogenesisDNA damageMetal ionMethylene blueNADHReactive oxygen species

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