Myricetin causes site-specific DNA damage via reactive oxygen species generation by redox interactions with copper ions

Yuichiro Hirao; Hatasu Kobayashi; Yurie Mori; Shinya Kato; Shosuke Kawanishi; Mariko Murata; Shinji Oikawa

doi:10.1016/j.mrgentox.2023.503694

Myricetin causes site-specific DNA damage via reactive oxygen species generation by redox interactions with copper ions

Mutat Res Genet Toxicol Environ Mutagen. 2023 Oct:891:503694. doi: 10.1016/j.mrgentox.2023.503694. Epub 2023 Sep 18.

Authors

Yuichiro Hirao¹, Hatasu Kobayashi², Yurie Mori², Shinya Kato³, Shosuke Kawanishi⁴, Mariko Murata², Shinji Oikawa⁵

Affiliations

¹ Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan; Department of Home Care Nursing, Mie Prefectural College of Nursing, Tsu, Mie, Japan.
² Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
³ Radioisotope Experimental Facility, Advanced Science Research Promotion Center, Mie University, Tsu, Mie, Japan.
⁴ Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, Japan.
⁵ Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan. Electronic address: s-oikawa@med.mie-u.ac.jp.

PMID: 37770136
DOI: 10.1016/j.mrgentox.2023.503694

Abstract

Myricetin (MYR), found in tea and berries, may have preventive effects on diseases, including Alzheimer's disease and cancer. However, MYR is also a mutagen, inducing DNA damage in the presence of metal ions. We have studied the molecular mechanisms of DNA damage by MYR in the presence of Cu(II) (MYR+Cu). Using ³²P-5'-end-labeled DNA fragments, we analyzed site-specific DNA damage caused by MYR+Cu. MYR+Cu caused concentration-dependent DNA strand breaks and base alterations, leading to cleavage of DNA at thymine, cytosine, and guanine nucleotides. Formation of the oxidative DNA damage indicator, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), in calf thymus DNA was increased by MYR+Cu. The production of 8-oxodG in MYR-treated HL-60 cells was significantly higher than in HP100 cells, which are more resistant to H₂O₂ than are HL-60 cells. Reactive oxygen species (ROS) scavengers were used to elucidate the mechanism of DNA damage. DNA damage was not inhibited by typical free hydroxyl radical (^•OH) scavengers such as ethanol, mannitol, or sodium formate. However, methional, catalase, and bathocuproine inhibited DNA damage induced by MYR+Cu. These results suggest that H₂O₂, Cu(I), and ROS other than ^•OH are involved in MYR+Cu-induced DNA damage. We conclude that the Cu(I)/Cu(II) redox cycle and concomitant H₂O₂ production via autoxidation of MYR generate a complex of H₂O₂ and Cu(I), probably Cu(I)-hydroperoxide, which induces oxidative DNA damage.

Keywords: 8-oxo-7,8-dihydro-2′-deoxyguanosine; Mutagen; Pharmacological activity; Phenolic compound; Pro-oxidant.