Abstract: Free Radical Research
ISSN: (Print) (Online) Journal homepage: www.tandfonline.com/journals/ifra20
Reactive oxygen species-mediated cytotoxic and
DNA-damaging mechanism of N4-hydroxycytidine,
a metabolite of the COVID-19 therapeutic drug
molnupiravir
Yurie Mori, Rinya Yogo, Hatasu Kobayashi, Hirotaka Katsuzaki, Yuichiro
Hirao, Shinya Kato, Hirokazu Kotani, Shosuke Kawanishi, Mariko Murata &
Shinji Oikawa
To cite this article: Yurie Mori, Rinya Yogo, Hatasu Kobayashi, Hirotaka Katsuzaki, Yuichiro
Hirao, Shinya Kato, Hirokazu Kotani, Shosuke Kawanishi, Mariko Murata & Shinji Oikawa (20
4
Feb 2025): Reactive oxygen species-mediated cytotoxic and DNA-damaging mechanism of N hydroxycytidine, a metabolite of the COVID-19 therapeutic drug molnupiravir, Free Radical
Research, DOI: 10.1080/10715762.2025.2469738
To link to this article: https://doi.org/10.1080/10715762.2025.2469738
© 2025 The Author(s). Published by Informa
UK Limited, trading as Taylor & Francis
Group
Accepted author version posted online: 20
Feb 2025.
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Revised manuscript
Reactive oxygen species-mediated cytotoxic and DNA-damaging
mechanism of N4-hydroxycytidine, a metabolite of the COVID-19
ip
t
therapeutic drug molnupiravir
Yurie Mori1,#, Rinya Yogo1,2,#, Hatasu Kobayashi1, Hirotaka Katsuzaki3, Yuichiro
cr
Hirao1, Shinya Kato4, Hirokazu Kotani 2, Shosuke Kawanishi5, Mariko Murata1, Shinji
an
Yurie Mori and Rinya Yogo should be considered joint first authors.
M
#
us
Oikawa1*
1. Department of Environmental and Molecular Medicine, Mie University Graduate
ed
School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan
pt
2. Department of Forensic Medicine and Sciences, Mie University Graduate School of
ce
Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan
3. Department of Life Sciences, Graduate School of Bioresources, Mie University,
Ac
1577 Kurimamachiya, Tsu, Mie 514-8507, Japan
4. Radioisotope Experimental Facility, Advanced Science Research Promotion Center,
Mie University, Edobashi 2-174, Tsu, Mie 514-8507, Japan
5. Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3,
Minamitamagaki, Suzuka, Mie, 513-8670, Japan
1
* Corresponding author at: Department of Environmental and Molecular Medicine, Mie
University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan.
E-mail address: s-oikawa@med.mie-u.ac.jp (S. Oikawa)
Running title: ROS generation mechanism of hydroxycytidine
Keywords: molnupiravir, N4-hydroxycytidine, cytidine deaminase, reactive oxygen
Ac
ce
pt
ed
M
an
us
cr
ip
t
species, cytotoxicity, DNA damage
2
Abstract
Molnupiravir is a prodrug of the antiviral ribonucleoside analogue N4-hydroxycytidine
(NHC), for use in treatment of coronavirus disease 2019 (COVID-19). However, it is
generally considered that NHC-triphosphate is incorporated into the host genome to
ip
t
induce mutations. In our previous preliminary report, we proposed oxidative DNA
cr
damage by NHC via cytidine deaminase (CDA)-mediated ROS formation. In the
us
present study, we investigated cell viability using the HL-60 human leukemia cell line
an
and its H2O2-resistant clone, HP100 cells. The survival rate was significantly reduced
in HL-60 cells treated with NHC, but not in HP100 cells. LC-MS..
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