Reactive oxygen species-mediated cytotoxic and DNA-damaging mechanism of N4-hydroxycytidine, a metabolite of the COVID-19 therapeutic drug molnupiravir
et al., Free Radical Research, doi:10.1080/10715762.2025.2469738, Feb 2025
In vitro study showing that molnupiravir may have cytotoxic and mutagenic effects in host cells via hydroxylamine production from N4-hydroxycytidine (NHC) by cytidine deaminase (CDA). Molnupiravir metabolite NHC may induce cytotoxicity and mutagenicity through CDA-mediated reactive oxygen species generation.
Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity1-15. Multiple analyses have identified variants potentially created by molnupiravir16-20. Studies show significantly increased risk of acute kidney injury21, cardiovascular toxocity22, and neurological symptoms21. Treatment may increase viral rebound23,24.
1.
Swanstrom et al., Lethal mutagenesis as an antiviral strategy, Science, doi:10.1126/science.abn0048.
2.
Hadj Hassine et al., Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity, Viruses, doi:10.3390/v14040841.
3.
Shum, C., An investigational study into the drug-associated mutational signature in SARS-CoV-2 viruses, The University of Hong Kong, PhD Thesis, hub.hku.hk/handle/10722/344396.
4.
Waters et al., Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir, Environmental and Molecular Mutagenesis, doi:10.1002/em.22471.
5.
Huntsman, M., An assessment of the reproductive toxicity of the anti-COVID-19 drug molnupiravir using stem cell-based embryo models, Master's Thesis, scholarspace.manoa.hawaii.edu/items/cd11342c-b4dc-44c0-8b44-ce6e3369c40b.
6.
Huntsman (B) et al., Detection of developmental toxicity of the anti-COVID-19 drug molnupiravir using gastruloid-based in vitro assays, Toxicological Sciences, doi:10.1093/toxsci/kfaf093.
7.
Zibat et al., N4-hydroxycytidine, the active compound of Molnupiravir, promotes SARS-CoV-2 mutagenesis and escape from a neutralizing nanobody, iScience, doi:10.1016/j.isci.2023.107786.
8.
Shiraki et al., Convenient screening of the reproductive toxicity of favipiravir and antiviral drugs in Caenorhabditis elegans, Heliyon, doi:10.1016/j.heliyon.2024.e35331.
9.
Gruber et al., Molnupiravir increases SARS‐CoV‐2 genome diversity and complexity: A case‐control cohort study, Journal of Medical Virology, doi:10.1002/jmv.29642.
10.
Marikawa et al., An active metabolite of the anti-COVID-19 drug molnupiravir impairs mouse preimplantation embryos at clinically relevant concentrations, Reproductive Toxicology, doi:10.1016/j.reprotox.2023.108475.
11.
Rahman, M., Elucidation of the DNA repair mechanisms involved in the repair of DNA damage caused by the Arabinosides and Anti-COVID-19 drugs, tokyo-metro-u.repo.nii.ac.jp/records/2000972.
12.
Zhou et al., β-D-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells, The Journal of Infectious Diseases, doi:10.1093/infdis/jiab247.
13.
Chamod et al., Molnupiravir Metabolite--N4-hydroxycytidine Causes Cytotoxicity and DNA Damage in Mammalian Cells in vitro: N4-hydroxycytidine Induced Cytotoxicity DNA Damage, Asian Medical Journal and Alternative Medicine, 23:3, asianmedjam.com/index.php/amjam/article/view/1448.
14.
Standing et al., Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients, Nature Communications, doi:10.1038/s41467-024-45641-0.
15.
Mori et al., Reactive oxygen species-mediated cytotoxic and DNA-damaging mechanism of N4-hydroxycytidine, a metabolite of the COVID-19 therapeutic drug molnupiravir, Free Radical Research, doi:10.1080/10715762.2025.2469738.
16.
Focosi et al., The fitness of molnupiravir-signed SARS-CoV-2 variants: imputation analysis based on prescription counts and GISAID analyses by country, Intervirology, doi:10.1159/000540282.
17.
Sanderson et al., A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes, Nature, doi:10.1038/s41586-023-06649-6.
18.
Fountain-Jones et al., Effect of molnupiravir on SARS-CoV-2 evolution in immunocompromised patients: a retrospective observational study, The Lancet Microbe, doi:10.1016/S2666-5247(23)00393-2.
19.
Kosakovsky Pond et al., Anti-COVID drug accelerates viral evolution, Nature, doi:10.1038/d41586-023-03248-3.
21.
Siby et al., Temporal Trends in Serious Adverse Events Associated with Oral Antivirals During the COVID-19 Pandemic: Insights from the FAERS Database (2020–2023), Open Forum Infectious Diseases, doi:10.1093/ofid/ofaf695.1825.
22.
Ozhan et al., Evaluation of the cardiopulmonary effects of repurposed COVID-19 therapeutics in healthy rats, Scientific Reports, doi:10.1038/s41598-025-31048-4.
Mori et al., 20 Feb 2025, Japan, peer-reviewed, 10 authors.
Contact: s-oikawa@med.mie-u.ac.jp.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
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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