Oxidative DNA Damage by N(4)-hydroxycytidine, a Metabolite of the SARS-CoV-2 Antiviral Molnupiravir

Molnupiravir is an antiviral agent recently used for treating coronavirus disease 2019 (COVID-19). Here, we demonstrate that N(4)-hydroxycytidine (NHC), a molnupiravir metabolite, treated with cytidine deaminase (CDA) induced Cu(II)-mediated oxidative DNA damage in isolated DNA. A colorimetric assay...

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Detalles Bibliográficos
Autores principales: Kobayashi, Hatasu, Mori, Yurie, Ahmed, Sharif, Hirao, Yuichiro, Kato, Shinya, Kawanishi, Shosuke, Murata, Mariko, Oikawa, Shinji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Brief Report
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10132762/
https://www.ncbi.nlm.nih.gov/pubmed/36461940
http://dx.doi.org/10.1093/infdis/jiac477
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author Kobayashi, Hatasu
Mori, Yurie
Ahmed, Sharif
Hirao, Yuichiro
Kato, Shinya
Kawanishi, Shosuke
Murata, Mariko
Oikawa, Shinji
author_facet Kobayashi, Hatasu
Mori, Yurie
Ahmed, Sharif
Hirao, Yuichiro
Kato, Shinya
Kawanishi, Shosuke
Murata, Mariko
Oikawa, Shinji
author_sort Kobayashi, Hatasu
collection PubMed
description Molnupiravir is an antiviral agent recently used for treating coronavirus disease 2019 (COVID-19). Here, we demonstrate that N(4)-hydroxycytidine (NHC), a molnupiravir metabolite, treated with cytidine deaminase (CDA) induced Cu(II)-mediated oxidative DNA damage in isolated DNA. A colorimetric assay revealed hydroxylamine generation from CDA-treated NHC. The site specificity of DNA damage also suggested involvement of hydroxylamine in the damage. Furthermore, Cu(I) and H(2)O(2) play an important role in the DNA damage. We propose oxidative DNA damage via CDA-mediated metabolism as a possible mutagenic mechanism of NHC, highlighting the need for careful risk assessment of molnupiravir use in therapies for viral diseases, including COVID-19.
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spelling pubmed-101327622023-04-27 Oxidative DNA Damage by N(4)-hydroxycytidine, a Metabolite of the SARS-CoV-2 Antiviral Molnupiravir Kobayashi, Hatasu Mori, Yurie Ahmed, Sharif Hirao, Yuichiro Kato, Shinya Kawanishi, Shosuke Murata, Mariko Oikawa, Shinji J Infect Dis Brief Report Molnupiravir is an antiviral agent recently used for treating coronavirus disease 2019 (COVID-19). Here, we demonstrate that N(4)-hydroxycytidine (NHC), a molnupiravir metabolite, treated with cytidine deaminase (CDA) induced Cu(II)-mediated oxidative DNA damage in isolated DNA. A colorimetric assay revealed hydroxylamine generation from CDA-treated NHC. The site specificity of DNA damage also suggested involvement of hydroxylamine in the damage. Furthermore, Cu(I) and H(2)O(2) play an important role in the DNA damage. We propose oxidative DNA damage via CDA-mediated metabolism as a possible mutagenic mechanism of NHC, highlighting the need for careful risk assessment of molnupiravir use in therapies for viral diseases, including COVID-19. Oxford University Press 2022-12-03 /pmc/articles/PMC10132762/ /pubmed/36461940 http://dx.doi.org/10.1093/infdis/jiac477 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Brief Report
Kobayashi, Hatasu
Mori, Yurie
Ahmed, Sharif
Hirao, Yuichiro
Kato, Shinya
Kawanishi, Shosuke
Murata, Mariko
Oikawa, Shinji
Oxidative DNA Damage by N(4)-hydroxycytidine, a Metabolite of the SARS-CoV-2 Antiviral Molnupiravir
title Oxidative DNA Damage by N(4)-hydroxycytidine, a Metabolite of the SARS-CoV-2 Antiviral Molnupiravir
title_full Oxidative DNA Damage by N(4)-hydroxycytidine, a Metabolite of the SARS-CoV-2 Antiviral Molnupiravir
title_fullStr Oxidative DNA Damage by N(4)-hydroxycytidine, a Metabolite of the SARS-CoV-2 Antiviral Molnupiravir
title_full_unstemmed Oxidative DNA Damage by N(4)-hydroxycytidine, a Metabolite of the SARS-CoV-2 Antiviral Molnupiravir
title_short Oxidative DNA Damage by N(4)-hydroxycytidine, a Metabolite of the SARS-CoV-2 Antiviral Molnupiravir
title_sort oxidative dna damage by n(4)-hydroxycytidine, a metabolite of the sars-cov-2 antiviral molnupiravir
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10132762/
https://www.ncbi.nlm.nih.gov/pubmed/36461940
http://dx.doi.org/10.1093/infdis/jiac477
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