Oxidative DNA Damage by N4-hydroxycytidine, a Metabolite of the SARS-CoV-2 Antiviral Molnupiravir.

Abstract

Molnupiravir is an antiviral agent recently used for treating coronavirus disease 2019 (COVID-19). Here, we demonstrate that N4-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 H2O2 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.

• Authors: Hatasu Kobayashi, Yurie Mori, Sharif Ahmed, Yuichiro Hirao, Shinya Kato, Shosuke Kawanishi, Mariko Murata, Shinji Oikawa
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 227 Issue 9 Pg. 1068-1072 (04 26 2023) ISSN: 1537-6613 [Electronic] United States
• PMID: 36461940 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Chemical References

• Antiviral Agents
• molnupiravir
• N(4)-hydroxycytidine
• Hydrogen Peroxide
• Hydroxylamines

Topics

• Humans
• Antiviral Agents (pharmacology, therapeutic use)
• SARS-CoV-2
• Hydrogen Peroxide
• COVID-19
• Hydroxylamines (pharmacology)
• Oxidative Stress
• DNA Damage