Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 227, Issue 9, Pages 1068-1072Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiac477
Keywords
8-oxo-7,8-dihydro-2'-deoxyguanosine; DNA damage; cytidine deaminase; hydroxylamine; molnupiravir; N (4)-hydroxycytidine; reactive oxygen species
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It is demonstrated that N-4-hydroxycytidine (NHC), a metabolite of molnupiravir, can induce Cu(II)-mediated oxidative DNA damage in isolated DNA when treated with cytidine deaminase (CDA).
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 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.
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