{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T19:42:46Z","timestamp":1786995766098,"version":"build-2736575974"},"reference-count":15,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T00:00:00Z","timestamp":1670025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["19H03885"],"award-info":[{"award-number":["19H03885"]}]},{"name":"JSPS KAKENHI","award":["18K19673"],"award-info":[{"award-number":["18K19673"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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.<\/jats:p>","DOI":"10.1093\/infdis\/jiac477","type":"journal-article","created":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T15:13:01Z","timestamp":1670080381000},"page":"1068-1072","source":"Crossref","is-referenced-by-count":18,"title":["Oxidative DNA Damage by <i>N<\/i>4-hydroxycytidine, a Metabolite of the SARS-CoV-2 Antiviral Molnupiravir"],"prefix":"10.1093","volume":"227","author":[{"given":"Hatasu","family":"Kobayashi","sequence":"first","affiliation":[{"name":"Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine , Tsu , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yurie","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine , Tsu , Japan"},{"name":"Faculty of Pharmacy, Gifu University of Medical Science , Kani , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharif","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine , Tsu , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichiro","family":"Hirao","sequence":"additional","affiliation":[{"name":"Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine , Tsu , Japan"},{"name":"Mie Prefectural College of Nursing , Tsu , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinya","family":"Kato","sequence":"additional","affiliation":[{"name":"Radioisotope Experimental Facility, Advanced Science Research Promotion Center, Mie University , Tsu , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shosuke","family":"Kawanishi","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Science, Suzuka University of Medical Science , Suzuka , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariko","family":"Murata","sequence":"additional","affiliation":[{"name":"Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine , Tsu , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Oikawa","sequence":"additional","affiliation":[{"name":"Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine , Tsu , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,12,3]]},"reference":[{"key":"2023042618003716200_jiac477-B1","doi-asserted-by":"crossref","first-page":"855496","DOI":"10.3389\/fimmu.2022.855496","article-title":"Molnupiravir and its antiviral activity against COVID-19","volume":"13","author":"Tian","year":"2022","journal-title":"Front Immunol"},{"key":"2023042618003716200_jiac477-B2","doi-asserted-by":"crossref","first-page":"o926","DOI":"10.1136\/bmj.o926","article-title":"Covid-19: what is the evidence for the antiviral molnupiravir?","volume":"377","author":"Extance","year":"2022","journal-title":"BMJ"},{"key":"2023042618003716200_jiac477-B3","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1093\/infdis\/jiab247","article-title":"\u03b2-D-N4-hydroxycytidine inhibits SARS-CoV-2 through lethal mutagenesis but is also mutagenic to mammalian cells","volume":"224","author":"Zhou","year":"2021","journal-title":"J Infect Dis"},{"key":"2023042618003716200_jiac477-B4","doi-asserted-by":"crossref","first-page":"n2663","DOI":"10.1136\/bmj.n2663","article-title":"Buyer beware: molnupiravir may damage DNA","volume":"375","author":"van Schalkwyk","year":"2021","journal-title":"BMJ"},{"key":"2023042618003716200_jiac477-B5","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.toxlet.2022.04.002","article-title":"Genotoxicity assessment of potentially mutagenic nucleoside analogues using ToxTracker\u00ae","volume":"362","author":"Brandsma","year":"2022","journal-title":"Toxicol Lett"},{"key":"2023042618003716200_jiac477-B6","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.cbi.2004.06.005","article-title":"Mechanism of metal-mediated DNA damage induced by a metabolite of carcinogenic acetamide","volume":"149","author":"Sakano","year":"2004","journal-title":"Chem Biol Interact"},{"key":"2023042618003716200_jiac477-B7","doi-asserted-by":"crossref","first-page":"503420","DOI":"10.1016\/j.mrgentox.2021.503420","article-title":"Mechanism of reactive oxygen species generation and oxidative DNA damage induced by acrylohydroxamic acid, a putative metabolite of acrylamide","volume":"873","author":"Mori","year":"2022","journal-title":"Mutat Res Genet Toxicol Environ Mutagen"},{"key":"2023042618003716200_jiac477-B8","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.mrfmmm.2012.03.010","article-title":"The relationship of copper to DNA damage and damage prevention in humans","volume":"733","author":"Linder","year":"2012","journal-title":"Mutat Res"},{"key":"2023042618003716200_jiac477-B9","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1093\/carcin\/7.11.1849","article-title":"Formation of 8-hydroxyguanine moiety in cellular DNA by agents producing oxygen radicals and evidence for its repair","volume":"7","author":"Kasai","year":"1986","journal-title":"Carcinogenesis"},{"key":"2023042618003716200_jiac477-B10","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/0039-9140(84)80237-4","article-title":"A sensitive spectrophotometric method for the determination of hydroxylamine by use of p-nitroaniline and N-(1-naphthyl)-ethylenediamine","volume":"31","author":"Verma","year":"1984","journal-title":"Talanta"},{"key":"2023042618003716200_jiac477-B11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s41021-022-00245-2","article-title":"Copper-mediated DNA damage caused by purpurin, a natural anthraquinone","volume":"44","author":"Kobayashi","year":"2022","journal-title":"Genes Environ"},{"key":"2023042618003716200_jiac477-B12","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1517\/17425255.2015.985648","article-title":"Role of cytidine deaminase in toxicity and efficacy of nucleosidic analogs","volume":"11","author":"Serdjebi","year":"2015","journal-title":"Expert Opin Drug Metab Toxicol"},{"key":"2023042618003716200_jiac477-B13","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1038\/s41594-021-00651-0","article-title":"Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis","volume":"28","author":"Kabinger","year":"2021","journal-title":"Nat Struct Mol Biol"},{"key":"2023042618003716200_jiac477-B14","doi-asserted-by":"crossref","first-page":"100770","DOI":"10.1016\/j.jbc.2021.100770","article-title":"Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template","volume":"297","author":"Gordon","year":"2021","journal-title":"J Biol Chem"},{"key":"2023042618003716200_jiac477-B15","doi-asserted-by":"crossref","first-page":"e02428-20","DOI":"10.1128\/AAC.02428-20","article-title":"Human safety, tolerability, and pharmacokinetics of molnupiravir, a novel broad-spectrum oral antiviral agent with activity against SARS-CoV-2","volume":"65","author":"Painter","year":"2021","journal-title":"Antimicrob Agents Chemother"}],"container-title":["The Journal of Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiac477\/48349323\/jiac477.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/227\/9\/1068\/50100897\/jiac477.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/227\/9\/1068\/50100897\/jiac477.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T18:02:48Z","timestamp":1682532168000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/article\/227\/9\/1068\/6869525"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,3]]},"references-count":15,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,12,3]]},"published-print":{"date-parts":[[2023,4,26]]}},"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiac477","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"value":"0022-1899","type":"print"},{"value":"1537-6613","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,5,1]]},"published":{"date-parts":[[2022,12,3]]}}}