Molnupiravir Active Metabolite–N4 hydroxycytidine causes Cytotoxicity to Mammalian Cells In Vitro

Pakotiprapha et al., ASPET 2024 Annual Meeting Abstract - Toxicology, doi:10.1124/jpet.212.937140

May 2024

Source PDF All Studies Meta AnalysisMeta

In Vitro study showing cytotoxicity of N4-hydroxycytidine (NHC), the active metabolite of molnupiravir, at concentrations relevant to therapeutic doses of molnupiravir in COR-L23 and HepG2 cancer cell lines, and compared with cytotoxicity in normal HaCaT cells. NHC showed cytotoxicity in all three lines, with HaCaT cells showing lower IC₅₀ values compared to both cancer cell lines at 3 and 5 days of treatment. The therapeutic dose of molnupiravir results in serum NHC concentrations close to the IC₅₀ values obtained in this study.

Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity1-14. Multiple analyses have identified variants potentially created by molnupiravir15-19.

Important missing comments or errors? Let us know.

1. Swanstrom et al., Lethal mutagenesis as an antiviral strategy, Science, doi:10.1126/science.abn0048.science.org, doi.org.

2. Hadj Hassine et al., Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity, Viruses, doi:10.3390/v14040841.mdpi.com, doi.org.

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.hku.hk.

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.wiley.com, doi.org.

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.hawaii.edu.

6. 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.sciencedirect.com, doi.org.

7. 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.sciencedirect.com, doi.org.

8. 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.wiley.com, doi.org.

9. 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.sciencedirect.com, doi.org.

10. 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.ac.jp.

11. 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.oup.com, doi.org.

12. 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.asianmedjam.com.

13. 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.nature.com, doi.org.

14. 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.tandfonline.com, doi.org.

15. 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.karger.com, doi.org.

16. Sanderson et al., A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes, Nature, doi:10.1038/s41586-023-06649-6.nature.com, doi.org.

17. 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.sciencedirect.com, doi.org.

18. Kosakovsky Pond et al., Anti-COVID drug accelerates viral evolution, Nature, doi:10.1038/d41586-023-03248-3.nature.com, doi.org.

19. twitter.com, twitter.com/LongDesertTrain/status/1597353291868155906.twitter.com/LongDesertTrain/status/1597353291868155906.

Pakotiprapha et al., 13 May 2024, peer-reviewed, 6 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

This Paper Molnupiravir All

DOI record: { "DOI": "10.1124/jpet.212.937140", "URL": "http://dx.doi.org/10.1124/jpet.212.937140", "alternative-id": [ "10.1124/jpet.212.937140" ], "author": [ { "affiliation": [], "family": "Pakotiprapha", "given": "Jessada", "sequence": "first" }, { "affiliation": [], "family": "Tangjittham", "given": "Krittin", "sequence": "additional" }, { "affiliation": [], "family": "Rimdusit", "given": "Tanaboon", "sequence": "additional" }, { "affiliation": [], "family": "Prajuabjinda", "given": "Onmanee", "sequence": "additional" }, { "affiliation": [], "family": "Poomirat", "given": "Saovapak", "sequence": "additional" }, { "affiliation": [], "family": "Sangsiri", "given": "Sutheera", "sequence": "additional" } ], "container-title": "ASPET 2024 Annual Meeting Abstract - Toxicology", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2024, 5, 13 ] ], "date-time": "2024-05-13T22:52:53Z", "timestamp": 1715640773000 }, "deposited": { "date-parts": [ [ 2024, 5, 13 ] ], "date-time": "2024-05-13T22:52:54Z", "timestamp": 1715640774000 }, "event": "ASPET 2024 Annual Meeting Abstract", "indexed": { "date-parts": [ [ 2024, 5, 14 ] ], "date-time": "2024-05-14T00:37:14Z", "timestamp": 1715647034068 }, "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2024, 5, 13 ] ] }, "link": [ { "URL": "https://syndication.highwire.org/content/doi/10.1124/jpet.212.937140", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "36", "original-title": [], "prefix": "10.1124", "published": { "date-parts": [ [ 2024, 5, 13 ] ] }, "published-online": { "date-parts": [ [ 2024, 5, 13 ] ] }, "published-print": { "date-parts": [ [ 2024, 6 ] ] }, "publisher": "American Society for Pharmacology and Experimental Therapeutics", "reference-count": 0, "references-count": 0, "relation": {}, "resource": { "primary": { "URL": "http://jpet.aspetjournals.org/lookup/doi/10.1124/jpet.212.937140" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "Molnupiravir Active Metabolite–N4 hydroxycytidine causes Cytotoxicity to Mammalian Cells<i>In Vitro</i>", "type": "proceedings-article" }

Download Image

Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.

Submit

Post

@CovidAnalysis

FAQ

Public domain CC0 1.0