Mass spectrometry‐based metabolomics reveals metabolism of molnupiravir may lead to metabolic disorders and hepatotoxicity

Chen et al., Biomedical Chromatography, doi:10.1002/bmc.5996

Aug 2024

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Analysis of molnupiravir induced liver injury. Molnupiravir treatment may disrupt metabolic homeostasis and cause liver injury by increasing levels of certain metabolites and activating inflammatory pathways.

Potential risks include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity1-10. Multiple analyses have identified variants potentially created by molnupiravir11-14.

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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. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

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

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

Chen et al., 23 Aug 2024, peer-reviewed, 8 authors.

This Paper Molnupiravir All

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MO treatment could cause mild liver injury. However, the underlying ' 'mechanism of MO‐induced liver injury and the metabolic pathway of MO in vivo are unclear. In ' 'this study, metabolomics analysis and molecular biology methods were used to explore these ' 'issues. Through metabolomics analysis, it was found that the homeostasis of pyrimidine, ' 'purine, lysophosphatidylcholine (LPC), and amino acids in mice was destroyed after MO ' 'treatment. A total of 80 changed metabolites were detected. Among these changed metabolites, ' '4‐ethylphenyl sulfate, dihydrouracil, and LPC 20:0 was related to the elevation of alkaline ' 'phosphatase (ALP), interleukin‐6 (IL6), and nuclear factor kappa‐B (NF‐κB). The levels of ' '4‐ethylphenyl sulfate, dihydrouracil, and LPC 20:0 in plasma were positively correlated with ' 'their levels in the liver, suggesting that these metabolites were associated with MO‐induced ' 'liver injury. MO treatment could increase NHC and cytidine levels, activate cytidine ' 'deaminase (CDA), and increase LPC levels. CDA and LPC could increase the mRNA expression ' 'level of toll‐like receptor (TLR). 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