New Study Reveals How a Metabolite of the COVID-19 Drug Molnupiravir Causes DNA Damage
Nikhil Prasad Fact checked by:Thailand Medical News Team Mar 08, 2025 1 month, 5 days, 2 hours, 9 minutes ago
Medical News: Researchers Investigate the Potential Risks of Molnupiravir Metabolite
A new scientific study has uncovered concerning evidence about a metabolite of the COVID-19 antiviral drug molnupiravir, suggesting that it may induce oxidative stress and cause damage to DNA. Researchers from Mie University Graduate School of Medicine and Suzuka University of Medical Science in Japan have conducted extensive laboratory experiments to understand how this metabolite, known as N4-hydroxycytidine (NHC), interacts with human cells.
New Study Reveals How a Metabolite of the COVID-19 Drug Molnupiravir Causes DNA Damage
Molnupiravir was developed as an antiviral treatment for COVID-19, working by introducing mutations into the RNA of the SARS-CoV-2 virus to prevent its replication. However, questions have been raised about whether this drug might also have unintended effects on human cells. This
Medical News report delves into the details of the latest study, which explores the role of NHC in potentially triggering cytotoxic effects and DNA damage through the generation of reactive oxygen species (ROS).
Understanding the Study Findings
To assess the impact of NHC on human cells, researchers conducted experiments using HL-60 leukemia cells and their hydrogen peroxide-resistant variant, HP100 cells. The results showed that HL-60 cells treated with NHC exhibited significantly lower survival rates, indicating that NHC might have toxic effects. Interestingly, the HP100 cells, which are more resistant to oxidative stress, did not show the same level of cell death, suggesting that oxidative stress plays a major role in the observed cytotoxicity.
Further analysis using liquid chromatography-mass spectrometry (LC-MS) revealed that NHC is metabolized into uridine and hydroxylamine when exposed to the enzyme cytidine deaminase (CDA). The researchers hypothesized that hydroxylamine could trigger the production of ROS, leading to oxidative damage in human DNA.
How NHC Causes DNA Damage
The study focused on examining the specific mechanisms by which NHC-induced oxidative stress affects DNA. Researchers found that CDA-treated NHC, when combined with copper ions, led to significant DNA damage. This damage was further intensified in the presence of NADH, a molecule involved in cellular energy production, indicating that the process might involve redox cycling.
Additional experiments were conducted using high-performance liquid chromatography (HPLC) to measure levels of 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG), a marker of oxidative DNA damage. The results confirmed that CDA-treated NHC caused an increase in 8-oxodG formation, with higher levels observed under normal oxygen conditions compared to hypoxic (low-oxygen) conditions. This finding suggests that the oxidative stress induced by NHC depends on the presence of oxygen.
Protective Measures and Implications
To better understand how ROS generation leads to DNA damage, the researchers tested the effects o
f various antioxidants and metal chelators. They found that catalase, an enzyme that breaks down hydrogen peroxide, significantly reduced DNA damage. Similarly, bathocuproine, a copper(I)-specific chelator, inhibited DNA damage, indicating that copper ions play a crucial role in this process. However, other common ROS scavengers, such as ethanol and mannitol, were ineffective in preventing damage.
The findings of this study suggest that the oxidative stress induced by NHC is closely linked to its metabolism and interaction with metal ions. Since oxidative stress and DNA damage are associated with genetic mutations and cancer development, these results raise important questions about the long-term safety of molnupiravir use.
Conclusion
While molnupiravir has been widely used as a COVID-19 treatment, this study highlights potential risks associated with its metabolite, NHC. The research suggests that oxidative stress and DNA damage could be a concern, particularly in individuals who take the drug for extended periods. Given these findings, further research is needed to assess whether the observed effects translate into actual health risks in humans.
Health authorities and researchers should consider these results when evaluating the safety of molnupiravir, particularly in relation to its potential long-term effects on human DNA. Additional studies should focus on confirming these findings in different cell types and assessing whether similar effects occur in animal models or clinical settings. Until more data is available, healthcare providers should weigh the benefits of molnupiravir treatment against its possible risks, especially for patients who may be more vulnerable to oxidative stress and DNA damage.
The study findings were published in the peer-reviewed journal: Free Radical Research.
https://www.tandfonline.com/doi/full/10.1080/10715762.2025.2469738#abstract
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