Molnupiravir (MOV) is used to treat COVID-19. In cells, MOV is converted to the ribonucleoside analog N4-hydroxycytidine (NHC) and incorporated into the SARS-CoV-2 RNA genome during its replication, resulting in RNA mutations. The widespread accumulation of such mutations inhibits SARS-CoV-2 propagation. Although safety assessments by many regulatory agencies across the world have concluded that the genotoxic risks associated with the clinical use of MOV are low, concerns remain that it could induce DNA mutations in patients, particularly because numerous in vitro studies have shown that NHC is a DNA mutagen. In this study, we used HiFi sequencing, a technique that can detect ultralow-frequency substitution mutations in whole genomes, to evaluate the mutagenic effects of MOV in E. coli and of MOV and NHC in mouse lymphoma L5178Y cells and human lymphoblastoid TK6 cells. In all models, exposure to these compounds increased genome-wide mutation frequencies in a dose-dependent manner, and these increases were mainly composed of A:T → G:C transitions. The NHC exposure concentrations used for mammalian cells were comparable to those observed in the plasma of humans who received clinical doses of MOV.

中文翻译：

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通过 HiFi 测序评估 Molnupiravir 和 N4-hydroxycytidine 在细菌和哺乳动物细胞中的致突变作用

Molnupiravir (MOV) 用于治疗 COVID-19。在细胞中，MOV 被转化为核糖核苷类似物 N4-羟基胞苷 (NHC)，并在其复制过程中掺入 SARS-CoV-2 RNA 基因组，导致 RNA 突变。这种突变的广泛积累抑​​制了 SARS-CoV-2 的传播。尽管全球许多监管机构的安全评估得出结论认为，与临床使用 MOV 相关的遗传毒性风险较低，但人们仍然担心它可能会诱发患者的 DNA 突变，特别是因为大量体外研究表明 NHC 是一种 DNA诱变剂。在这项研究中，我们使用 HiFi 测序（一种可以检测整个基因组中的超低频替代突变的技术）来评估 MOV 在大肠杆菌中的致突变作用小鼠淋巴瘤 L5178Y 细胞和人淋巴母细胞 TK6 细胞中的 MOV 和 NHC。在所有模型中，暴露于这些化合物以剂量依赖的方式增加了全基因组突变频率，这些增加主要由 A:T → G:C 转换组成。用于哺乳动物细胞的 NHC 暴露浓度与在接受临床剂量的 MOV 的人类血浆中观察到的浓度相当。