Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology, University of Hawaii John A. Burns School of Medicine, Honolulu, HI 96813, USA.
Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology, University of Hawaii John A. Burns School of Medicine, Honolulu, HI 96813, USA.
Reprod Toxicol. 2023 Oct;121:108475. doi: 10.1016/j.reprotox.2023.108475. Epub 2023 Sep 23.
Molnupiravir is a nucleoside analog antiviral that is authorized for use in the treatment of COVID-19. For its therapeutic action, molnupiravir is converted after ingestion to the active metabolite N-hydroxycytidine, which is incorporated into the viral genome to cause lethal mutagenesis. Molnupiravir is not recommended for use during pregnancy, because preclinical animal studies suggest that it is hazardous to developing embryos. However, the mechanisms underlying the embryotoxicity of molnupiravir are currently unknown. To gain mechanistic insights into its embryotoxic action, the effects of molnupiravir and N-hydroxycytidine were examined on the in vitro development of mouse preimplantation embryos. Molnupiravir did not prevent blastocyst formation even at concentrations that were much higher than the therapeutic plasma levels. By contrast, N-hyroxycytidine exhibited potent toxicity, as it interfered with blastocyst formation and caused extensive cell death at concentrations below the therapeutic plasma levels. The adverse effects of N-hydroxycytidine were dependent on the timing of exposure, such that treatment after the 8-cell stage, but not before it, caused embryotoxicity. Transcriptomic analysis of N-hydroxycytidine-exposed embryos, together with the examination of eIF-2a protein phosphorylation level, suggested that N-hydroxycytidine induced the integrated stress response. The adverse effects of N-hydroxycytidine were significantly alleviated by the co-treatment with S-(4-nitrobenzyl)-6-thioinosine, suggesting that the embryotoxic potential of N-hydroxycytidine requires the activity of nucleoside transporters. These findings show that the active metabolite of molnupiravir impairs preimplantation development at clinically relevant concentrations, providing mechanistic foundation for further studies on the embryotoxic potential of molnupiravir and other related nucleoside antivirals.
莫努匹韦是一种核苷类似物抗病毒药物，被授权用于治疗 COVID-19。为了发挥治疗作用，莫努匹韦在摄入后转化为活性代谢物 N-羟基胞苷，该物质掺入病毒基因组中导致致命的诱变。由于临床前动物研究表明莫努匹韦对发育中的胚胎有危险，因此不建议在怀孕期间使用。然而，莫努匹韦胚胎毒性的机制目前尚不清楚。为了深入了解其胚胎毒性作用的机制，研究人员检查了莫努匹韦和 N-羟基胞苷对体外培养的小鼠着床前胚胎发育的影响。即使在远远高于治疗血浆水平的浓度下，莫努匹韦也不能阻止囊胚形成。相比之下，N-羟基胞苷表现出很强的毒性，因为它干扰囊胚形成，并在低于治疗血浆水平的浓度下引起广泛的细胞死亡。N-羟基胞苷的不良反应取决于暴露的时间，即只有在 8 细胞阶段之后而不是之前进行处理才会导致胚胎毒性。对 N-羟基胞苷暴露的胚胎进行转录组分析，并检查 eIF-2a 蛋白磷酸化水平，表明 N-羟基胞苷诱导了综合应激反应。用 S-(4-硝基苄基)-6-硫代肌苷共同处理可显著减轻 N-羟基胞苷的不良反应，表明 N-羟基胞苷的胚胎毒性需要核苷转运体的活性。这些发现表明，莫努匹韦的活性代谢物在临床相关浓度下损害着床前发育，为进一步研究莫努匹韦和其他相关核苷抗病毒药物的胚胎毒性潜力提供了机制基础。
