Organomercurials (RHg⁺), especially methylmercury (MeHg⁺) and ethylmercury (EtHg⁺), are considered to be more neurotoxic than the inorganic counterpart (Hg²⁺). They cause massive DNA damage in cells, especially in neurons, where cellular glutathione (GSH) levels are significantly low. However, the mechanism by which RHg⁺ exerts massive DNA damage at cytotoxic concentrations in brain cells remains obscure. In this study, we investigated the effect of RHg⁺ on the structural and electronic properties of nucleosides and its effects on DNA damage. The direct interaction of RHg⁺ with the nucleoside significantly weakens N-glycosidic bonds, decreases the C–H bond energy of sugar moieties, and increases the electrophilicity of the C₈-center of purine bases. As a consequence, RHg⁺-conjugated DNA molecules are extremely labile and highly sensitive to any nucleophiles/radicals present in GSH-depleted cells and, thus, undergo enhanced oxidative and unusual alkylative DNA damage. We also report a functional model of organomercurial lyase, which showed excellent cytoprotective effect against RHg⁺-induced cytotoxicity; this reverses the activity of glutathione reductase inhibited by MeHgCl and ceases oxidative and alkylating DNA damage. This intriguing finding provides new mechanistic insight into the mode of action of organomercurials in GSH-depleted cells and their adverse effects on individuals with neurodegenerative disorders associated with oxidative stress.

中文翻译：

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揭示谷胱甘肽耗尽细胞中细胞毒性浓度下甲基汞对 DNA 损伤的作用：来自实验和计算研究的见解

有机汞 (RHg ⁺ )，特别是甲基汞 (MeHg ⁺ ) 和乙基汞 (EtHg ^{+ )，被认为比无机对应物 (Hg 2+} )更具神经毒性。它们会导致细胞中大量 DNA 损伤，尤其是神经元中，细胞内谷胱甘肽 (GSH) 水平显着降低。然而，RHg ⁺在细胞毒性浓度下对脑细胞造成大量 DNA 损伤的机制仍不清楚。在本研究中，我们研究了 RHg ⁺对核苷结构和电子特性的影响及其对 DNA 损伤的影响。 RHg ⁺与核苷的直接相互作用显着削弱了N-糖苷键，降低了糖部分的C-H键能，并增加了嘌呤碱基C ₈ -中心的亲电性。因此，RHg ⁺结合的 DNA 分子极其不稳定，并且对 GSH 耗尽的细胞中存在的任何亲核试剂/自由基高度敏感，因此会经历增强的氧化和不寻常的烷基化 DNA 损伤。我们还报道了有机汞裂解酶的功能模型，该模型对 RHg ⁺诱导的细胞毒性表现出优异的细胞保护作用；这会逆转 MeHgCl 抑制的谷胱甘肽还原酶的活性，并停止氧化和烷基化 DNA 损伤。这一有趣的发现为了解有机汞在谷胱甘肽耗尽的细胞中的作用模式及其对氧化应激相关神经退行性疾病个体的不利影响提供了新的机制见解。