<br>HepG2 细胞中乙酰胆碱酯酶肟再激活剂诱导的氧化应激的体外评价,Chemical Research in Toxicology

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HepG2 细胞中乙酰胆碱酯酶肟再激活剂诱导的氧化应激的体外评价
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2023-11-11 , DOI: 10.1021/acs.chemrestox.3c00203
Nela Váňová ₁ , L'ubica Múčková ₂ , Tereza Kalíšková ₁ , Lukáš Lochman ₁ , Petr Bzonek ₂ , František Švec ₃

Affiliation

乙酰胆碱酯酶 (AChE) 肟再激活剂可用作有机磷神经毒剂和杀虫剂有意或无意中毒的解毒剂。尽管尽一切努力开发新的乙酰胆碱酯酶再激活剂，但这些候选药物都没有取代传统的临床使用肟。除了治疗功效外，确定安全性在临床前药物评价中也至关重要。肟毒性的确切机制和结构-毒性关系是正在进行的研究主题，其中氧化应激被认为是一种可能的机制。在本研究中，我们研究了四种有前景的双吡啶鎓肟AChE重激活剂K048、K074、K075和K203，以及它们在体外诱导氧化应激的能力。培养的人肝癌细胞暴露于肟，其浓度对应于24小时后通过MTT测定确定的IC ₅₀值。在暴露 1、4 和 24 小时时评估了它们产生活性氧、干扰硫醇抗氧化系统和诱导脂质过氧化的能力。与含有双键的 K075 和 K203 相比，四碳连接基中不带双键的再激活剂 K048 和 K074 显示出更大的诱导氧化应激的潜力。与具有三碳长连接基的肟不同，连接到吡啶鎓部分的醛肟基团的数量并不决定 K048、K074、K075 和 K203 肟的氧化应激诱导。总之，我们的结果强调肟的结构在诱导氧化应激中起着关键作用，并且这种关系与其以IC ₅₀值表示的细胞毒性无关。然而，值得注意的是，不能忽视氧化应激是肟相关副作用的潜在因素。

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In Vitro Evaluation of Oxidative Stress Induced by Oxime Reactivators of Acetylcholinesterase in HepG2 Cells

Oxime reactivators of acetylcholinesterase (AChE) are used as causal antidotes for intended and unintended poisoning by organophosphate nerve agents and pesticides. Despite all efforts to develop new AChE reactivators, none of these drug candidates replaced conventional clinically used oximes. In addition to the therapeutic efficacy, determining the safety profile is crucial in preclinical drug evaluation. The exact mechanism of oxime toxicity and the structure–toxicity relationship are subjects of ongoing research, with oxidative stress proposed as a possible mechanism. In the present study, we investigated four promising bispyridinium oxime AChE reactivators, K048, K074, K075, and K203, and their ability to induce oxidative stress in vitro. Cultured human hepatoma cells were exposed to oximes at concentrations corresponding to their IC₅₀ values determined by the MTT assay after 24 h. Their potency to generate reactive oxygen species, interfere with the thiol antioxidant system, and induce lipid peroxidation was evaluated at 1, 4, and 24 h of exposure. Reactivators without a double bond in the four-carbon linker, K048 and K074, showed a greater potential to induce oxidative stress compared with K075 and K203, which contain a double bond. Unlike oximes with a three-carbon-long linker, the number of aldoxime groups attached to the pyridinium moieties does not determine the oxidative stress induction for K048, K074, K075, and K203 oximes. In conclusion, our results emphasize that the structure of oximes plays a critical role in inducing oxidative stress, and this relationship does not correlate with their cytotoxicity expressed as the IC₅₀ value. However, it is important to note that oxidative stress cannot be disregarded as a potential contributor to the side effects associated with oximes.

更新日期：2023-11-11

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