Estragole, naturally occurring in a variety of herbs and spices, can form DNA adducts after bioactivation. Estragole DNA adduct formation and repair was studied in in vitro liver cell models, and a molecular dynamics simulation was used to investigate the conformation dependent (in)efficiency of N2-(trans-isoestragol-3'-yl)-2'-deoxyguanosine (E-3'-N2-dG) DNA adduct repair. HepG2, HepaRG cells, primary rat hepatocytes and CHO cells (including CHO wild-type and three NER-deficient mutants) were exposed to 50 μM estragole or 1'-hydroxyestragole and DNA adduct formation was quantified by LC-MS immediately following exposure and after a period of repair. Results obtained from CHO cell lines indicated that NER plays a role in repair of E-3'-N2-dG adducts, however, with limited efficiency since in the CHO wt cells 80% DNA adducts remained upon 24 h repair. Inefficiency of DNA repair was also found in HepaRG cells and primary rat hepatocytes. Changes in DNA structure resulting from E-3'-N2-dG adduct formation were investigated by molecular dynamics simulations. Results from molecular dynamics simulations revealed that conformational changes in double-stranded DNA by E-3'-N2-dG adduct formation are small, providing a possible explanation for the restrained repair, which may require larger distortions in the DNA structure. NER-mediated enzymatic repair of E-3'-N2-dG DNA adducts upon exposure to estragole will be limited, providing opportunities for accumulation of damage upon repeated daily exposure. The inability of this enzymatic repair is likely due to a limited distortion of the DNA double-stranded helix resulting in inefficient activation of nucleotide excision repair.

中文翻译：

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对雌二醇 DNA 加合物的细胞水平和分子动力学模拟表明，由于双链 DNA 螺旋的扭曲有限，修复效率低下。

Estragole 天然存在于多种药草和香料中，经生物活化后可形成 DNA 加合物。在体外肝细胞模型中研究了雌二醇 DNA 加合物的形成和修复，并使用分子动力学模拟来研究 N2-(trans-isoestragol-3'-yl)-2'-deoxyguanosine 的构象依赖性（无效）效率。 E-3'-N2-dG) DNA 加合物修复。将 HepG2、HepaRG 细胞、原代大鼠肝细胞和 CHO 细胞（包括 CHO 野生型和三种 NER 缺陷型突变体）暴露于 50 μM 草蒿脑或 1'-羟基草蒿脑，并在暴露后立即通过 LC-MS 定量 DNA 加合物的形成。一段修复期。从 CHO 细胞系获得的结果表明，NER 在 E-3'-N2-dG 加合物的修复中发挥作用，然而，效率有限，因为在 CHO wt 细胞中，80% 的 DNA 加合物在 24 小时修复后仍然存在。在 HepaRG 细胞和原代大鼠肝细胞中也发现 DNA 修复效率低下。通过分子动力学模拟研究了由 E-3'-N2-dG 加合物形成引起的 DNA 结构变化。分子动力学模拟的结果表明，E-3'-N2-dG 加合物形成对双链 DNA 的构象变化很小，这为受限修复提供了可能的解释，这可能需要 DNA 结构发生更大的扭曲。NER 介导的 E-3'-N2-dG DNA 加合物在暴露于 estragle 后的酶促修复将受到限制，从而为每天重复暴露时累积损伤提供机会。