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Loss of NQO1 generates genotoxic estrogen-DNA adducts in Fuchs Endothelial Corneal Dystrophy.
Free Radical Biology and Medicine ( IF 7.4 ) Pub Date : 2019-12-17 , DOI: 10.1016/j.freeradbiomed.2019.12.014
Taiga Miyajima 1 , Geetha Melangath 2 , Shan Zhu 2 , Neha Deshpande 2 , Shivakumar Vasanth 2 , Bodhisattwa Mondal 3 , Varun Kumar 2 , Yuming Chen 2 , Marianne O Price 4 , Francis W Price 4 , Eleanor G Rogan 3 , Muhammad Zahid 3 , Ula V Jurkunas 2
Affiliation  

Fuchs Endothelial Corneal Dystrophy (FECD) is an age-related genetically complex disease characterized by increased oxidative DNA damage and progressive degeneration of corneal endothelial cells (HCEnCs). FECD has a greater incidence and advanced phenotype in women, suggesting a possible role of hormones in the sex-driven differences seen in the disease pathogenesis. In this study, catechol estrogen (4-OHE2), the byproduct of estrogen metabolism, induced genotoxic estrogen-DNA adducts formation, macromolecular DNA damage, and apoptotic cell death in HCEnCs; these findings were potentiated by menadione (MN)-mediated reactive oxygen species (ROS). Expression of NQO1, a key enzyme that neutralizes reactive estrogen metabolites, was downregulated in FECD, indicating HCEnC susceptibility to reactive estrogen metabolism in FECD. NQO1 deficiency in vitro exacerbated the estrogen-DNA adduct formation and loss of cell viability, which was rescued by the supplementation of N-acetylcysteine, a ROS scavenger. Notably, overexpression of NQO1 in HCEnCs treated with MN and 4-OHE2 quenched the ROS formation, thereby reducing the DNA damage and endothelial cell loss. This study signifies a pivotal role for NQO1 in mitigating the macromolecular oxidative DNA damage arising from the interplay between intracellular ROS and impaired endogenous estrogen metabolism in post-mitotic ocular tissue cells. A dysfunctional Nrf2-NQO1 axis in FECD renders HCEnCs susceptible to catechol estrogens and estrogen-DNA adducts formation. This novel study highlights the potential role of NQO1-mediated estrogen metabolite genotoxicity in explaining the higher incidence of FECD in females.

中文翻译:

在 Fuchs 内皮性角膜营养不良中,NQO1 的缺失会产生遗传毒性雌激素-DNA 加合物。

福克斯内皮性角膜营养不良 (FECD) 是一种与年龄相关的复杂遗传疾病,其特征是 DNA 氧化损伤增加和角膜内皮细胞 (HCEnC) 进行性退化。FECD 在女性中发病率较高且表型较晚,这表明激素在该疾病发病机制中性别驱动差异中可能发挥作用。在这项研究中,雌激素代谢的副产物儿茶酚雌激素(4-OHE2)诱导HCEnCs中基因毒性雌激素-DNA加合物的形成、大分子DNA损伤和细胞凋亡;甲萘醌(MN)介导的活性氧(ROS)强化了这些发现。NQO1(一种中和反应性雌激素代谢物的关键酶)的表达在 FECD 中下调,表明 HCEnC 对 FECD 中反应性雌激素代谢敏感。体外 NQO1 缺乏加剧了雌激素-DNA 加合物的形成和细胞活力的丧失,通过补充 ROS 清除剂 N-乙酰半胱氨酸可以挽救这种情况。值得注意的是,用 MN 和 4-OHE2 处理的 HCEnC 中 NQO1 的过度表达可抑制 ROS 的形成,从而减少 DNA 损伤和内皮细胞损失。这项研究表明,NQO1 在减轻有丝分裂后眼组织细胞中细胞内 ROS 与受损的内源雌激素代谢之间的相互作用引起的大分子氧化 DNA 损伤方面发挥着关键作用。FECD 中功能失调的 Nrf2-NQO1 轴使 HCEnC 容易受到儿茶酚雌激素和雌激素-DNA 加合物形成的影响。这项新研究强调了 NQO1 介导的雌激素代谢物基因毒性在解释女性 FECD 发病率较高方面的潜在作用。
更新日期:2019-12-18
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