Xu Ningge, Ge Jianqiang, Huang Kaibo, Liu Mengyue, Wen Zheng, Sang Shenggang, Yu Fabiao, Wang Juan, Liu Heng
Key Laboratory of Haikou Trauma, Key Laboratory of Hainan Trauma and Disaster Rescue, Key Laboratory of Emergency and Trauma of Ministry of Education, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou 571199, China.
Engineering Research Center for Hainan Bio-Smart Materials and Bio-Medical Devices, Key Laboratory of Hainan Functional Materials and Molecular Imaging, College of Emergency and Trauma, Hainan Medical University, Haikou 571199, China.
Anal Chem. 2025 Jul 1;97(25):13292-13299. doi: 10.1021/acs.analchem.5c01433. Epub 2025 Jun 18.
Estradiol (E2), the most potent form of estrogen, holds a central position in regulating physiological functions and influencing disease states across the female lifecycle. Carboxylesterases (CEs), as a widely distributed drug-metabolizing enzyme in human liver and plasma, play a crucial role in the hydrolytic metabolism of drugs, and their activities are significantly affected by estrogen levels, making the interplay between E2 and CEs particularly important. Thus, elucidating how E2 modulates CEs is vital for refining drug therapy, particularly for pregnant and postmenopausal women. In this study, we presented a proximity-labeled fluorogenic probe DCI2F-MC. This probe reacted with CEs, producing a quinone methide (QM) intermediate bound to the enzyme's active site and emitting fluorescence signals, enabling highly selective detection and in situ imaging of CEs activity. DCI2F-MC exhibited superior spectral response properties and facilitated the screening of cell lines based on variations in CEs levels. Additional experiments revealed that E2 decreased the CEs expression in LO2 cells in a dose-dependent manner, potentially through transcriptional regulation or the AP-1 pathway. Most importantly, in an ovariectomized mouse model, E2 supplementation markedly reduced CEs activity in the liver, the finding confirmed by fluorescence imaging and Western blot analysis. Our results provided chemical tools for understanding the mechanisms of estrogen regulation of CEs and offered a scientific basis for personalized drug therapy in women under different physiological conditions.
雌二醇（E2）是雌激素中活性最强的形式，在调节女性整个生命周期的生理功能和影响疾病状态方面占据核心地位。羧酸酯酶（CEs）作为一种在人体肝脏和血浆中广泛分布的药物代谢酶，在药物的水解代谢中起着关键作用，其活性受雌激素水平的显著影响，使得E2与CEs之间的相互作用尤为重要。因此，阐明E2如何调节CEs对于优化药物治疗至关重要，特别是对于孕妇和绝经后女性。在本研究中，我们展示了一种邻近标记的荧光探针DCI2F-MC。该探针与CEs反应，产生与酶活性位点结合的醌甲基化物（QM）中间体并发出荧光信号，从而能够对CEs活性进行高度选择性检测和原位成像。DCI2F-MC表现出优异的光谱响应特性，并有助于基于CEs水平的变化对细胞系进行筛选。进一步的实验表明，E2以剂量依赖性方式降低LO2细胞中CEs的表达，可能是通过转录调控或AP-1途径。最重要的是，在去卵巢小鼠模型中，补充E2显著降低了肝脏中的CEs活性，荧光成像和蛋白质印迹分析证实了这一发现。我们的结果为理解雌激素调节CEs的机制提供了化学工具，并为不同生理条件下女性的个性化药物治疗提供了科学依据。
