Department of Obstetrics and Gynecology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Department of Anesthesiology and Perioperative Medicine, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education; Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
Department of Obstetrics and Gynecology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
Ecotoxicol Environ Saf. 2024 Nov 1;286:117244. doi: 10.1016/j.ecoenv.2024.117244. Epub 2024 Oct 25.
Aromatase (CYP19A1), a pivotal enzyme in the biosynthesis of estradiol from testosterone, is predominantly expressed in reproductive tissues including placentas. This study investigated the effects of paraben acid and nine parabens on the activity of human and rat CYP19A1 using microsomes derived from human and rat placentas and on estradiol secretion in human choriocarcinoma BeWo cells. The results showed that propyl, butyl, hexyl, heptyl, and nonyl parabens significantly inhibited human CYP19A1 activity, with IC values of 66.37, 61.08, 55.65, 48.26, and 27.24 μM, respectively. In BeWo cells, these parabens notably diminished estradiol secretion at concentrations of 100 μM. Similarly, rat CYP19A1 was inhibited by these parabens, with IC values of 98.07, 70.10, 41.30, 27.93, and 6.33 μM for propyl, butyl, hexyl, heptyl, and nonyl parabens, respectively. Kinetic analysis identified these compounds as mixed inhibitors. Bivariate correlation analysis revealed a negative correlation between the partition coefficient value, molecular weight, the number of carbon atoms in the alcohol moiety, as well as heavy atom number and IC values. Three-dimensional quantitative structure-activity relationship analysis highlighted the critical role of hydrophobic regions in determining inhibitory potency. Docking studies suggested that parabens interact with the heme-iron binding site of both human and rat CYP19A1. This study elucidates the inhibitory effects of various parabens on CYP19A1 and their binding mechanisms, thereby providing a deeper understanding of their potential impact on estrogen biosynthesis.
芳香酶（CYP19A1）是睾丸酮合成雌二醇的关键酶，主要在包括胎盘在内的生殖组织中表达。本研究使用人源和大鼠源胎盘微粒体研究了对羟基苯甲酸和 9 种对羟基苯甲酸酯对人源和大鼠源 CYP19A1 活性的影响，并研究了对羟基苯甲酸酯对人绒毛膜癌细胞 BeWo 中雌二醇分泌的影响。结果表明，丙基、丁基、己基、庚基和壬基对羟基苯甲酸酯显著抑制人 CYP19A1 活性，IC 值分别为 66.37、61.08、55.65、48.26 和 27.24µM。在 BeWo 细胞中，这些对羟基苯甲酸酯在 100µM 浓度下显著减少雌二醇分泌。同样，这些对羟基苯甲酸酯抑制大鼠 CYP19A1，IC 值分别为丙基、丁基、己基、庚基和壬基对羟基苯甲酸酯 98.07、70.10、41.30、27.93 和 6.33µM。动力学分析表明这些化合物为混合抑制剂。双变量相关分析表明，分配系数值、分子量、醇部分的碳原子数以及重原子数与 IC 值呈负相关。三维定量构效关系分析强调了疏水区在确定抑制效力方面的关键作用。对接研究表明对羟基苯甲酸酯与人源和大鼠源 CYP19A1 的血红素铁结合部位相互作用。本研究阐明了各种对羟基苯甲酸酯对 CYP19A1 的抑制作用及其结合机制，从而深入了解其对雌激素生物合成的潜在影响。
