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.
J Agric Food Chem. 2024 Nov 6;72(44):24797-24807. doi: 10.1021/acs.jafc.4c04265. Epub 2024 Oct 25.
Salicylate preservatives are widely used in consumer products and pharmaceuticals. This study investigates their potential endocrine-disrupting effects on neurosteroidogenesis, focusing on 5α-reductase type 1 (SRD5A1). We evaluated the effects of 13 salicylates on human SRD5A1 using SF126 glioblastoma cell microsomes and rat brain microsomes, examining dihydrotestosterone production in SF126 cells. Results revealed a hierarchy of inhibitory potency against human SRD5A1, with methyl salicylate (IC, 71.93 μM) to menthyl salicylate (2.41 μM), indicating increasing potency. Kinetic analysis indicates their mixed/noncompetitive inhibitions. In SF126 cells, all salicylates at 100 μM significantly reduced dihydrotestosterone production. Rat SRD5A1 showed reduced sensitivity, with menthyl salicylate as the most potent inhibitor (IC, 17.12 μM). Docking analysis suggests salicylates bind to the reduced nicotinamide adenine dinucleotide phosphate site of both human and rat SRD5A1. Bivariate correlation analysis highlights the influence of LogP, molecular weight, carbon number in the alcohol moiety, and p on inhibitory potency. 3D-QSAR revealed the importance of hydrophobic aromatic regions in SRD5A1 binding. This study delineates the inhibitory effects of salicylates and binding mechanisms on human and rat SRD5A1, providing insights into their impact on neurosteroid production.
水杨酸酯防腐剂广泛应用于消费品和制药行业。本研究调查了它们对神经甾体生成的潜在内分泌干扰作用，重点关注 5α-还原酶 1 型（SRD5A1）。我们使用 SF126 神经胶质瘤细胞微粒体和大鼠脑微粒体评估了 13 种水杨酸酯对人 SRD5A1 的影响，检测 SF126 细胞中二氢睾酮的产生。结果显示，人 SRD5A1 的抑制效力存在一个等级，其中甲基水杨酸（IC50，71.93 μM）到薄荷醇水杨酸（2.41 μM），表明效力逐渐增强。动力学分析表明它们具有混合/非竞争性抑制作用。在 SF126 细胞中，所有水杨酸酯在 100 μM 时均显著降低二氢睾酮的产生。大鼠 SRD5A1 的敏感性降低，其中薄荷醇水杨酸的抑制效力最强（IC50，17.12 μM）。对接分析表明水杨酸酯结合到人和大鼠 SRD5A1 的还原型烟酰胺腺嘌呤二核苷酸磷酸结合位点。二元相关分析突出了 LogP、分子量、醇部分的碳原子数和 p 值对抑制效力的影响。3D-QSAR 揭示了 SRD5A1 结合中疏水性芳香区域的重要性。本研究描绘了水杨酸酯对人和大鼠 SRD5A1 的抑制作用及其结合机制，深入了解它们对神经甾体生成的影响。
