Qi Shufang, Cai Li, Lu Xinmiao, Wang Shaowei, Shao Siming, Hector Nikita Jacintha, Mao Baiping, Wang Yiyan, Ge Ren-Shan, Shangguan Wangning
Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China.
Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou 325027, Zhejiang, China.
Chem Res Toxicol. 2025 Jul 21;38(7):1215-1226. doi: 10.1021/acs.chemrestox.5c00063. Epub 2025 Jul 2.
Isothiazole disinfectants are widely used antimicrobial preservatives found in various consumer products, raising concerns about their potential effects on human health. This study investigated the inhibitory effects of seven isothiazole disinfectants on human and rat steroid 5α-reductase type 1 (SRD5A1), a key enzyme in neurosteroid biosynthesis. Among the tested compounds, dichlorooctylisothiazole exhibited the strongest suppression on human SRD5A1 with an IC value of 3.23 μM, followed by octylisothiazole (5.10 μM), butylbenzo[]isothiazol-3(2H)-one (16.51 μM), benzisothiazole (31.64 μM), and methylchloroisothiazole (42.65 μM). Enzyme kinetics and molecular docking analyses revealed that these compounds acted through mixed/noncompetitive inhibition by binding to the NADPH-binding pocket via van der Waals and hydrogen bonds. Cell-based studies in human SF126 glioblastoma cells confirmed that these compounds penetrated cell membranes and reduced dihydrotestosterone production. Structure-activity relationship analysis showed that compounds with higher LogP, molecular weight, volume, heavy atom number, and apolar desolvation exhibited stronger inhibitory activity. 3D quantitative structure-activity relationship analysis incorporated hydrogen bond acceptor and hydrophobicity domain features. Additionally, dichlorooctylisothiazole showed significant inhibition of rat SRD5A1 with an IC of 21.47 μM. In conclusion, these findings reveal some isothiazole disinfectants as potential endocrine disruptors targeting neurosteroid biosynthesis via SRD5A1 and highlight clear structure-activity relationship and species-dependent variance.
异噻唑类消毒剂是广泛应用于各种消费品中的抗菌防腐剂，这引发了人们对其对人体健康潜在影响的担忧。本研究调查了七种异噻唑类消毒剂对人及大鼠1型类固醇5α-还原酶（SRD5A1）的抑制作用，SRD5A1是神经甾体生物合成中的关键酶。在所测试的化合物中，二氯辛基异噻唑对人SRD5A1的抑制作用最强，IC值为3.23 μM，其次是辛基异噻唑（5.10 μM）、丁基苯并异噻唑-3(2H)-酮（16.51 μM）、苯并异噻唑（31.64 μM）和甲基氯异噻唑（42.65 μM）。酶动力学和分子对接分析表明，这些化合物通过范德华力和氢键与NADPH结合口袋结合，以混合/非竞争性抑制方式发挥作用。在人SF126胶质母细胞瘤细胞中进行的基于细胞的研究证实，这些化合物可穿透细胞膜并减少二氢睾酮的产生。构效关系分析表明，具有较高LogP、分子量、体积、重原子数和非极性去溶剂化作用的化合物表现出更强的抑制活性。三维定量构效关系分析纳入了氢键受体和疏水区特征。此外，二氯辛基异噻唑对大鼠SRD5A1也有显著抑制作用，IC值为21.47 μM。总之，这些发现揭示了一些异噻唑类消毒剂可能是通过SRD5A1靶向神经甾体生物合成的潜在内分泌干扰物，并突出了明确的构效关系和物种依赖性差异。
