Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
Department of Anaesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
J Steroid Biochem Mol Biol. 2023 Jan;225:106202. doi: 10.1016/j.jsbmb.2022.106202. Epub 2022 Oct 12.
Human 3β-hydroxysteroid dehydrogenase type I (HSD3B1) and rat type IV (HSD3B4) in placentas catalyze the conversion of pregnenolone to progesterone, which plays a key role in maintaining pregnancy. Many phenolic compounds potentially inhibit HSD3B in placentas as endocrine disruptors. In this study, the effects of 16 phenolic compounds on the activity of human HSD3B1 and rat HSD3B4 were determined and the structure-activity relationship was compared. HSD3B1 in human placental microsomes and HSD3B4 in rat placental microsomes were used to measure their activities and pregnenolone and NAD were used as substrates. Of the 16 phenolic compounds, 4-nonylphenol, pentabromophenol, and 2-bromophenol resulted in residual human HSD3B1 activity lower than 50 % and 4-nonylphenol and pentabromophenol resulted in residual rat HSD3B4 activity lower than 50 %. 4-Nonylphenol, pentabromophenol, and 2-bromophenol were mixed inhibitors of human HSD3B1, with Ki values of 2.31, 3.58 and 4.86 µM, respectively, while 4-nonylphenol and pentabromophenol were noncompetitive inhibitors of rat HSD3B4 with Ki values of 20.86 and 141.8 µM. Molecular docking showed that 4-nonylphenol, pentabromophenol, and 2-bromophenol docked to the active sites of human HSD3B1 and rat HSD3B4, and the shift of residue S125 in human HSD3B1 to T125 in rat HSD3B4 could explain the species-dependent difference in their inhibitory potency and mode of action. This study demonstrates that 4-nonylphenol, pentabromophenol, and 2-bromophenol are mixed inhibitors of human placental HSD3B1, while 4-nonylphenol and pentabromophenol are noncompetitive inhibitors of rat HSD3B4, possibly blocking the placental steroidogenesis.
人 3β-羟甾脱氢酶类型 I（HSD3B1）和大鼠类型 IV（HSD3B4）在胎盘内催化孕烯醇酮转化为孕酮，这在维持妊娠中起着关键作用。许多酚类化合物作为内分泌干扰物，可能抑制胎盘内的 HSD3B。在这项研究中，测定了 16 种酚类化合物对人 HSD3B1 和大鼠 HSD3B4 活性的影响，并比较了它们的构效关系。用人胎盘微粒体中的 HSD3B1 和大鼠胎盘微粒体中的 HSD3B4 来测量它们的活性，以孕烯醇酮和 NAD 为底物。在 16 种酚类化合物中，4-壬基酚、五溴苯酚和 2-溴苯酚导致残留的人 HSD3B1 活性低于 50%，4-壬基酚和五溴苯酚导致残留的大鼠 HSD3B4 活性低于 50%。4-壬基酚、五溴苯酚和 2-溴苯酚是 HSD3B1 的混合抑制剂，Ki 值分别为 2.31、3.58 和 4.86µM，而 4-壬基酚和五溴苯酚是大鼠 HSD3B4 的非竞争性抑制剂，Ki 值分别为 20.86 和 141.8µM。分子对接表明，4-壬基酚、五溴苯酚和 2-溴苯酚与 HSD3B1 和大鼠 HSD3B4 的活性部位结合，人 HSD3B1 中残基 S125 向大鼠 HSD3B4 中 T125 的移位可以解释其抑制效力和作用方式的种属差异。本研究表明，4-壬基酚、五溴苯酚和 2-溴苯酚是人胎盘 HSD3B1 的混合抑制剂，而 4-壬基酚和五溴苯酚是大鼠 HSD3B4 的非竞争性抑制剂，可能阻断胎盘类固醇生成。
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