Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Computer-Aided Molecular Design Group, Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
Int J Mol Sci. 2017 Sep 19;18(9):2007. doi: 10.3390/ijms18092007.
Parabens are effective preservatives widely used in cosmetic products and processed food, with high human exposure. Recent evidence suggests that parabens exert estrogenic effects. This work investigated the potential interference of parabens with the estrogen-activating enzyme 17β-hydroxysteroid dehydrogenase (17β-HSD) 1 and the estrogen-inactivating 17β-HSD2. A ligand-based 17β-HSD2 pharmacophore model was applied to screen a cosmetic chemicals database, followed by in vitro testing of selected paraben compounds for inhibition of 17β-HSD1 and 17β-HSD2 activities. All tested parabens and paraben-like compounds, except their common metabolite -hydroxybenzoic acid, inhibited 17β-HSD2. Ethylparaben and ethyl vanillate inhibited 17β-HSD2 with IC values of 4.6 ± 0.8 and 1.3 ± 0.3 µM, respectively. Additionally, parabens size-dependently inhibited 17β-HSD1, whereby hexyl- and heptylparaben were most active with IC values of 2.6 ± 0.6 and 1.8 ± 0.3 µM. Low micromolar concentrations of hexyl- and heptylparaben decreased 17β-HSD1 activity, and ethylparaben and ethyl vanillate decreased 17β-HSD2 activity. However, regarding the very rapid metabolism of these compounds to the inactive -hydroxybenzoic acid by esterases, it needs to be determined under which conditions low micromolar concentrations of these parabens or their mixtures can occur in target cells to effectively disturb estrogen effects in vivo.
对羟基苯甲酸酯是一种有效的防腐剂，广泛应用于化妆品和加工食品中，人体接触量较高。最近的证据表明，对羟基苯甲酸酯具有雌激素效应。本研究旨在探讨对羟基苯甲酸酯是否会对雌激素激活酶 17β-羟甾脱氢酶（17β-HSD）1 和雌激素失活酶 17β-HSD2 产生干扰。本研究应用基于配体的 17β-HSD2 药效团模型对化妆品化学物质数据库进行筛选，然后对选定的对羟基苯甲酸酯化合物进行体外测试，以检测其对 17β-HSD1 和 17β-HSD2 活性的抑制作用。所有测试的对羟基苯甲酸酯和对羟基苯甲酸酯类似物（其常见代谢物 - 羟基苯甲酸除外）均抑制 17β-HSD2。乙基对羟基苯甲酸酯和乙基香草酸对 17β-HSD2 的抑制作用的 IC 值分别为 4.6 ± 0.8 和 1.3 ± 0.3 μM。此外，对羟基苯甲酸酯还可剂量依赖性地抑制 17β-HSD1，其中己基和庚基对羟基苯甲酸酯的 IC 值分别为 2.6 ± 0.6 和 1.8 ± 0.3 μM。低微摩尔浓度的己基和庚基对羟基苯甲酸酯可降低 17β-HSD1 的活性，而乙基对羟基苯甲酸酯和乙基香草酸则降低 17β-HSD2 的活性。然而，鉴于这些化合物通过酯酶快速代谢为无活性的 - 羟基苯甲酸，需要确定在何种条件下，这些对羟基苯甲酸酯或其混合物的低微摩尔浓度可以在靶细胞中出现，从而有效地干扰体内的雌激素作用。
