Department of Pharmaceutical Sciences, University of Basel, Switzerland.
Biochem Pharmacol. 2010 Apr 15;79(8):1189-99. doi: 10.1016/j.bcp.2009.12.005. Epub 2009 Dec 11.
The prevalence of male reproductive disorders and testicular cancer is steadily increasing. Because the exposure to chemicals disrupting natural hormone action has been associated with these diseases, it is important to identify endocrine disrupting chemicals (EDCs) and their targets of action. Here, a 3D-structural database that can be applied for virtual screening approaches to facilitate the identification of EDCs was constructed. The database was screened using pharmacophores of 17beta-hydroxysteroid dehydrogenase type 3 (17beta-HSD3), which catalyzes the last step of testosterone synthesis in testicular Leydig cells and plays an essential role during male sexual development. Among other chemicals, benzophenone (BP) UV-filters were predicted as potential 17beta-HSD3 inhibitors. Biological analyses revealed (2,4-dihydroxyphenyl)-phenylmethanone (also known as benzophenone-1, BP-1) as an inhibitor of human 17beta-HSD3 (IC(50) 1.05microM). BP-1 also efficiently blocked conversion of androstenedione to testosterone by mouse and rat 17beta-HSD3 in whole-organ enzyme assays. Moreover, BP-1 antagonized the testosterone-dependent activation of androgen receptors (IC(50) 5.7microM), suggesting synergistic anti-androgenic effects of BP-1 by preventing testosterone formation and blocking receptor activation. In addition, analyses of several commonly used UV-filters on estrogen- and androgen-metabolizing 17beta-HSD enzymes revealed 3-benzylidene camphor (3-BC) and 4-methylbenzylidene camphor (4-MBC) as low micromolar 17beta-HSD2 inhibitors. In conclusion, screening of virtual chemical structure libraries can facilitate the identification of compounds interfering with hormone action. The potential disruption of 17beta-HSD enzyme function by the UV-filters BP-1, 3-BC and 4-MBC requires further investigation and should be considered for safety assessment of these chemicals.
男性生殖系统疾病和睾丸癌的发病率正在稳步上升。由于接触扰乱天然激素作用的化学物质与这些疾病有关,因此确定内分泌干扰化学物质(EDC)及其作用靶点非常重要。在这里,构建了一个可用于虚拟筛选方法的 3D 结构数据库,以促进 EDC 的鉴定。该数据库使用 17β-羟甾脱氢酶 3 型(17β-HSD3)的药效团进行筛选,17β-HSD3 催化睾丸间质细胞中睾酮合成的最后一步,在男性性发育过程中起着至关重要的作用。在其他化学物质中,二苯甲酮(BP)紫外线滤光剂被预测为潜在的 17β-HSD3 抑制剂。生物学分析表明,(2,4-二羟基苯基)-苯甲酮(也称为二苯甲酮-1,BP-1)是人类 17β-HSD3 的抑制剂(IC50 为 1.05μM)。BP-1 还能有效地阻止小鼠和大鼠 17β-HSD3 在整个器官酶测定中雄烯二酮转化为睾酮。此外,BP-1 拮抗了睾酮依赖性的雄激素受体激活(IC50 为 5.7μM),这表明 BP-1 通过阻止睾酮形成和阻断受体激活,具有协同的抗雄激素作用。此外,对几种常用的紫外线滤光剂对雌激素和雄激素代谢 17β-HSD 酶的分析表明,3-亚苄基樟脑(3-BC)和 4-甲基亚苄基樟脑(4-MBC)是低微摩尔 17β-HSD2 抑制剂。总之,虚拟化学结构文库的筛选有助于鉴定干扰激素作用的化合物。紫外线滤光剂 BP-1、3-BC 和 4-MBC 对 17β-HSD 酶功能的潜在破坏需要进一步研究,并应考虑对这些化学物质进行安全性评估。