The UV-filter benzophenone-1 inhibits 17β-hydroxysteroid dehydrogenase type 3: Virtual screening as a strategy to identify potential endocrine disrupting chemicals

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 17 beta-hydroxysteroid dehydrogenase type 3 (17 beta-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 17 beta-HSD3 inhibitors. Biological analyses revealed (2,4-dihydroxyphenyl)-phenylmethanone (also known as benzophenone-1, BP-1) as an inhibitor of human 17 beta-HSD3 (IC50 1.05 mu M). BP-1 also efficiently blocked conversion of androstenedione to testosterone by mouse and rat 17 beta-HSD3 in whole-organ enzyme assays. Moreover, BP-I antagonized the testosterone-dependent activation of androgen receptors (IC50 5.7 mu M), 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 17 beta-HSD enzymes revealed 3-benzylidene camphor (3-BC) and 4-methylbenzylidene camphor (4-MBC) as low micromolar 17 beta-HSD2 inhibitors. In conclusion, screening of virtual chemical structure libraries can facilitate the identification of compounds interfering with hormone action. The potential disruption of 17 beta-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. (C) 2009 Elsevier Inc. All rights reserved.