UV-filter benzophenones suppress human, pig, rat, and mouse 11β-hydroxysteroid dehydrogenase 1: Structure-activity relationship and in silico docking analysis

• Published in: Comparative biochemistry and physiology. Toxicology & pharmacology 2024-07, Vol.281, p.109900-109900, Article 109900
• Main Authors: Hao, Ting, Zhao, Xin, Ji, Zhongyao, Xia, Miaomiao, Lu, Han, Sang, Jianmin, Wang, Shaowei, Li, Linxi, Ge, Ren-shan, Zhu, Qiqi
• Format: Article
• Language: English
• Subjects: 11β-HSD1; Benzophenone; Docking; Glucocorticoid; Metabolic activation
• ISSN: 1532-0456; 1878-1659
• DOI: 10.1016/j.cbpc.2024.109900

Benzophenone chemicals (BPs) have been developed to prevent the adverse effects of UV radiation and they are widely contaminated. 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) catalyze the conversion of inactive glucocorticoid to active glucocorticoid, playing critical role in many physiological function. However, the direct effect of BPs on human, pig, rat, and mouse 11β-HSD1 remains unclear. In this study, we screened the inhibitory strength of 12 BPs on 4 species, and performed the structure-activity relationship (SAR) and in silico docking analysis. The inhibitory potency of BPs was: for human 11β-HSD1, BP6 (IC50 = 18.76 μM) > BP8 (40.84 μM) > BP (88.89 μM) > other BPs; for pig 11β-HSD1, BP8 (45.57 μM) > BP6 (59.44 μM) > BP2 (65.12 μM) > BP (135.56 μM) > other BPs; for rat 11β-HSD1, BP7 (67.17 μM) > BP (68.83 μM) > BP8 (133.04 μM) > other BPs; and for mouse 11β-HSD1, BP8 (41.41 μM) > BP (50.61 μM) > other BPs. These BP chemicals were mixed/competitive inhibitors of these 11β-HSD1 enzymes. The 2,2′-dihydroxy substitutions in two benzene rings play a key role in enhancing the effectiveness of inhibiting 11β-HSD1, possibly via increasing hydrogen bond interactions. Docking analysis shows that these BPs bind to NADPH/glucocorticoid binding sites and forms hydrogen bonds with catalytic residues Ser and/or Tyr. In conclusion, this study demonstrates that BP chemicals can inhibit 11β-HSD1 from 4 species, and there are subtle species-dependent difference in the inhibitory strength and structural variations of BPs. [Display omitted] •BP, BP6 and BP8 significantly inhibited human 11β-HSD1 activity•BP, BP2, BP6 and BP8 significantly inhibited pig 11β-HSD1 activity•BP, BP2, BP3, BP7and BP8 significantly inhibited rat 11β-HSD1 activity, with the residual activity of less than 50% for BP, BP7, and BP8 when compared with the control•BP and BP8 significantly inhibited mouse 11β-HSD1 activity•These BPs bind to NADPH/glucocorticoid binding sites and forms hydrogen bonds with catalytic residues Ser and/or Tyr