Benzophenone-1 and -2 UV-filters potently inhibit human, rat, and mouse gonadal 3β-hydroxysteroid dehydrogenases: Structure-activity relationship and in silico docking analysis.

Benzophenone (BP) ultraviolet (UV) -filters have been widely used to prevent adverse effects of UV. Whether they can disrupt gonadal steroidogenesis remains unclear. Gonadal 3β-hydroxysteroid dehydrogenases (3β-HSD) catalyse the conversion of pregnenolone to progesterone. This study explored the effect of 12 BPs on human, rat, and mouse 3β-HSD isoforms, and analysed the structure-activity relationship (SAR) and underlying mechanisms. The inhibitory potency was BP-1 (IC50, 5.66 ± 0.95 μM) > BP-2 (5.84 ± 2.22 μM) > BP-6 (185.8 ± 115.2 μM) > BP3-BP12 on human KGN 3β-HSD2, BP-2 (5.90 ± 1.02 μM) > BP-1 (7.55 ± 1.26 μM) > BP3-B12 on rat testicular 3β-HSD1, and BP-1 (15.04 ± 5.20 μM) > BP-2 (22.64 ± 11.81 μM) > BP-6（125.1 ± 34.65 μM）> BP-7 (161.1 ± 102.4 μM) > other BPs on mouse testicular 3β-HSD6. BP-1 is a mixed inhibitor of human, rat, and mouse 3β-HSDs, and BP-2 is a mixed inhibitor of human and rat 3β-HSDs and a noncompetitive inhibitor of mouse 3β-HSD6. 4-Hydroxyl substitution in the benzene ring plays a key role in enhancing potency of inhibiting human, rat, and mouse gonadal 3β-HSDs. BP-1 and BP-2 can penetrate human KGN cells to inhibit progesterone secretion at ≥ 10 μM. Docking analysis revealed that the 4-hydroxyl group of BP-1 and BP-2 forms hydrogen bonds with residue Ser123 of human 3β-HSD2 and residue Asp127 of rat 3β-HSD1. In conclusion, this study demonstrates that BP-1 and BP-2 are the most potent inhibitors of human, rat, and mouse gonadal 3β-HSDs and that there is a significant SAR difference.