Benzophenone-type ultraviolet filters inhibit human and rat placental 38-hydroxysteroid dehydrogenases: Structure-activity relationship and in silico docking analysis

Benzophenones (BPs) are a class of chemicals found in various personal care and cosmetic products, such as sunscreens and lotions. Their usage is known to cause reproductive and hormonal health risks, but the exact mechanism of action remains unknown. In this study, we investigated the effects of BPs on human and rat placental 38-hydroxysteroid dehydrogenases (38-HSDs), which play a crucial role in the biosynthesis of steroid hormones, particularly progesterone. We tested inhibitory effects of 12 BPs, and performed structure-activity relationship (SAR) and in silico docking analysis. The potency of BPs to inhibit human 38-HSD1 (h38-HSD1) is BP-1 (IC50, 8.37 & mu;M)>BP-2 (9.06 & mu;M)>BP-12 (94.24 & mu;M)>BP-7 (1160 & mu;M) >BP-8 (1257 & mu;M) >BP-6 (1410 & mu;M) > other BPs (ineffective at 100 & mu;M). The potency of BPs on rat r38-HSD4 is BP-1 (IC50, 4.31 & mu;M)>BP-2 (117.3 & mu;M)>BP-6 (669 & mu;M) >BP-3 (820 & mu;M)>other BPs (ineffective at 100 & mu;M). BP-1, BP-2, and BP-12 are mixed h38-HSD1 inhibitors and BP-1 is a mixed r38-HSD4 inhibitor. LogP, lowest binding energy, and molecular weight were positively associated with IC50 for h38-HSD1, while LogS was negatively associated with IC50. The 4-OH substitution in the benzene ring plays a key role in enhancing the effectiveness of inhibiting h38-HSD1 and r38-HSD4, possibly through increasing water solubility and decreasing lipophilicity by forming hydrogen bonds. BP-1 and BP-2 inhibited progesterone production in human JAr cells. Docking analysis shows that 2-OH of BP-1 forms hydrogen bonds with catalytic residue Ser125 of h38-HSD1 and Thr125 of r38-HSD4. In conclusion, this study demonstrates that BP-1 and BP-2 are moderate inhibitors of h38-HSD1 and BP-1 is a moderate inhibitor of r38-HSD4. There is a significant SAR differences for 38-HSD homologues between BPs and distinct species-dependent inhibition of placental 38-HSDs.