Benzophenone-type ultraviolet filters inhibit human and rat placental 3β-hydroxysteroid dehydrogenases: Structure-activity relationship and in silico docking analysis.

Article

作者: Liu, Yi ; Li, Huitao ; Zhu, Yang ; Chen, Xiaofang ; Tang, Yunbing ; Wang, Yiyan ; Ge, Ren-Shan ; Hu, Zhiyan ; Lin, Hao ; Wang, Shaowei

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 3β-hydroxysteroid dehydrogenases (3β-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 3β-HSD1 (h3β-HSD1) is BP-1 (IC₅₀, 8.37 μM)>BP-2 (9.06 μM)>BP-12 (94.24 μM)>BP-7 (1160 μM) >BP-8 (1257 μM) >BP-6 (1410 μM) > other BPs (ineffective at 100 μM). The potency of BPs on rat r3β-HSD4 is BP-1 (IC₅₀, 4.31 μM)>BP-2 (117.3 μM)>BP-6 (669 μM) >BP-3 (820 μM)>other BPs (ineffective at 100 μM). BP-1, BP-2, and BP-12 are mixed h3β-HSD1 inhibitors and BP-1 is a mixed r3β-HSD4 inhibitor. LogP, lowest binding energy, and molecular weight were positively associated with IC₅₀ for h3β-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 h3β-HSD1 and r3β-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 h3β-HSD1 and Thr125 of r3β-HSD4. In conclusion, this study demonstrates that BP-1 and BP-2 are moderate inhibitors of h3β-HSD1 and BP-1 is a moderate inhibitor of r3β-HSD4. There is a significant SAR differences for 3β-HSD homologues between BPs and distinct species-dependent inhibition of placental 3β-HSDs.

2023-06-01·The Journal of Steroid Biochemistry and Molecular Biology

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

Article

作者: Fei, Qianjin ; Li, Huitao ; Yu, Yang ; Tang, Yunbing ; Wang, Yiyan ; Wang, Mengyun ; Pan, Chengshuang ; Hu, Zhiyan ; Ge, Ren-Shan ; Zhu, Yang

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.

2020-10-01·Water Research1区 · 环境科学与生态学

In vitro and in vivo screening for environmentally friendly benzophenone-type UV filters with beneficial tyrosinase inhibition activity

1区 · 环境科学与生态学

Article

作者: Chen, Pei-Jen ; Chou, Pei-Hsin ; Thia, Eveline

Benzophenones (BPs) are a group of chemically similar organic compounds commonly used in formulations of sunscreen and other personal care products as UV filters to protect our skin against sunlight overexposure. Studies have shown that the occurrence of certain BPs (e.g., BP-3 and its metabolite BP-1) in multiple environmental matrices may increase the incidence of coral planulae bleaching and estrogenic effects on aquatic life. Currently, most BPs are not yet comprehensively screened in vitro and in vivo for their ecotoxicity under environmentally relevant concentrations. This study systematically assessed the in vitro and in vivo toxicity and activity of the 7 most commonly used BPs (BP-1, BP-2, BP-3, BP-4, BP-6, BP-7 and BP-8) to select BP alternatives with lower ecotoxicity and extra beneficial functions. BP-2 (LC₅₀ = 18.43 µM) was least toxic and BP-3 (LC₅₀ = 4.10 µM) and BP-8 (LC₅₀ =1.62 µM) were less and most toxic, respectively, in terms of 96-hr acute mortality of medaka larvae. BP-2 at environmentally relevant concentrations (5-50 nM) did not significantly alter locomotion and oxidative stress responses of medaka larvae from 24-hr to 7-day exposure, whereas BP-3 and BP-8 at 5 nM induced hypoactivity or changed fish swimming angles. Only BP-2 was able to inhibit in vitro mushroom tyrosinase activity, with EC₅₀ value 19.7 µM. Also, BP-2 could effectively suppress melanin formation and tyrosinase activity in zebrafish embryos. Among the 7 tested BPs, BP-2 was the least toxic and the most environmentally friendly UV filter with extra benefit for tyrosinase inhibition and could be a promising alternative to the use of toxic BPs.

100 项与 BP-007 相关的药物交易

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