Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, Basel 4056, Switzerland; Swiss Centre for Applied Human Toxicology and Department of Pharmaceutical Sciences, University of Basel, Missionsstrasse 64, 4055 Basel, Switzerland.
Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, Basel 4056, Switzerland.
Toxicology. 2024 Dec;509:153997. doi: 10.1016/j.tox.2024.153997. Epub 2024 Nov 10.
Parabens and UV-filters are frequently used additives in cosmetics and body care products that prolong shelf-life. They are assessed for potential endocrine disrupting properties. Antiandrogenic effects of parabens and benzophenone-type UV-filters by blocking androgen receptor (AR) activity have been reported. Effects on local androgen formation received little attention. Local 5α-dihydrotestosterone (DHT) production with subsequent AR activation is required for male external genitalia formation during embryogenesis. We investigated whether parabens and benzophenone-type UV-filters might cause potential antiandrogenic effects by inhibiting oxidative 3α-hydroxysteroid dehydrogenases (3α-HSDs) involved in the backdoor pathway of DHT formation. Five different 3α-HSDs were assessed for their efficiency to catalyze the 3α-oxidation reaction to form DHT and activate AR. 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), retinol dehydrogenases type 5 and 16 were further assessed using a radiometric in vitro activity assay to determine the conversion of 5α-androstane-3α-ol-17-one to 5α-androstane-3,17-dione in lysates of overexpressing HEK-293 cells. All parabens tested, except p-hydroxybenzoic acid (a main metabolite) inhibited HSD17B6 activity. Hexyl- and heptylparaben, as well as benzophenone (BP)-1 and BP-2, showed the highest inhibitory potencies, with nanomolar IC values. Molecular modeling predicted binding modes for the inhibitory parabens and BPs and provided an explanation for the observed structure-activity-relationship. Our results propose a novel mechanism of antiandrogenic action for commercially used parabens and BP UV-filters by inhibiting HSD17B6 and lowering DHT synthesis. Follow-up studies should assess BP-3 metabolism after topical application and whether the identified inhibitors reach concentrations in liver, testis, or prostate to inhibit HSD17B6, thereby causing antiandrogenic effects.
对羟基苯甲酸及其酯类和紫外线滤光剂是化妆品和身体护理产品中常用的添加剂，可延长产品保质期。这些添加剂的潜在内分泌干扰特性已经过评估。有报道称，对羟基苯甲酸酯类和二苯甲酮型紫外线滤光剂通过阻断雄激素受体 (AR) 活性，具有抗雄激素作用。然而，这些添加剂对局部雄激素形成的影响却很少受到关注。在胚胎发生过程中，男性外生殖器的形成需要局部 5α-二氢睾酮 (DHT) 的产生，随后通过 AR 激活。我们研究了对羟基苯甲酸酯类和二苯甲酮型紫外线滤光剂是否可能通过抑制参与 DHT 形成的后门途径的氧化 3α-羟甾类脱氢酶 (3α-HSDs) 来引起潜在的抗雄激素作用。评估了五种不同的 3α-HSD 对催化 3α-氧化反应形成 DHT 和激活 AR 的效率。使用放射性体外活性测定法进一步评估 17β-羟甾脱氢酶 6 型 (HSD17B6)、视黄醇脱氢酶 5 型和 16 型，以确定在过表达 HEK-293 细胞的裂解物中，5α-雄烷-3α-醇-17-酮转化为 5α-雄烷-3,17-二酮。除了对羟基苯甲酸 (主要代谢物) 之外，所有测试的对羟基苯甲酸酯均抑制 HSD17B6 活性。己基和庚基对羟基苯甲酸酯以及二苯甲酮 (BP)-1 和 BP-2 的抑制作用最强，具有纳摩尔 IC 值。分子建模预测了抑制性对羟基苯甲酸酯和 BPs 的结合模式，并为观察到的结构-活性关系提供了解释。我们的研究结果表明，商业上使用的对羟基苯甲酸酯和 BP 紫外线滤光剂通过抑制 HSD17B6 和降低 DHT 合成，提出了一种新的抗雄激素作用机制。后续研究应评估局部应用 BP-3 后的代谢情况，以及所鉴定的抑制剂是否达到肝脏、睾丸或前列腺中的浓度，以抑制 HSD17B6，从而引起抗雄激素作用。
