Department of Environmental Medicine, University of Rochester Medical Center, New York 14642.
Department of Biomedical Engineering, University of Rochester, Rochester, New York 14627.
Toxicol Sci. 2020 Sep 1;177(1):188-201. doi: 10.1093/toxsci/kfaa091.
Ultraviolet radiation (UVR) is a consistent part of the environment that has both beneficial and harmful effects on human health. UVR filters in the form of commercial sunscreens have been widely used to reduce the negative health effects of UVR exposure. Despite their benefit, literature suggests that some filters can penetrate skin and have off-target biological effects. We noted that many organic filters are hydrophobic and contain aromatic rings, making them potential modulators of Aryl hydrocarbon Receptor (AhR) signaling. We hypothesized that some filters may be able to act as agonists or antagonists on the AhR. Using a luciferase reporter cell line, we observed that the UVR filter octinoxate potentiated the ability of the known AhR ligand, 6-formylindolo[3,2-b]carbazole (FICZ), to activate the AhR. Cotreatments of keratinocytes with octinoxate and FICZ lead to increased levels of cytochrome P4501A1 (CYP1A1) and P4501B1 (CYP1B1) mRNA transcripts, in an AhR-dependent fashion. Mechanistic studies revealed that octinoxate is an inhibitor of CYP1A1 and CYP1B1, with IC50 values at approximately 1 µM and 586 nM, respectively. In vivo topical application of octinoxate and FICZ also elevated CYP1A1 and CYP1B1 mRNA levels in mouse skin. Our results show that octinoxate is able to indirectly modulate AhR signaling by inhibiting CYP1A1 and CYP1B1 enzyme function, which may have important downstream consequences for the metabolism of various compounds and skin integrity. It is important to continue studying the off-target effects of octinoxate and other UVR filters, because they are used on skin on a daily basis world-wide.
紫外线辐射（UVR）是环境中持续存在的一部分，对人类健康既有有益影响，也有有害影响。商业防晒霜中的 UVR 过滤器已被广泛用于减少 UVR 暴露对健康的负面影响。尽管它们有益，但文献表明，一些过滤器可能会穿透皮肤并产生非靶向的生物学效应。我们注意到，许多有机过滤器是疏水性的，并且含有芳香环，使它们成为芳香烃受体（AhR）信号的潜在调节剂。我们假设，一些过滤器可能能够作为 AhR 的激动剂或拮抗剂发挥作用。使用荧光素酶报告细胞系，我们观察到 UVR 过滤器辛氧烷能增强已知的 AhR 配体 6-甲氧基吲哚并[3,2-b]咔唑（FICZ）激活 AhR 的能力。用辛氧烷和 FICZ 共同处理角质形成细胞会导致细胞色素 P4501A1（CYP1A1）和 P4501B1（CYP1B1）mRNA 转录物水平增加，这是一种 AhR 依赖性方式。机制研究表明，辛氧烷是 CYP1A1 和 CYP1B1 的抑制剂，IC50 值分别约为 1µM 和 586nM。辛氧烷和 FICZ 的体内局部应用也能提高小鼠皮肤中 CYP1A1 和 CYP1B1 的 mRNA 水平。我们的结果表明，辛氧烷能够通过抑制 CYP1A1 和 CYP1B1 酶的功能间接调节 AhR 信号，这可能对各种化合物的代谢和皮肤完整性产生重要的下游影响。继续研究辛氧烷和其他 UVR 过滤器的非靶向效应非常重要，因为它们在全球范围内每天都被用于皮肤。
