Potent trienone and dienone steroid hormones undergo a coupled photohydration (in light)-thermal dehydration (in dark) cycle that ultimately increases their environmental persistence. Here, we studied the photolysis of dienogest, a dienone progestin prescribed as a next-generation oral contraceptive, and used high resolution mass spectrometry and both 1D and 2D nuclear magnetic resonance spectroscopy to identify its phototransformation products. Dienogest undergoes rapid direct photolysis (t1/2 ~ 1-10 min), forming complex photoproduct mixtures across the pH range examined (pH 2 to 7). Identified products include three photohydrates that account for ~ 80% of the converted mass at pH 7 and revert back to parent dienogest in the absence of light. Notably, we also identified two estrogenic compounds produced via the A-ring aromatization of dienogest, evidence for a photochemically-induced increase in estrogenic activity in product mixtures. These results imply that dienogest will undergo complete and facile photolytic transformation in sunlit surface water, yet exhibit greater environmental persistence than might be anticipated by inspection of kinetic rates. Photoproduct mixtures also include transformation products with different nuclear receptor binding capabilities than the parent compound dienogest. These outcomes reveal a dynamic fate and biological risk profile for dienogest that must also take into account the composition and endocrine activity of its transformation products. Collectively, this study further illustrates the need for more holistic regulatory, risk assessment, and monitoring approaches for high potency synthetic pharmaceuticals and their bioactive transformation products.

中文翻译：

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Dienogest的环境光化学：转化为雌激素产物并通过可逆光合作用增加环境持久性

强大的三烯酮和二烯酮类固醇激素经历了光合（轻度）-热脱水（黑暗）的耦合循环，最终增加了它们的环境持久性。在这里，我们研究了二烯酮黄体酮（一种被指定为下一代口服避孕药的二烯酮黄体酮）的光解作用，并使用高分辨率质谱法和一维和二维核磁共振波谱法来鉴定其光转化产物。Dienogest经过快速直接光解（t1 / 2〜1-10分钟），在所检查的pH范围（pH 2至7）中形成复杂的光产物混合物。鉴定出的产品包括三种光水合物，它们在pH值为7时约占转化质量的80％，并在不存在光照的情况下恢复为母体双歧杆菌。值得注意的是，我们还发现了通过苦杏仁酸的A环芳构化产生的两种雌激素化合物，光化学诱导产物混合物中雌激素活性增加的证据。这些结果表明，在阳光照射的地表水中，地诺孕酮将进行完全而又容易的光解转化，但是与通过动力学速率检查所预期的相比，仍表现出更大的环境持久性。光产物混合物还包括具有与母体化合物二诺孕不同的核受体结合能力的转化产物。这些结果揭示了去死孕的动态命运和生物学风险状况，还必须考虑其转化产物的组成和内分泌活性。总的来说，这项研究进一步说明了需要进行更全面的监管，风险评估，