Formerly: Sustainable Chemistry and Material Resources, Institute of Sustainable Environmental Chemistry, Leuphana University Lüneburg, C13, DE-21335 Lüneburg, Germany.
Sustainable Chemistry and Material Resources, Institute of Sustainable Environmental Chemistry, Leuphana University Lüneburg, C13, DE-21335 Lüneburg, Germany.
Sci Total Environ. 2018 Mar 15;618:697-711. doi: 10.1016/j.scitotenv.2017.08.040. Epub 2017 Oct 19.
The lack of studies on the fate and effects of drug metabolites in the environment is of concern. As their parent compounds, metabolites enter the aquatic environment and are subject to biotic and abiotic process. In this regard, photolysis plays an important role. This study combined experimental and in silico quantitative structure-activity relationship (QSAR) methods to assess the fate and effects of Mesoridazine (MESO), a pharmacologically active human drug and metabolite of the antipsychotic agent Thioridazine, and its transformation products (TPs) formed through a Xenon lamp irradiation. After 256min, the photodegradation of MESO⋅besylate (50mgL) achieved 90.4% and 6.9% of primary elimination and mineralization, respectively. The photon flux emitted by the lamp (200-600nm) was 169.55Jcm. Sixteen TPs were detected by means of liquid chromatography-high resolution mass spectrometry (LC-HRMS), and the structures were proposed based on MS fragmentation patterns. The main transformation reactions were sulfoxidation, hydroxylation, dehydrogenation, and sulfoxide elimination. A back-transformation of MESO to Thioridazine was evidenced. Aerobic biodegradation tests (OECD 301 D and 301F) were applied to MESO and the mixture of TPs present after 256min of photolysis. Most of TPs were not biodegraded, demonstrating their tendency to persist in aquatic environments. The ecotoxicity towards Vibrio fischeri showed a decrease in toxicity during the photolysis process. The in silico QSAR tools QSARINS and US-EPA PBT profiler were applied for the screening of TPs with character of persistence, bioaccumulation, and toxicity (PBT). They have revealed the carbazole derivatives TP 355 and TP 337 as PBT/vPvB (very persistent and very bioaccumulative) compounds. In silico QSAR predictions for mutagenicity and genotoxicity provided by CASE Ultra and Leadscope® indicated positive alerts for mutagenicity on TP 355 and TP 337. Further studies regarding the carbazole derivative TPs should be considered to confirm their hazardous character.
药物代谢物在环境中的归宿和效应研究的缺乏令人关注。作为其母体化合物，代谢物进入水生态环境并受到生物和非生物过程的影响。在这方面，光解起着重要作用。本研究结合实验和定量构效关系（QSAR）方法评估了 Mesoridazine（MESO）的归宿和效应，MESO 是一种具有药理活性的人类药物，也是抗精神病药物 Thioridazine 的代谢物，以及通过氙灯辐照形成的其转化产物（TPs）。256 分钟后，MESO·苯甲酸盐（50mgL）的光降解分别达到了 90.4%和 6.9%的初级消除和矿化。灯发射的光子通量（200-600nm）为 169.55Jcm。通过液相色谱-高分辨质谱（LC-HRMS）检测到 16 个 TPs，并根据 MS 碎片模式提出了结构。主要的转化反应为磺氧化、羟化、脱氢和亚砜消除。证明了 MESO 向 Thioridazine 的反转化。应用好氧生物降解试验（OECD 301 D 和 301F）对 MESO 和光解 256 分钟后存在的 TPs 混合物进行了测试。大多数 TPs 未被生物降解，表明它们有在水生态环境中持久存在的倾向。对发光菌 Vibrio fischeri 的生态毒性在光解过程中显示出毒性降低。QSARINS 和 US-EPA PBT 特性筛选工具被用于筛选具有持久性、生物累积性和毒性（PBT）特征的 TPs。结果表明，咔唑衍生物 TP 355 和 TP 337 为 PBT/vPvB（非常持久和非常生物累积）化合物。CASE Ultra 和 Leadscope®提供的用于致突变性和遗传毒性的计算毒理学 QSAR 预测表明，TP 355 和 TP 337 具有致突变性的阳性警报。应进一步研究咔唑衍生物 TPs，以确认其危害性。
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