Evans S, Bagnall J, Kasprzyk-Hordern B
Department of Chemistry, University of Bath, BA2 7AY, Bath, UK.
Department of Chemistry, University of Bath, BA2 7AY, Bath, UK.
Environ Pollut. 2017 Nov;230:368-377. doi: 10.1016/j.envpol.2017.06.070. Epub 2017 Jun 30.
Due to concerns regarding the release of pharmaceuticals into the environment and the understudied impact of stereochemistry of pharmaceuticals on their fate and biological potency, we focussed in this paper on stereoselective transformation pathways of selected chiral pharmaceuticals (16 pairs) at both microcosm (receiving waters and activated sludge wastewater treatment simulating microcosms) and macrocosm (wastewater treatment plant (WWTP) utilising activated sludge technology and receiving waters) scales in order to test the hypothesis that biodegradation of chiral drugs is stereoselective. Our monitoring programme of a full scale activated sludge WWTP and receiving environment revealed that several chiral drugs, those being marketed mostly as racemates, are present in wastewater and receiving waters enriched with one enantiomeric form (e.g. fluoxetine, mirtazapine, salbutamol, MDMA). This is most likely due to biological metabolic processes occurring in humans and other organisms. Both activated sludge and receiving waters simulating microcosms confirmed our hypothesis that chiral drugs are subject to stereoselective microbial degradation. It led, in this research, to preferential degradation of S-(+)-enantiomers of amphetamines, R-(+)-enantiomers of beta-blockers and S-(+)-enantiomers of antidepressants. In the case of three parent compound - metabolite pairs (venlafaxine - desmethylvenlafaxine, citalopram - desmethylcitalopram and MDMA - MDA), while parent compounds showed higher resistance to both microbial metabolism and photodegradation, their desmethyl metabolites showed much higher degradation rate both in terms of stereoselective metabolic and non-stereoselective photochemical processes. It is also worth noting that metabolites tend to be, as expected, enriched with enantiomers of opposite configuration to their parent compounds, which might have significant toxicological consequences when evaluating the metabolic residues of chiral pollutants.
由于担心药物释放到环境中，以及药物立体化学对其归宿和生物活性的研究不足，我们在本文中重点研究了选定的手性药物（16对）在微观世界（受纳水体和模拟活性污泥废水处理的微观世界）和宏观世界（采用活性污泥技术的污水处理厂（WWTP）和受纳水体）尺度上的立体选择性转化途径，以检验手性药物的生物降解具有立体选择性这一假设。我们对一座全规模活性污泥污水处理厂及其受纳环境的监测计划表明，几种主要以外消旋体形式销售的手性药物存在于废水中，并且在受纳水体中一种对映体形式富集（例如氟西汀、米氮平、沙丁胺醇、摇头丸）。这很可能是由于人类和其他生物体内发生的生物代谢过程。活性污泥和模拟微观世界的受纳水体均证实了我们的假设，即手性药物会经历立体选择性微生物降解。在本研究中，这导致苯丙胺类的S-(+)-对映体、β-受体阻滞剂的R-(+)-对映体和抗抑郁药的S-(+)-对映体优先降解。对于三对母体化合物 - 代谢物对（文拉法辛 - 去甲基文拉法辛、西酞普兰 - 去甲基西酞普兰和摇头丸 - MDA），虽然母体化合物对微生物代谢和光降解均表现出更高的抗性，但它们的去甲基代谢物在立体选择性代谢和非立体选择性光化学过程方面均表现出更高的降解速率。还值得注意的是，正如预期的那样，代谢物往往会富集与其母体化合物构型相反的对映体，这在评估手性污染物的代谢残留物时可能会产生重大的毒理学后果。
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