Enantioselective occurrence and fate of chiral drugs in the aqueous environment

药物是具有潜在危险的生物活性的新兴污染物，因为它们中的许多是普遍存在的和持久的，对水生生物具有怀疑或已确定的毒性。此外，由于它们不断进入环境并通过联合平行作用产生协同效应，即使是低持久性的药物也可能在环境中产生意想不到的影响。每年有数百吨这些化合物被分配到社区，随后通过废水进入环境。几组药物，如-受体阻滞剂、抗生素或止痛药，之前已经在环境中进行了研究，但令人惊讶的是，它们的手性特征却被环境研究人员忽视了。目前使用的药物中有一半以上是手性化合物，其中许多是由两种对映异构体的等摩尔混合物组成的外消旋体。一个手性分子至少有一个手性中心（通常是不对称碳），因此它具有旋光性。它以两种对映体的形式存在，是彼此不可重叠的镜像。对映体具有相同的化学式和理化性质，但它们的旋光性和空间排列不同。手性化合物的对映体与手性环境（如体内酶）的相互作用不同。因此，在生物系统中，它们可以被认为是两种不同的物质，引起不同的反应：同一药物的一种对映体可能产生所需的治疗活性，而另一种对映体可能无效甚至有毒。手性药物在给药、体内代谢和排出体外后，其活性/非活性对映体的比例会发生显著变化。在生物废水处理过程中，当药物已经存在于环境中时，它可以随后改变。这是因为对映体的降解可能具有立体特异性，并且在某些情况下可能导致药物毒性的增加。这一领域的研究很重要，因为随着西方国家人口老龄化和发展中世界消费水平的增加，越来越多的药物进入环境，迄今为止，对环境中这些污染物的流行程度和特征的研究范围有限。此外，现有的报告，由于其非对映体特异性分析方法，没有解决药物的手性问题，因此这些研究不能明确区分生物（对映体选择性）和非生物（非对映体选择性）过程。因此，本项目旨在确定水环境中的手性药物，并验证其在水环境中的分布具有立体选择性的假设，以及控制其命运的立体选择机制本质上是生物学的。这一假设将通过对西约克郡（考尔德河）地表水样本的一系列分析来验证，重点是人口稠密的地区，那里的环境最有可能被药物污染。将考虑到当地的废水处理活动，对污染进行分析，从而更准确地了解与环境中存在手性药物有关的风险。为了实现这一目标，将建立一种多残留分析方法，允许同时识别和定量环境基质中滥用手性药物的痕量浓度（低ppt水平）。在考虑非立体选择性非生物（光化学过程、水解、吸附）和立体选择性生物（微生物）变量后，手性药物在水环境中降解的立体选择性也将在实验室规模上使用微观方案和模型化合物进行验证。

Drugs are potentially hazardous biologically active emerging contaminants as many of them are ubiquitous and persistent with suspected or identified toxicity towards aquatic organisms. Additionally, due to their continuous introduction into the environment and synergistic effects through combined parallel action, even drugs of a low persistence might cause unwanted effects in the environment. Hundreds of tonnes of these compounds are dispensed in communities every year and subsequently enter the environment through wastewater. Several groups of drugs such as beta-blockers, antibiotics or analgesics have been studied before in the environment but surprisingly their chiral character has been overlooked by environmental researchers. More than half of the drugs currently in use are chiral compounds and many of those are distributed as racemates consisting of an equimolar mixture of two enantiomers. A chiral molecule has at least one chiral centre (usually asymmetric carbon) as a result of which it shows optical activity. It exists in the form of two enantiomers, being the non-superimposable mirror images of each other. Enantiomers have the same chemical formula and physicochemical properties but they differ in their optical activity and spatial arrangement. The enantiomers of chiral compounds differ in interactions with chiral environments such as enzymes in the body. Therefore in biological systems they can be recognised as two different substances that elicit different responses: one enantiomer of the same drug may produce the desired therapeutic activity, while the other may be inactive or even toxic. The ratio of active/inactive enantiomer of the chiral drug can change significantly after its administration, metabolism in and excretion from the body. It can be subsequently altered during biological wastewater treatment and when the drug is already present in the environment. This is because degradation of enantiomers can be stereo-specific and can in some cases lead to an increase in the drug's toxicity. Research in this area is important as with the ageing population in western countries and an increase in consumption levels in the developing world increasing quantities of drugs are entering the environment and, to date, studies of the prevalence and characteristics of these contaminants in the environment have been limited in scope. Furthermore, existing reports, due to their non-enantiospecific analytical methodology, do not tackle the problem of chirality of drugs, so these studies cannot unequivocally differentiate between biological (enantioselective) and abiotic (non-enantioselective) processes. Therefore this project aims to identify chiral drugs in the aqueous environment and to test the hypothesis that their distribution in the aqueous environment is stereoselective and that stereoselective mechanisms governing their fate are biological in nature. The hypothesis will be tested through a series of analyses of surface water samples in West Yorkshire (the River Calder), concentrating on densely populated areas where the environment has the greatest potential to be contaminated with drugs. Analysis of contamination will be undertaken taking account of local wastewater treatment activity, thus achieving a more accurate understanding of the risk associated with the presence of chiral drugs in the environment. To achieve this a multi-residue analytical methodology that will allow for simultaneous identification and quantification of trace concentrations (low ppt levels) of chiral drugs of abuse in environmental matrices will be established. Verification of the stereoselectivity of the degradation of chiral drugs in the aqueous environment after taking into consideration non-stereoselective abiotic (photochemical processes, hydrolysis, sorption) and stereoselective biological (microbial) variables will also be undertaken at the laboratory scale with the usage of microcosm protocol and model compounds.