喹诺酮类抗生素在氯化消毒体系中的生物毒性转化机制
文献类型：学位论文
| 作者 | 李敏 |
| 学位类别 | 博士 |
| 答辩日期 | 2014-05 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 杜宇国,魏东斌 |
| 关键词 | 喹诺酮 氯化消毒 遗传毒性 急性毒性 定量构效相关 莫西沙星 Quinolone genotoxicity acute toxicity chlorination QSAR moxifloxacin. |
| 其他题名 | Toxicity variation of quinolone antibiotics in chlorination system |
| 学位专业 | 环境科学 |
| 中文摘要 | 喹诺酮类抗生素因为其抗菌谱广、药效良好等优点而广泛应用于人及牲畜的疾病治疗及预防。但由于不合理利用及滥用，这些药物母体可以经过多种途径最终进入环境。残留于环境中的药物原体存在一定的环境健康风险，一方面，其可直接对环境中的微生物和动植物产生危害；另一方面，可诱导耐药菌的产生，增加人类及牲畜疾病治愈难度。城市污水处理厂对此类药物的环境污染控制具有重要作用。考虑到氯消毒在城市污水处理领域的普遍应用，与水体有效氯的反应对喹诺酮类化合物的环境行为与环境健康效应具有重要作用。本课题以SOS/umuC遗传毒性以及发光细菌急性毒性测试为先导，首先检测了21种喹诺酮类化合物氯化反应前后的遗传毒性及急性毒性效应，并应用定量结构活性相关（QSARs）方法对喹诺酮类化合物生物毒性效应进行二维和三维构效关系的研究。进而筛选出典型化合物莫西沙星，对其氯化反应进行深入研究。主要研究成果如下： （1）、所检测的喹诺酮化合物在nmol/L水平即可表现出显著的遗传毒性效应，构效关系显示分子结构中1、7、8位取代基性质与其遗传毒性大小密切相关。具体表现为：① 增加1位取代基体积或正电荷效应；② 增加7位取代基负电荷效应；③ 增加8位取代基负电荷效应或减小其体积，会增大喹诺酮化合物的遗传毒性效应。 （2）、氯化消毒处理后大部分喹诺酮化合物（19/21）遗传毒性降低，少部分化合物存在遗传毒性升高的现象，其氯化消毒过程中遗传毒性的变化与喹诺酮分子结构密切相关。本研究建立了一个新指标——遗传毒性生成潜势（lgGeF）来定量评价喹诺酮化合物氯化前后遗传毒性的变化。进一步研究表明，增大喹诺酮化合物分子亲水性、减少分子中氢键供体并且增加1位取代基负电荷效应，会导致氯化过程中喹诺酮类化合物遗传毒性增大。 （3）、喹诺酮化合物对发光细菌敏感性较低，大部分所检测的化合物短期暴露（15 min）后在μmol/L水平表现出毒性效应。但是氯化处理后，多个化合物急性毒性呈显著上升趋势，如莫西沙星、左氧氟沙星、帕珠沙星等。 （4）、莫西沙星在低剂量氯化反应（氯剂量小于5当量）过程中生成遗传毒性大于母体的氯代产物。在高剂量氯化反应（氯剂量大于5当量）过程中，非常容易生成众多具有同分异构效应的氯化产物。采用模型反应对其高剂量氯化反应进行研究发现，高剂量氯化反应破坏了莫西沙星分子4-喹诺酮母环结构，且具有生成氯代苯醌类消毒副产物的风险。 综上，本论文选取目前用量大、环境残留高、生物毒性效应显著的喹诺酮类抗生素作为目标研究化合物，通过对大量喹诺酮化合物（21种）的毒性测试深入研究了其分子结构与毒性效应之间的构效关系，进而对其中典型化合物莫西沙星的氯化转化机制进行了深入探讨，旨在全面揭示喹诺酮类抗生素在水处理典型工艺氯化消毒过程中的生物毒性变化规律和转化机制。本研究将为环境中喹诺酮类污染物的污染防治、风险管理提供一定的科学依据。 |
| 英文摘要 | Quinolones, the most important antibacterial antibiotics with broad-spectrum activity and good potency, have been widely used for the clinical treatment of both human and veterinary diseases. Unfortunately, due to the excessive addition in the feed, those drugs entered directly into the environment via multiple pathways and have been found in variety of different environmental matrices. The persistent residue of quinolones in aquatic system could pose serious threat to ecosystem and human health, and even lead to the formation of antimicrobial resistance. The sewage treatment plant plays an important role in controlling of those drugs as pollutants. Chlorination disinfection has been used extensively as a disinfectant for reducing pathogenic risk because of its strong oxidation potential. Quinilones, however, can react with free available chlorine to generate disinfection products in chiloriantion process, which could have an essential impact on human health and ecological safety. In this study, the short-term SOS/umu test for genotoxicity and the photobacterium Vibio fischeri for acute toxicity test were uesd to examine 21 quinolone antibiotics both before and after chlorination disinfection treatment. The quantitative structure-activity relationship (QSAR) method was used to investigate the relationship between toxicity and molecular structure. Finally, a typical compound named as moxifloxacin was choose and its transformation behavior in chlorination was explored. The main works carried out in this research were as follows: (1) The tested quinilones exhibited high genotoxicity even at nmol/L level. The specific effect on three key active sites (1-, 7- and 8-positions) of quinolone ring was investigated using the quantitative structure-activity relationship method. From our modeling, the genotoxicity increased when substituents had: ① big volume and/or positive charge at 1-position; ② negative charge at 7-position; ③ small volume and/or negative charge at 8-position. (2) Most of the tested quinolones exhibited getoxicity decreasing following the chlorination process, except several compounds with complex structure did give genotoxicity increasing in chlorination. The index of genotoxicity formation (GeF) was defined and calculated to quantify any changes. The results of QSAR studies revealed that compounds bearing hydrophilic substituents with less H-bond donors and negative charge at the 1-position of the quinolone ring, would lead to an increase in the genotoxicity of the quinolone compounds following the chlorination process. (3) Quinolone antibiotics were not sensitive to the photobacterium V. fischeri and showed low acute toxicity at μmol/L level. While after chlorination, most of the tested compounds exhibited toxicity increasing, such as moxifloxacin, levofloxacin and pazufloxacin. (4) Chlorine substitution was the main route in moxifloxacin chlorination with low FAC (free available chlorine) dose ([FAC]0:[MOX]0<5), and genotoxicity in SOS/umuC assay had an elevation after chlorination, which was attributed to the formation of monochlorinated product with m/z of 436. With the high FAC dose ([FAC]0:[MOX]0≥5), porducts with destroyed 4-quinolone ring and chloro-p-benzoquinone analogues were detected. In conclusion, quinolone antibiotics were chosen as targets, and the relationship between their genotic/acute toxicities and chemical structures were explored. Then the moxifloxacin was chosen as target to explore the transformation mechanism in chloriantion. The results of the current study could be used to provide useful information for evaluating the potential environmental risk associated with the quinolones pollution. |
| 公开日期 | 2015-07-07 |
| 源URL | [http://ir.rcees.ac.cn/handle/311016/15703]  |
| 专题 | 生态环境研究中心_环境化学与生态毒理学国家重点实验室 |
| 推荐引用方式 GB/T 7714 | 李敏. 喹诺酮类抗生素在氯化消毒体系中的生物毒性转化机制[D]. 北京. 中国科学院研究生院. 2014. |
入库方式： OAI收割
来源：生态环境研究中心
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