4-氨基安替比林的氧化应激效应及其作用机理的研究
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摘要
药物及其中间体残留带来的污染问题已经对生态环境安全及人体健康构成威胁。4-氨基安替比林(AAP)作为一种原料或者中间体,大量用于生产镇痛、消炎、抗菌类的新型药物,AAP会引起粒性白血球缺乏症等毒性作用,已经成为一种暴露于环境中的污染物。
研究表明氧化应激与所有的疾病有关,环境污染物对生物体产生的危害与氧化应激密切相关。在氧化应激过程中,活性氧类物质(ROS)在生物体内大量表达,参与并促进多种疾病的发生发展过程,造成DNA/RNA、蛋白质、脂类等生物分子的氧化损伤,从而导致机体代谢紊乱,引发疾病。因此,利用氧化应激这一生物学指标来评价环境污染物的毒性效应,有助于人们了解环境污染物的致病机理,全面评价其毒性,为疾病的早期诊断、预防和治疗提供科学依据。
本论文以环境毒理学、现代仪器分析科学为背景,从实验动物、单细胞、蛋白质分子三个层面研究4-氨基安替比林的氧化应激效应及其作用机理。本论文主要包括以下五个部分：
第一章介绍了AAP的特性和用途,概述了AAP毒性效应的研究进展；介绍了活性氧物质和抗氧化系统的组成和特点,综述子环境氧化应激的诱发因素；归纳了氧化应激与疾病的相关关系；总结了环境毒理学中氧化应激的评价方法。
第二章以斑马鱼作为研究对象,从实验动物层面进行了急性染毒实验,测定了AAP对斑马鱼的半数致死浓度LC50-24h,对斑马鱼肝脏中抗氧化系统以及氧化损伤程度的影响,评价了AAP的氧化应激效应。结果表明,AAP导致ROS清除直接相关的CAT和GPx酶活性增大,间接对抗ROS的GR和GST酶活性减小,SOD酶活性没有显著变化,GSH含量显著下降,GSSG含量上升,GSH/GSSG比率显著下降,肝脏组织中的氧化还原平衡被打破,诱发了氧化应激。MDA的含量逐渐增大,说明体内氧化应激损伤产物LOP增多,造成了脂肪组织的氧化损伤。
第三章以人血红细胞作为研究对象,对其进行体外染毒,从单细胞水平研究AAP对人血红细胞中GSH含量的影响,评价其氧化应激效应。结果表明,在低AAP染毒浓度时,虽然GSH含量的平均值没有显著的变化,但是单细胞分析的结果显示低GSH含量的细胞开始出现。当AAP浓度增大,AAP对GSH含量有显著的影响,低GSH含量的细胞增加,GSH减少可达14.53%。GSH的消耗导致红细胞内环境向氧化型转变。
第四章选取血液中的传输蛋白(牛血清白蛋白和牛血红蛋白)为研究对象,从蛋白质分子水平上研究AAP与血液中传输蛋白的相互作用。污染物与血液中传输蛋白的结合决定了其在体内的传输和分布。利用多种光谱和分子模拟技术,建立二者间的作用模型,探讨其结合作用机理。
1)利用光谱和分子模拟的方法在模拟生理条件下研究AAP与牛血清白蛋白(BSA)相互作用的结果表明,AAP与BSA之间属于静态猝灭猝灭,AAP与BSA之间具有较强的相互作用,显正电性的AAP可以通过静电作用自发的跟带BSA分子上带负电的区域相结合,结合在BSA的亚域ⅢA处,导致了BSA微环境和空间构象的改变。
2)利用荧光、同步荧光、紫外-可见吸收和圆二色谱技术研究了AAP和牛血红蛋白(BHb)的结合作用。结果表明,AAP和BHb具有较强的相互作用,并且通过范德华力和氢键以1：1的比例结合,AAP导致BHb微环境发生变化,骨架结构变的松散。
第五章选取氧化应激直接相关的三种酶(超氧化物歧化酶、过氧化氢酶、辣根过氧化物酶)作为研究对象,利用光谱和分子模拟技术,从分子水平上研究了AAP对抗氧化酶的毒性作用机理。由于谷胱甘肽过氧化物酶(GPx)价格昂贵且不易保存,我们选用同类的辣根过氧化物酶(Hrp)来模拟GPx。
1)酶活性评定、光谱和分子模拟的研究结果表明,AAP可以通过氢键和范德华力自发地跟Cu/ZnSOD结合,形成AAP-Cu/ZnSOD结合物,AAP结合在Cu/ZnSOD两个子域的交界面上。AAP诱发了Cu/ZnSOD二级结构发生改变,导致Cu/ZnSOD骨架松散,内部疏水性的多肽链对水的暴露增加,影响了活性位点的微环境,从而对Cu/ZnSOD酶活性产生了抑制作用。
2)光谱实验和分子模拟的研究结果表明,带正电的AAP可以通过静电作用自发的与带负电的过氧化氢酶(CAT)以1：1的比例结合在CAT中心疏水腔内。CAT的微环境和空间结构受到AAP的影响,导致CAT骨架结构松散,从而影响了CAT活性位点的微环境,造成了血红细胞中CAT酶活性的抑制作用。
3)利用荧光、紫外-可见、同步荧光和圆二色谱等技术研究了AAP和辣根过氧化物酶(Hrp)的作用机理,考察了二者的结合参数(结合常数、结合位点数、热力学常数和结合力类型)以及AAP对Hrp空间结构的影响。AAP和Hrp具有较强的相互作用,并且通过静电作用以1：1的比例结合,AAP导致了Hrp微环境、二级结构和构象发生变化,造成Hrp的空间结构松散。
动物和分子水平上的研究结果表明,抗氧化酶活性受到三方面因素的影响,第一,AAP与抗氧化酶二者间直接结合作用会对抗氧化酶活性产生抑制作用；第二,组织发生氧化应激时,抗氧化酶处于ROS大量表达的环境中,直接催化分解ROS的抗氧化酶的酶促反应底物含量增大,这将有刺激抗氧化酶数量增加的趋势；第三,AAP急性染毒会对抗氧化酶的含量产生影响。这三个因素影响的相对大小,最终决定了在动物实验中抗氧化酶酶活性的表观变化情况。
第六章最后对论文的各研究部分进行了总结,分析了本研究中AAP氧化应激效应评价方法的优势与不足,展望了该领域的发展方向。本研究从分子、细胞和动物整体实验的角度较系统、全面地提供了AAP诱发机体氧化应激效应的评价结果,丰富了环境污染物诱发氧化应激效应的评价方法,有助于人们从分子水平了解环境污染物的致病机理和全面评价污染物毒性,为相关疾病的早期诊断、预防和治疗提供了参考和判定依据。
The pollutions caused by residues of drug and drug inermediates pose a threat to the eco-environmental safety and human health. As a raw material or intermediate,4-aminoantipyrine (AAP) has been widely used in the production of analgesic, anti-inflammatory, antibacterial drugs. Moreover, AAP can cause side effects, such as agranulocytosis. Thus, AAP has become an environmental pollutant exposed in the environment.
Many studies have shown that oxidative stress is related with all diseases. The hazards of environmental pollutants on organisms are related with oxidative stress. In the process of oxidative stress, reactive oxygen species (ROS) in vivo largely express, participate in and promote the progression of many diseases, cause oxidative damages of biological macromolecules such as DNA/RNA, proteins and lipids, further lead to metabolic disorders of the body and cause diseases. Therefore, the evaluation of toxic effects of environmental pollutants from the point of view of oxidative stress will help people to understand the pathogenesis of environmental pollutants and evaluate on pollutant toxicity comprehensively. That can provide a scientific basis for early diagnosis, prevention and treatment of related diseases.
This thesis has a background in environmental toxicology and modern instrumental analytical science. We studied the oxidative stress effects of AAP and its mechanism from three levels of experimental animals, single cell and protein macromolecules. This thesis includes the following five sections:
In the first chapter, the characteristics and applications of AAP were described. The research progress of toxic effects of AAP was overviewed. The compositions and characteristics of ROS and antioxidant system were introduced. The inducing factors of environmental oxidative stress were reviewed. The relationships of oxidative stress and diseases were summarized. The analysis and evaluation methods of oxidative stress in environmental toxicology were summarized.
In the second chaper, the zebrafish was used as the research target. Acute exposure experiments were carried out from experimental animal level. The AAP-induced half lethal concentration (LC50-24h) was determined. We investigated the effects of AAP on antioxidant system and oxidative damages in zebrafish liver and evaluated on the oxidative stress effects of AAP. The results showed that AAP caused an increase in CAT and GPx activities, a decrease in GR and GST activities and SOD activity did not change significantly. AAP also led to a significant reduction in GSH content, a increase in GSSG content and a significantly decrease in the ratio of GSH/GSSG. The redox equilibrium of liver tissue was broken, indicating that oxidative stress was formed. MDA content gradually increased, indicating that the product of oxidative damage (LOP) increased. The progress resulted in oxidative damages of adipose tissue.
In the third chapter, we used human erythrocytes as research targets. The erythrocytes were exposed by AAP in vitro. We investigated the effects of AAP on GSH contents in single human erythrocytes from single cell level and evaluated on the oxidative stress effects of AAP. When cells were exposed in low AAP concentration, although the GSH average content was not significant changed, the single-cell analysis revealed that the cells of low GSH contents began to appear. When the AAP concentration increased, AAP had a significant impact on the GSH content. The number of cells with low GSH content increased. GSH contents reduced up to14.53%. GSH depletion induced the internal environmente of erythrocytes changed into oxidized state.
In the fourth chapter, we used transport proteins in the blood (BSA and BHb) as research targets. The interactions of AAP and transport proteins were investigated from protein macromolecule level. The transmission and distribution of pollutants in the body was determined by the binding of pollutants and transport proteins. Based on multi-spectroscopy and molecular simulation techniques, we established the binding model and investigated the binding mechanisms.
1) By using spectroscopy and molecular modeling methods, the interaction between AAP and BSA was investigated in simulated physiological conditions. The results showed that BSA was quenched by AAP significantly through a static quenching mechanism. There was a strong interaction between AAP and BSA. The positively charged AAP can spontaneously bind with the negatively charged region of BSA through electrostatic forces. AAP bound to BSA on the subdomain ⅢA. The microenrironment and conformation of BSA were demonstrably changed in the presence of AAP.
2) With multiple spectroscopic techniques including fluorescence spectra, synchronous fluorescence spectra, UV-vis absorption spectra and CD spectra, the interaction mechanism of AAP and BHb was investigated. The results showed that there was a strong interaction between AAP and BHb. AAP bound to BHb through van der Waals interactions and hydrogen bonds with approximately one binding site. The microenvironment of BHb was changed by AAP and the skeletal structure of BHb loosened.
In the fifth chapter, we selected three kinds of oxidative stress directly related enzymes (SOD, CAT and Hrp) as research targets. Based on spectroscopy and molecular modeling techniques, the mechanism of toxic effects of AAP on antioxidative enzymes was researched from molecular level. Since GPx was expensive and difficult to save, we used Hrp to simulate the GPx.
1) The results of spectroscopic, molecular docking and enzyme activity assessment methods showed that AAP can spontaneously bind with Cu/ZnSOD to form AAP-Cu/ZnSOD complex with one binding site mainly through hydrogen bond and van der Waals forces. AAP bound into the Cu/ZnSOD interface of two subdomains. AAP triggered changes in the secondary structure of Cu/ZnSOD. The skeleton structure of Cu/ZnSOD loosened, exposing internal hydrophobic peptide strands to the solution. As the binding of AAP influenced the microenvironment of the activity sites, AAP led to the inhibition of Cu/ZnSOD activity.
2) On the basis of spectroscopic and molecular docking results, the positively charged AAP can spontaneously bound with the negatively charged CAT with one binding site mainly through electrostatic forces. The results of molecular docking simulation revealed that AAP bound into CAT central cavity. AAP triggered changes in the microenvironment and conformation of CAT. The skeleton structure of CAT loosened, exposing internal hydrophobic peptide strands to the solution. As the binding of AAP influenced the microenvironment of the activity sites, AAP led to the inhibition of CAT activity.
3) The interaction mechanism of AAP and Hrp was investigated by multiple spectroscopic techniques including fluorescence spectra, synchronous fluorescence spectra, UV-vis absorption spectra and CD spectra. We studied the binding parameters (association constants, number of binding sites, thermodynamic parameters and binding forces) of the interaction and the effect of AAP on the conformation of Hrp. There was a strong interaction between AAP and Hrp. AAP bound to Hrp through electrostatic forces with approximately one binding site. The microenvironment, secondary tructure and conformation of Hrp was changed by AAP and the skeletal structure of Hrp loosened.
The research results from animal and molecular level showed that antioxidant enzyme activities were affected by two factors. First of all, the direct binding of the AAP and antioxidant enzymes would inhibit the antioxidant enzyme activities. Second, when oxidative stress was generated in tissue, antioxidant enzymes were in the environment of excessive expressed ROS. The substrate content in the catalytic reaction of antioxidant enzymes increased, which would stimulate antioxidant enzyme activity to increase. Third, AAP acute exposure would have an impact on antioxidant enzyme contents. The relative influence degree of these three factors finally determined the apparent changes of the antioxidant enzyme activities in animal experiments.
In sixth chapter, finally, each section of the thesis was summarized. We analyzed the advantages and disadvantages of the evaluation method of oxidative stress induced by AAP in this thesis and discussed the future development of the field. The study provided more systematic and comprehensive evaluation results of AAP-induced oxidative stress effects from the perspective of molecular, cellular and experimental animal levels. This research has enriched the research on the evaluation method of oxidative stress effects of environmental pollutants, provided some reference gists for the toxicities and pathogenesis of environmental pollutantst.
研究表明氧化应激与所有的疾病有关,环境污染物对生物体产生的危害与氧化应激密切相关。在氧化应激过程中,活性氧类物质(ROS)在生物体内大量表达,参与并促进多种疾病的发生发展过程,造成DNA/RNA、蛋白质、脂类等生物分子的氧化损伤,从而导致机体代谢紊乱,引发疾病。因此,利用氧化应激这一生物学指标来评价环境污染物的毒性效应,有助于人们了解环境污染物的致病机理,全面评价其毒性,为疾病的早期诊断、预防和治疗提供科学依据。
本论文以环境毒理学、现代仪器分析科学为背景,从实验动物、单细胞、蛋白质分子三个层面研究4-氨基安替比林的氧化应激效应及其作用机理。本论文主要包括以下五个部分：
第一章介绍了AAP的特性和用途,概述了AAP毒性效应的研究进展；介绍了活性氧物质和抗氧化系统的组成和特点,综述子环境氧化应激的诱发因素；归纳了氧化应激与疾病的相关关系；总结了环境毒理学中氧化应激的评价方法。
第二章以斑马鱼作为研究对象,从实验动物层面进行了急性染毒实验,测定了AAP对斑马鱼的半数致死浓度LC50-24h,对斑马鱼肝脏中抗氧化系统以及氧化损伤程度的影响,评价了AAP的氧化应激效应。结果表明,AAP导致ROS清除直接相关的CAT和GPx酶活性增大,间接对抗ROS的GR和GST酶活性减小,SOD酶活性没有显著变化,GSH含量显著下降,GSSG含量上升,GSH/GSSG比率显著下降,肝脏组织中的氧化还原平衡被打破,诱发了氧化应激。MDA的含量逐渐增大,说明体内氧化应激损伤产物LOP增多,造成了脂肪组织的氧化损伤。
第三章以人血红细胞作为研究对象,对其进行体外染毒,从单细胞水平研究AAP对人血红细胞中GSH含量的影响,评价其氧化应激效应。结果表明,在低AAP染毒浓度时,虽然GSH含量的平均值没有显著的变化,但是单细胞分析的结果显示低GSH含量的细胞开始出现。当AAP浓度增大,AAP对GSH含量有显著的影响,低GSH含量的细胞增加,GSH减少可达14.53%。GSH的消耗导致红细胞内环境向氧化型转变。
第四章选取血液中的传输蛋白(牛血清白蛋白和牛血红蛋白)为研究对象,从蛋白质分子水平上研究AAP与血液中传输蛋白的相互作用。污染物与血液中传输蛋白的结合决定了其在体内的传输和分布。利用多种光谱和分子模拟技术,建立二者间的作用模型,探讨其结合作用机理。
1)利用光谱和分子模拟的方法在模拟生理条件下研究AAP与牛血清白蛋白(BSA)相互作用的结果表明,AAP与BSA之间属于静态猝灭猝灭,AAP与BSA之间具有较强的相互作用,显正电性的AAP可以通过静电作用自发的跟带BSA分子上带负电的区域相结合,结合在BSA的亚域ⅢA处,导致了BSA微环境和空间构象的改变。
2)利用荧光、同步荧光、紫外-可见吸收和圆二色谱技术研究了AAP和牛血红蛋白(BHb)的结合作用。结果表明,AAP和BHb具有较强的相互作用,并且通过范德华力和氢键以1：1的比例结合,AAP导致BHb微环境发生变化,骨架结构变的松散。
第五章选取氧化应激直接相关的三种酶(超氧化物歧化酶、过氧化氢酶、辣根过氧化物酶)作为研究对象,利用光谱和分子模拟技术,从分子水平上研究了AAP对抗氧化酶的毒性作用机理。由于谷胱甘肽过氧化物酶(GPx)价格昂贵且不易保存,我们选用同类的辣根过氧化物酶(Hrp)来模拟GPx。
1)酶活性评定、光谱和分子模拟的研究结果表明,AAP可以通过氢键和范德华力自发地跟Cu/ZnSOD结合,形成AAP-Cu/ZnSOD结合物,AAP结合在Cu/ZnSOD两个子域的交界面上。AAP诱发了Cu/ZnSOD二级结构发生改变,导致Cu/ZnSOD骨架松散,内部疏水性的多肽链对水的暴露增加,影响了活性位点的微环境,从而对Cu/ZnSOD酶活性产生了抑制作用。
2)光谱实验和分子模拟的研究结果表明,带正电的AAP可以通过静电作用自发的与带负电的过氧化氢酶(CAT)以1：1的比例结合在CAT中心疏水腔内。CAT的微环境和空间结构受到AAP的影响,导致CAT骨架结构松散,从而影响了CAT活性位点的微环境,造成了血红细胞中CAT酶活性的抑制作用。
3)利用荧光、紫外-可见、同步荧光和圆二色谱等技术研究了AAP和辣根过氧化物酶(Hrp)的作用机理,考察了二者的结合参数(结合常数、结合位点数、热力学常数和结合力类型)以及AAP对Hrp空间结构的影响。AAP和Hrp具有较强的相互作用,并且通过静电作用以1：1的比例结合,AAP导致了Hrp微环境、二级结构和构象发生变化,造成Hrp的空间结构松散。
动物和分子水平上的研究结果表明,抗氧化酶活性受到三方面因素的影响,第一,AAP与抗氧化酶二者间直接结合作用会对抗氧化酶活性产生抑制作用；第二,组织发生氧化应激时,抗氧化酶处于ROS大量表达的环境中,直接催化分解ROS的抗氧化酶的酶促反应底物含量增大,这将有刺激抗氧化酶数量增加的趋势；第三,AAP急性染毒会对抗氧化酶的含量产生影响。这三个因素影响的相对大小,最终决定了在动物实验中抗氧化酶酶活性的表观变化情况。
第六章最后对论文的各研究部分进行了总结,分析了本研究中AAP氧化应激效应评价方法的优势与不足,展望了该领域的发展方向。本研究从分子、细胞和动物整体实验的角度较系统、全面地提供了AAP诱发机体氧化应激效应的评价结果,丰富了环境污染物诱发氧化应激效应的评价方法,有助于人们从分子水平了解环境污染物的致病机理和全面评价污染物毒性,为相关疾病的早期诊断、预防和治疗提供了参考和判定依据。
The pollutions caused by residues of drug and drug inermediates pose a threat to the eco-environmental safety and human health. As a raw material or intermediate,4-aminoantipyrine (AAP) has been widely used in the production of analgesic, anti-inflammatory, antibacterial drugs. Moreover, AAP can cause side effects, such as agranulocytosis. Thus, AAP has become an environmental pollutant exposed in the environment.
Many studies have shown that oxidative stress is related with all diseases. The hazards of environmental pollutants on organisms are related with oxidative stress. In the process of oxidative stress, reactive oxygen species (ROS) in vivo largely express, participate in and promote the progression of many diseases, cause oxidative damages of biological macromolecules such as DNA/RNA, proteins and lipids, further lead to metabolic disorders of the body and cause diseases. Therefore, the evaluation of toxic effects of environmental pollutants from the point of view of oxidative stress will help people to understand the pathogenesis of environmental pollutants and evaluate on pollutant toxicity comprehensively. That can provide a scientific basis for early diagnosis, prevention and treatment of related diseases.
This thesis has a background in environmental toxicology and modern instrumental analytical science. We studied the oxidative stress effects of AAP and its mechanism from three levels of experimental animals, single cell and protein macromolecules. This thesis includes the following five sections:
In the first chapter, the characteristics and applications of AAP were described. The research progress of toxic effects of AAP was overviewed. The compositions and characteristics of ROS and antioxidant system were introduced. The inducing factors of environmental oxidative stress were reviewed. The relationships of oxidative stress and diseases were summarized. The analysis and evaluation methods of oxidative stress in environmental toxicology were summarized.
In the second chaper, the zebrafish was used as the research target. Acute exposure experiments were carried out from experimental animal level. The AAP-induced half lethal concentration (LC50-24h) was determined. We investigated the effects of AAP on antioxidant system and oxidative damages in zebrafish liver and evaluated on the oxidative stress effects of AAP. The results showed that AAP caused an increase in CAT and GPx activities, a decrease in GR and GST activities and SOD activity did not change significantly. AAP also led to a significant reduction in GSH content, a increase in GSSG content and a significantly decrease in the ratio of GSH/GSSG. The redox equilibrium of liver tissue was broken, indicating that oxidative stress was formed. MDA content gradually increased, indicating that the product of oxidative damage (LOP) increased. The progress resulted in oxidative damages of adipose tissue.
In the third chapter, we used human erythrocytes as research targets. The erythrocytes were exposed by AAP in vitro. We investigated the effects of AAP on GSH contents in single human erythrocytes from single cell level and evaluated on the oxidative stress effects of AAP. When cells were exposed in low AAP concentration, although the GSH average content was not significant changed, the single-cell analysis revealed that the cells of low GSH contents began to appear. When the AAP concentration increased, AAP had a significant impact on the GSH content. The number of cells with low GSH content increased. GSH contents reduced up to14.53%. GSH depletion induced the internal environmente of erythrocytes changed into oxidized state.
In the fourth chapter, we used transport proteins in the blood (BSA and BHb) as research targets. The interactions of AAP and transport proteins were investigated from protein macromolecule level. The transmission and distribution of pollutants in the body was determined by the binding of pollutants and transport proteins. Based on multi-spectroscopy and molecular simulation techniques, we established the binding model and investigated the binding mechanisms.
1) By using spectroscopy and molecular modeling methods, the interaction between AAP and BSA was investigated in simulated physiological conditions. The results showed that BSA was quenched by AAP significantly through a static quenching mechanism. There was a strong interaction between AAP and BSA. The positively charged AAP can spontaneously bind with the negatively charged region of BSA through electrostatic forces. AAP bound to BSA on the subdomain ⅢA. The microenrironment and conformation of BSA were demonstrably changed in the presence of AAP.
2) With multiple spectroscopic techniques including fluorescence spectra, synchronous fluorescence spectra, UV-vis absorption spectra and CD spectra, the interaction mechanism of AAP and BHb was investigated. The results showed that there was a strong interaction between AAP and BHb. AAP bound to BHb through van der Waals interactions and hydrogen bonds with approximately one binding site. The microenvironment of BHb was changed by AAP and the skeletal structure of BHb loosened.
In the fifth chapter, we selected three kinds of oxidative stress directly related enzymes (SOD, CAT and Hrp) as research targets. Based on spectroscopy and molecular modeling techniques, the mechanism of toxic effects of AAP on antioxidative enzymes was researched from molecular level. Since GPx was expensive and difficult to save, we used Hrp to simulate the GPx.
1) The results of spectroscopic, molecular docking and enzyme activity assessment methods showed that AAP can spontaneously bind with Cu/ZnSOD to form AAP-Cu/ZnSOD complex with one binding site mainly through hydrogen bond and van der Waals forces. AAP bound into the Cu/ZnSOD interface of two subdomains. AAP triggered changes in the secondary structure of Cu/ZnSOD. The skeleton structure of Cu/ZnSOD loosened, exposing internal hydrophobic peptide strands to the solution. As the binding of AAP influenced the microenvironment of the activity sites, AAP led to the inhibition of Cu/ZnSOD activity.
2) On the basis of spectroscopic and molecular docking results, the positively charged AAP can spontaneously bound with the negatively charged CAT with one binding site mainly through electrostatic forces. The results of molecular docking simulation revealed that AAP bound into CAT central cavity. AAP triggered changes in the microenvironment and conformation of CAT. The skeleton structure of CAT loosened, exposing internal hydrophobic peptide strands to the solution. As the binding of AAP influenced the microenvironment of the activity sites, AAP led to the inhibition of CAT activity.
3) The interaction mechanism of AAP and Hrp was investigated by multiple spectroscopic techniques including fluorescence spectra, synchronous fluorescence spectra, UV-vis absorption spectra and CD spectra. We studied the binding parameters (association constants, number of binding sites, thermodynamic parameters and binding forces) of the interaction and the effect of AAP on the conformation of Hrp. There was a strong interaction between AAP and Hrp. AAP bound to Hrp through electrostatic forces with approximately one binding site. The microenvironment, secondary tructure and conformation of Hrp was changed by AAP and the skeletal structure of Hrp loosened.
The research results from animal and molecular level showed that antioxidant enzyme activities were affected by two factors. First of all, the direct binding of the AAP and antioxidant enzymes would inhibit the antioxidant enzyme activities. Second, when oxidative stress was generated in tissue, antioxidant enzymes were in the environment of excessive expressed ROS. The substrate content in the catalytic reaction of antioxidant enzymes increased, which would stimulate antioxidant enzyme activity to increase. Third, AAP acute exposure would have an impact on antioxidant enzyme contents. The relative influence degree of these three factors finally determined the apparent changes of the antioxidant enzyme activities in animal experiments.
In sixth chapter, finally, each section of the thesis was summarized. We analyzed the advantages and disadvantages of the evaluation method of oxidative stress induced by AAP in this thesis and discussed the future development of the field. The study provided more systematic and comprehensive evaluation results of AAP-induced oxidative stress effects from the perspective of molecular, cellular and experimental animal levels. This research has enriched the research on the evaluation method of oxidative stress effects of environmental pollutants, provided some reference gists for the toxicities and pathogenesis of environmental pollutantst.
引文
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