天然产物抗氧化组分的毛细管电泳-化学发光法筛选与评价
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摘要
随着自由基生物学的发展和分子生物学技术的应用,有关人体病变的自由基理论的研究在过去10年间取得了令人信服的进展,而具有清除自由基能力的抗氧化剂的研究也日益成为热点。由于合成抗氧化剂多具有毒副作用,含有抗氧化组分的天然产物以其低毒、高效、价廉的优势逐渐受到研究者的重视。但天然产物为多组分复杂基体,对其所含组分展开逐一筛选和评价无法通过传统的抗氧化剂研究方法得以实现。毛细管电泳(CE)-化学发光(CL)联用模式是近年来提出的针对复杂体系各组分进行抗氧化活性在线评价的新方法,其原理是将自由基氧化发光试剂的反应体系与CE技术耦合,通过抗氧化剂对自由基的清除造成发光被抑制从而实现检测。然而CE-CL方法目前仅被用于少量抗氧化剂标准化合物混合假体系的评价,并未对天然产物真实体系展开广泛探索。本研究针对天然产物抗氧化组分缺乏系统研究的现状,以CE-CL联用方法为手段,不仅对抗氧化组分进行在线筛选与活性表征,还建立了抗氧化生物指纹图谱用于天然产物的质量控制,更对抗氧化组分的血浆蛋白结合率、脂水分配系数等药效药动学参数进行了探究。
本论文由两部分构成:
第一部分(第2章),构建了CE-CL联用仪器,以luminol为化学发光试剂,对NaClO-H_2O_2、Cu~(2+)-H_2O_2两个自由基体系用作CE柱后检测的最佳CL条件进行了优化,以苦参碱和氧化苦参碱为研究对象,对在线定量评价抗氧化剂的方法进行了探讨,并结合荧光光谱法,验证了CE-CL系统和采用的发光体系在抗氧化剂筛选及活性评价方面的可行性及可靠性。
第二部分(第3、4、5章),在第2章获得的两个自由基体系最佳发光条件下,对含有生物碱类、黄酮类、醌类、酚酸类化合物的天然产物中的抗氧组分进行了研究。
第3章,对麻黄、苦参、黄连、黄柏、贝母5种富含生物碱类化合物的天然产物进行了抗氧化组分的在线筛选,以相对自由基清除率为指标,对抗氧化组分的分布信息进行了探讨,获得这5种天然产物中,苦参含有的抗氧化组分种类最多并且活性最强,其余依次是黄柏、麻黄、黄连和贝母。并进一步通过平衡透析法,对5种天然产物提取物与血浆蛋白的结合作用进行了研究,获得了麻黄提取物中麻黄碱与血浆蛋白的结合率。
第4章,以富含多种黄酮类化合物的中药黄芪为对象,对内蒙古、安徽、东北、福建、山西、广西、浙江、河南8个产地黄芪中抗氧化组分的种类及活性的相似度进行了比较,通过构建黄芪的抗氧化生物指纹图谱,达到了以药效为指标对中药进行质量控制的目的。此外,通过对黄芪注射液抗氧化成分分析,对中药材制剂加工过程的质量控制进行了初步探索。
第5章,以含有醌类及酚酸类化合物的中药丹参为研究对象,采用MEEKC-CL的方法,实现了丹参提取物中脂溶性、水溶性抗氧化成分的同时分析,并对部分组分的脂水分配系数进行了测算,获得丹参主要有效成分丹参酮ⅡA和丹酚酸B的log Pow值分别为2.013和1.630。
研究结果表明,CE-CL联用模式不仅可用于多组分复杂体系中抗氧化剂的在线筛选与评价,基于此模式还可展开组分的药效学、药动学参数测算,可为天然产物开发、质量控制、药理研究提供基础参数。
Reactive oxygen species (ROS) are commonly involved in many oxidative chain reactions in organisms related to the life processes. Researches on the ROS and antioxidants are recently being a focus with the development of free radical biology and preventive medicine. Synthetic antioxidants usually have various side effects, thus, there is a growing tendency to replace synthetic antioxidants by those from natural resources of low toxicity and high efficiency. But there are several deficiencies in the evaluation of antioxidants in hebral medicines by traditional methods, which didn’t combine with separation techniques. Capillary electrophoresis (CE) coupled with chemiluminescence (CL) detection was proposed recently for on-line screening and evaluation of antioxidants from complex matrix, which depended on the principal of luminol-ROS reaction. However, this CE-CL method was limited to the analysis of only few standard compounds.
In this thesis, the CE-CL method was used for the systemic assessment of various kinds of herbal medicines containing antioxidative components, especially aimed at obtaining some pharmacodynamic and pharmacokinetic parameters of antioxidants in herbal medicines for pharmaceutical exploitation and clinical application. The main research work and obtained results are as follow:
1. A CE coupled with CL detection system was designed and established based on a CE-CL interface. The applicability of developed CE-CL system for antioxidants assessment was examined by employing the luminol oxidation assay. Two types of ROS system including singlet oxygen (~1O_2) and hydroxyl radical (·OH) were respectively investigated to achieve constant CL condition. Under optimum CL conditions, the antioxidative activity of matrine and oxymatrine against ~1O_2 and·OH were evaluated, the IC50 was introduced to determine the ROS scavenging capacity of compounds. Furthermore, fluorospectrophotometry as an auxiliary measurement was applied to examine the reliability of results obtained by CE-CL system.
2. The proposed CE-CL system was used to screen the antioxidants in five representative herbal medicines with alkaloids as major components, including Herba Ephedrae, Radix Sophorae Flavescentis, Rhizoma Coptidis, Cortex Phellodendri Chinensis, and Bulbus Fritillariae Cirrhosae, under the optimum conditions by employing the ~1O_2 system. The distribution and activity differences of antioxidants in herbal medicines were revealed by the calculation of relative ROS scavenging ratios. Furthermore, plasma protein binding effects of extracts from herbal medicines was studied by employing equilibrium dialysis.
3. The CE-CL method was used to establish novel antioxidative biological fingerprints. The repeatability and reproducibility of Radix Astragalus from 8 different regions were investigated, and the similarities in scavenging·OH of samples were calculated. Based on the curvilinear equation between concentrations and scavenging ratios for·OH of astragaloside, the content of astragaloside in Radix Astragalus was determined. Furthermore, the antioxidants in Radix Astragalus injection were examined for quality control in pharmaceutical engineering.
4. Microemulsion was introduced to realize the combination of microemulsion electrokinetic chromatography (MEEKC) with CL detection, as to improve the on-line assessment of antioxidants, especially those of lipid-solubility. Four types of microemulsion constructed with different surfactants including SDS, Tween-80, Tx-100, and Np-40 were separately investigated on their application in CE-CL. The extracts from Radix et Rhizoma Salviae Miltiorrhizae were analyed under optimum conditions, and the log Pow values of some antioxidants in Radix et Rhizoma Salviae Miltiorrhizae were caculated.
The methodology may be further developed by improving CE-CL interface and employing some enzyme reactions to genarate ROS for the evaluation of more antioxidative herbal medicines.
本论文由两部分构成:
第一部分(第2章),构建了CE-CL联用仪器,以luminol为化学发光试剂,对NaClO-H_2O_2、Cu~(2+)-H_2O_2两个自由基体系用作CE柱后检测的最佳CL条件进行了优化,以苦参碱和氧化苦参碱为研究对象,对在线定量评价抗氧化剂的方法进行了探讨,并结合荧光光谱法,验证了CE-CL系统和采用的发光体系在抗氧化剂筛选及活性评价方面的可行性及可靠性。
第二部分(第3、4、5章),在第2章获得的两个自由基体系最佳发光条件下,对含有生物碱类、黄酮类、醌类、酚酸类化合物的天然产物中的抗氧组分进行了研究。
第3章,对麻黄、苦参、黄连、黄柏、贝母5种富含生物碱类化合物的天然产物进行了抗氧化组分的在线筛选,以相对自由基清除率为指标,对抗氧化组分的分布信息进行了探讨,获得这5种天然产物中,苦参含有的抗氧化组分种类最多并且活性最强,其余依次是黄柏、麻黄、黄连和贝母。并进一步通过平衡透析法,对5种天然产物提取物与血浆蛋白的结合作用进行了研究,获得了麻黄提取物中麻黄碱与血浆蛋白的结合率。
第4章,以富含多种黄酮类化合物的中药黄芪为对象,对内蒙古、安徽、东北、福建、山西、广西、浙江、河南8个产地黄芪中抗氧化组分的种类及活性的相似度进行了比较,通过构建黄芪的抗氧化生物指纹图谱,达到了以药效为指标对中药进行质量控制的目的。此外,通过对黄芪注射液抗氧化成分分析,对中药材制剂加工过程的质量控制进行了初步探索。
第5章,以含有醌类及酚酸类化合物的中药丹参为研究对象,采用MEEKC-CL的方法,实现了丹参提取物中脂溶性、水溶性抗氧化成分的同时分析,并对部分组分的脂水分配系数进行了测算,获得丹参主要有效成分丹参酮ⅡA和丹酚酸B的log Pow值分别为2.013和1.630。
研究结果表明,CE-CL联用模式不仅可用于多组分复杂体系中抗氧化剂的在线筛选与评价,基于此模式还可展开组分的药效学、药动学参数测算,可为天然产物开发、质量控制、药理研究提供基础参数。
Reactive oxygen species (ROS) are commonly involved in many oxidative chain reactions in organisms related to the life processes. Researches on the ROS and antioxidants are recently being a focus with the development of free radical biology and preventive medicine. Synthetic antioxidants usually have various side effects, thus, there is a growing tendency to replace synthetic antioxidants by those from natural resources of low toxicity and high efficiency. But there are several deficiencies in the evaluation of antioxidants in hebral medicines by traditional methods, which didn’t combine with separation techniques. Capillary electrophoresis (CE) coupled with chemiluminescence (CL) detection was proposed recently for on-line screening and evaluation of antioxidants from complex matrix, which depended on the principal of luminol-ROS reaction. However, this CE-CL method was limited to the analysis of only few standard compounds.
In this thesis, the CE-CL method was used for the systemic assessment of various kinds of herbal medicines containing antioxidative components, especially aimed at obtaining some pharmacodynamic and pharmacokinetic parameters of antioxidants in herbal medicines for pharmaceutical exploitation and clinical application. The main research work and obtained results are as follow:
1. A CE coupled with CL detection system was designed and established based on a CE-CL interface. The applicability of developed CE-CL system for antioxidants assessment was examined by employing the luminol oxidation assay. Two types of ROS system including singlet oxygen (~1O_2) and hydroxyl radical (·OH) were respectively investigated to achieve constant CL condition. Under optimum CL conditions, the antioxidative activity of matrine and oxymatrine against ~1O_2 and·OH were evaluated, the IC50 was introduced to determine the ROS scavenging capacity of compounds. Furthermore, fluorospectrophotometry as an auxiliary measurement was applied to examine the reliability of results obtained by CE-CL system.
2. The proposed CE-CL system was used to screen the antioxidants in five representative herbal medicines with alkaloids as major components, including Herba Ephedrae, Radix Sophorae Flavescentis, Rhizoma Coptidis, Cortex Phellodendri Chinensis, and Bulbus Fritillariae Cirrhosae, under the optimum conditions by employing the ~1O_2 system. The distribution and activity differences of antioxidants in herbal medicines were revealed by the calculation of relative ROS scavenging ratios. Furthermore, plasma protein binding effects of extracts from herbal medicines was studied by employing equilibrium dialysis.
3. The CE-CL method was used to establish novel antioxidative biological fingerprints. The repeatability and reproducibility of Radix Astragalus from 8 different regions were investigated, and the similarities in scavenging·OH of samples were calculated. Based on the curvilinear equation between concentrations and scavenging ratios for·OH of astragaloside, the content of astragaloside in Radix Astragalus was determined. Furthermore, the antioxidants in Radix Astragalus injection were examined for quality control in pharmaceutical engineering.
4. Microemulsion was introduced to realize the combination of microemulsion electrokinetic chromatography (MEEKC) with CL detection, as to improve the on-line assessment of antioxidants, especially those of lipid-solubility. Four types of microemulsion constructed with different surfactants including SDS, Tween-80, Tx-100, and Np-40 were separately investigated on their application in CE-CL. The extracts from Radix et Rhizoma Salviae Miltiorrhizae were analyed under optimum conditions, and the log Pow values of some antioxidants in Radix et Rhizoma Salviae Miltiorrhizae were caculated.
The methodology may be further developed by improving CE-CL interface and employing some enzyme reactions to genarate ROS for the evaluation of more antioxidative herbal medicines.
引文
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