DNA氧化损伤标记物8-羟基脱氧鸟苷的毛细管电泳安培检测方法研究
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摘要
毛细管电泳是上世纪80年代建立并迅速发展起来的一种新型分离分析技术,具有分离效率高、分析速度快、重现性好及样品用量少等特点,已广泛应用于化学、生命科学、药物和环境分析等领域。
研究表明,活性氧自由基(reactive oxygen species,ROS)如O_2~(-·)、O~(-·)、HO_2~·、~·OH、H_2O_2、RO~·、ROO~·等可导致DNA氧化损伤,这与衰老、肿瘤的发生、恶变以及糖尿病和心血管疾病等密切相关。在二十多种DNA氧化损伤产物中,8-羟基脱氧鸟苷(8-hydroxy-2'-deoxyguanosine,8-OHdG)被公认为是最重要的标志物之一。它与DNA复制与修复过程中,导致鸟嘌呤与胞嘧啶及腺嘌呤与胸腺嘧啶发生错位(G:C→A:T),碱基脱落及DNA链断裂,诱发DNA点突变有关。8-OHdG将是一种很好的评价致突变和癌变危险的标记物。由于尿中的8-OHdG不能被进一步代谢,因此尿中8-OHdG对评价个体癌变危险或诊断与氧自由基相关疾病方面是一种很有用的标记物,在临床上具有很高的应用价值和推广意义。
要将8-OHdG作为肿瘤标记物用于临床常规诊断,首先要建立一种分析速度快、分离效率高、灵敏度高、选择性好、价廉、易商品化、可用于常规分离检测8-OHdG的方法。本论文的主要工作就是发展了一种基于分子印迹萃取、毛细管电泳-安培检测(capillary electrophoresis-amperometric detection,CE-AD)联用方法。利用一步分子印记固相微萃取预处理尿样,结合毛细管在柱富集技术——动态pH调节进样(dynamic pHjunction),进一步提高了方法的灵敏度,使其检测限达到2.6 nmol/L(S/N=3);8-OHdG浓度在10 nmol/L～1.5μmol/L浓度范围内与其峰面积呈现良好的线性关系(R=0.9999);迁移时间和峰面积的相对标准偏差分别为1.1%和4.0%,尿样的加标回收率为85.1%。论文中详细讨论了分离电压、检测电位、缓冲液浓度及pH值等因素对分析的影响,确定了最优化的分离检测条件。本方法具有简单、灵敏而高效的特点,并已用于健康人和癌症患者尿中8-OHdG水平的评价,结果令人满意。
论文的另外一部分工作是研究了两种毛细管电泳在柱富集方法(场放大样品堆积和碱堆积)在测定8-OHdG中的应用。论文中详细讨论了两种技术的富集原理,以及各种实验条件对分离检测的影响。在优化的条件下,两种方法对8-OHdG的富集均可以达到20倍。
Capillary electrophoresis(CE) is a new-style separation technique which was established and quickly developed in the early 1980's.Nowadays,CE has been widely used in the fields of chemistry,life science,pharmaceutics,environment analysis and so on,due to its charming advantages of high separation efficiency,short analytical time,good resolution,and small requirements for samples.
Reactive oxygen species(ROS),such us Superoxide(O_2~(-·))、hydroxyl radical(~·OH)、hydrogen peroxide(H_2O_2) and so on can lead to DNA oxidative damage,which has been considered to be important contributor to aging,cancer and other age-related degenerative processes.Of about 20 known adducts of oxidative DNA damage,8-OHdG has aroused considerable attention because of its demonstrated mutagenic potential,which has been shown to induce mainly G:C→T:A transversion.Currently,the pre-mutagenic 8-OHdG modification is considered to be an excellent marker for oxidative DNA damage.8-OHdG are excreted into urine without further metabolism,thus determination of urinary 8-OHdG has been proposed as a noninvasive assay of in vivo oxidative DNA damage and diagnosis of cancer early.Until now,8-OHdG mostly has been used as a biomarker of mutagenesis and carcinogenesis of chemical.
A number of aging-related degenerative disease,especially cancer,are threatening human's health now.Therefore,fast、sensitive and simple-to-use methods for determination of urinary 8-OHdG as a biomarker to diagnose cancer early,are needed.In this thesis,a method for detection of urinary 8-OHdG was developed,based on capillary zone electrophoresis with end-column amperometric detection(CE-AD).Using single-step solid phase extraction with molecular imprinting for urine pretreatment and a sample focusing mode-dynamic pH junction injection for increasing sensitivity,the limit of detection of the method was 2.6 nmol/L for 8-OHdG at the signal-to-noise ratio of 3.The linear relationship between the peak area and the concentration of 8-OHdG is exhibited over the range from 10 nmol/L to 1.5μmol/L(R=0.9999).The precision obtained in R.S.D.was 1.1%for migration time and 4.0%for peak area,the spiked recovery of the urinary 8-OHdG was 85.1%.In order to achieve optimum condition,the effects of different factors including separation voltage, detection potential,buffer concentration and pH values,were investigated in detail.The optimized method shows good reproducibility,high sensitivity and simplicity,and has been applied to evaluate urinary 8-OHdG in healthy persons and cancer patients with satisfactory results.
In the second part of the thesis,two modes of sample pre-concentration on column (field-enhanced sample stacking and base stacking) for enhancing the detection sensitivity of 8-OHdG by capillary electrophoresis were studied.The principles,characteristics of the two sample on-line pre-concentration techniques,and the effects of different factors were investigated in detail.Under the optimum conditions,the detection sensitivitys of 8-OHdG using two methods above were both enhanced approximately 20 times.
研究表明,活性氧自由基(reactive oxygen species,ROS)如O_2~(-·)、O~(-·)、HO_2~·、~·OH、H_2O_2、RO~·、ROO~·等可导致DNA氧化损伤,这与衰老、肿瘤的发生、恶变以及糖尿病和心血管疾病等密切相关。在二十多种DNA氧化损伤产物中,8-羟基脱氧鸟苷(8-hydroxy-2'-deoxyguanosine,8-OHdG)被公认为是最重要的标志物之一。它与DNA复制与修复过程中,导致鸟嘌呤与胞嘧啶及腺嘌呤与胸腺嘧啶发生错位(G:C→A:T),碱基脱落及DNA链断裂,诱发DNA点突变有关。8-OHdG将是一种很好的评价致突变和癌变危险的标记物。由于尿中的8-OHdG不能被进一步代谢,因此尿中8-OHdG对评价个体癌变危险或诊断与氧自由基相关疾病方面是一种很有用的标记物,在临床上具有很高的应用价值和推广意义。
要将8-OHdG作为肿瘤标记物用于临床常规诊断,首先要建立一种分析速度快、分离效率高、灵敏度高、选择性好、价廉、易商品化、可用于常规分离检测8-OHdG的方法。本论文的主要工作就是发展了一种基于分子印迹萃取、毛细管电泳-安培检测(capillary electrophoresis-amperometric detection,CE-AD)联用方法。利用一步分子印记固相微萃取预处理尿样,结合毛细管在柱富集技术——动态pH调节进样(dynamic pHjunction),进一步提高了方法的灵敏度,使其检测限达到2.6 nmol/L(S/N=3);8-OHdG浓度在10 nmol/L～1.5μmol/L浓度范围内与其峰面积呈现良好的线性关系(R=0.9999);迁移时间和峰面积的相对标准偏差分别为1.1%和4.0%,尿样的加标回收率为85.1%。论文中详细讨论了分离电压、检测电位、缓冲液浓度及pH值等因素对分析的影响,确定了最优化的分离检测条件。本方法具有简单、灵敏而高效的特点,并已用于健康人和癌症患者尿中8-OHdG水平的评价,结果令人满意。
论文的另外一部分工作是研究了两种毛细管电泳在柱富集方法(场放大样品堆积和碱堆积)在测定8-OHdG中的应用。论文中详细讨论了两种技术的富集原理,以及各种实验条件对分离检测的影响。在优化的条件下,两种方法对8-OHdG的富集均可以达到20倍。
Capillary electrophoresis(CE) is a new-style separation technique which was established and quickly developed in the early 1980's.Nowadays,CE has been widely used in the fields of chemistry,life science,pharmaceutics,environment analysis and so on,due to its charming advantages of high separation efficiency,short analytical time,good resolution,and small requirements for samples.
Reactive oxygen species(ROS),such us Superoxide(O_2~(-·))、hydroxyl radical(~·OH)、hydrogen peroxide(H_2O_2) and so on can lead to DNA oxidative damage,which has been considered to be important contributor to aging,cancer and other age-related degenerative processes.Of about 20 known adducts of oxidative DNA damage,8-OHdG has aroused considerable attention because of its demonstrated mutagenic potential,which has been shown to induce mainly G:C→T:A transversion.Currently,the pre-mutagenic 8-OHdG modification is considered to be an excellent marker for oxidative DNA damage.8-OHdG are excreted into urine without further metabolism,thus determination of urinary 8-OHdG has been proposed as a noninvasive assay of in vivo oxidative DNA damage and diagnosis of cancer early.Until now,8-OHdG mostly has been used as a biomarker of mutagenesis and carcinogenesis of chemical.
A number of aging-related degenerative disease,especially cancer,are threatening human's health now.Therefore,fast、sensitive and simple-to-use methods for determination of urinary 8-OHdG as a biomarker to diagnose cancer early,are needed.In this thesis,a method for detection of urinary 8-OHdG was developed,based on capillary zone electrophoresis with end-column amperometric detection(CE-AD).Using single-step solid phase extraction with molecular imprinting for urine pretreatment and a sample focusing mode-dynamic pH junction injection for increasing sensitivity,the limit of detection of the method was 2.6 nmol/L for 8-OHdG at the signal-to-noise ratio of 3.The linear relationship between the peak area and the concentration of 8-OHdG is exhibited over the range from 10 nmol/L to 1.5μmol/L(R=0.9999).The precision obtained in R.S.D.was 1.1%for migration time and 4.0%for peak area,the spiked recovery of the urinary 8-OHdG was 85.1%.In order to achieve optimum condition,the effects of different factors including separation voltage, detection potential,buffer concentration and pH values,were investigated in detail.The optimized method shows good reproducibility,high sensitivity and simplicity,and has been applied to evaluate urinary 8-OHdG in healthy persons and cancer patients with satisfactory results.
In the second part of the thesis,two modes of sample pre-concentration on column (field-enhanced sample stacking and base stacking) for enhancing the detection sensitivity of 8-OHdG by capillary electrophoresis were studied.The principles,characteristics of the two sample on-line pre-concentration techniques,and the effects of different factors were investigated in detail.Under the optimum conditions,the detection sensitivitys of 8-OHdG using two methods above were both enhanced approximately 20 times.
引文
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