中药复杂成分样品的电喷雾质谱分析方法研究
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摘要
基于电喷雾质谱快速、灵敏、准确以及能与其它检测手段联合应用于物质分析的特点,使其在中药分析领域的应用越来越广,然而由于中药中成分众多,造成样品在检测的过程中干扰较大,灵敏度较低,甚至部分成分难以进行检测或区分。此外中药协同作用的原理要求中药分析要尽可能检测更多的指标成分,提供更多维的信息,大大提高了对中药成分分析的要求,给电喷雾质谱在中药成分分析中的应用增加了难度。在实际研究中主要遇到以下困难:
中药及其体内样品复杂成分鉴定(无对照品的成分难于鉴定)
中药代谢产物指纹图谱检测
中药同分异构成分区分(碎裂途径相似的同分异构成分难于区分)
中药部分成分质谱响应困难
针对上述难题本论文展开以下研究:
1中药延胡索复杂成分质谱鉴定方法
本部分以中药延胡索为例,对中药复杂成分的质谱鉴定方法进行探讨,建立延胡索中生物碱成分在电喷雾质谱下的鉴定方法,并以此为基础对其在血浆中的原型成分和代谢产物进行分析。基于生物合成规律,在无对照品情况下,通过对复杂成分样品的质谱分析,鉴定了延胡索甲素、四氢黄连碱、坎那定、别隐片碱、黄连碱、小檗碱等14种生物碱成分,并对延胡索中一种新的生物碱结构进行推测。以此为基础,在无对照品的条件下,对其在血浆中原型成分和代谢产物进行分析,检测到14种移行成分,其中原形10种,代谢产物4种,主要的代谢途径为氢化和水合等还原反应。该方法简化了中药化学成分分析鉴定的过程,在中药物质基础研究中具有广泛的应用价值。
本部分首次对延胡索中四种不同类型生物碱的裂解途径的区别进行了系统的总结,在对延胡索甲素裂解途径的研究中,发现一种RDA裂解的新方式,该裂解不仅可以发生在该化合物的C环上,也可通过重排和电子转移使B环发生裂解,形成互补的碎片离子,为通过RDA裂解鉴定部分四氢原小檗碱型生物碱提供了新的指标。
2中药枳壳代谢产物质谱指纹图谱检测方法研究
本部分以中药枳壳为例,探讨其主要成分在大鼠尿样中代谢产物的指纹图谱检测方法进行研究。以电喷雾多级质谱技术为基础,依据质谱裂解行为和代谢特征相结合获取双重信息的研究思路,对大鼠灌服枳壳提取液后的尿液进行系统研究。鉴定了21种代谢产物,这些代谢产物主要来自于枳壳中的黄酮二糖苷类成分,主要的代谢途径是:水解、葡萄糖醛酸化、磺酸化以及环开裂氢化等。
在对代谢产物进行结构分析的基础上,为更好地反映不同类型代谢产物在不同时间段浓度的变化情况及相互关系,对枳壳中黄酮二糖苷类成分在大鼠尿液中代谢产物指纹图谱进行了系统研究。采用多离子选择监控模式(MRM),通过设立11个不同的区段,以各个代谢产物的分子量及主要碎片离子的双重信息为检测目标,在MRM模式下对大鼠口服枳壳后0-3、3-6、6-9、9-12、12-24h的尿液进行检测,提供了大鼠在24小时5个时间段的代谢产物指纹图谱,揭示了枳壳中黄酮二糖苷类成分在体内先水解成苷元再发生葡萄糖醛酸化和磺酸化反应的主要代谢途径。
3香豆素及黄酮苷类同分异构成分质谱区分方法
同分异构体的区分一直是质谱在中药复杂成分分析中的难题,尤其是碎裂途径相似的同分异构体,常规的质谱检测方法往往难以区分。本章通过比较主要碎片离子的相对强度,区分了四对碎裂途径相似的同分异构体:补骨脂素和异补骨脂素、欧前胡素和异欧前胡素(香豆素)、橙皮苷和新橙皮苷、柚皮苷和柚皮芸香苷(黄酮苷)。与常规的质谱区分方法不同,本文以结构的差别为线索,通过对产生相对丰度变化的碎裂机理进行深入研究,从而达到区分的目的。通过比较失去2CO和CO_2形成的碎片离子相对丰度实现了两类呋喃香豆素类成分的区分。通过比较糖裂环产生的碎片离子相对丰度区分了黄酮二糖苷类同分异构体,并对该方法在不同碎裂条件和中药复杂体系中的稳定性进行了研究。该方法简便准确,适用于中药复杂体系中同分异构成分的分析鉴定。
4中药难检测成分衍生化方法
本部分主要针对中药中低极性成分和低分子量成分进行研究,分别通过衍生上易离子化基团和增加分子量的方法解决它们在质谱检测中的困难。
难电离成分的衍生:对低极性成分采用衍生上易离子化基团的办法使其得以检测,从而解决这类成分在检测上的难题。以龙脑,薯蓣皂苷元,胆固醇三种低极性的化学成分为例,通过磺酸化(负离子模式检测)和苯甲酰化(正离子模式检测)两种方法对这几种难电离成分进行衍生,并对复方制剂丹参滴丸及龙脑对大鼠灌胃1h后的血浆样品进行磺酸衍生化,结果表明复杂的中药样品体系并未影响衍生化结果。
糖类的衍生:电喷雾质谱在低端的干扰较大,这使分子量小的各种单糖在质谱检测中比较困难。采用PMP法对六种单糖进行衍生,使衍生后的结构分子量增加,从而易于检测,并对六种单糖衍生结构的裂解途径进行总结,从而通过保留时间,碎片离子,分子量三重信息实现对单糖的结构鉴定,有利于增加单糖鉴别试验的准确性。此外,在区分单糖衍生结构的同分异构成分中,本部分延续了第四章利用碎片离子相对丰度区分同分异构体的研究思路,通过比较衍生结构失水后碎片离子相对丰度的方法,对单糖衍生结构中的同分异构成分达到了很好的区分效果。
本文创新点
本论文主要创新性研究成果如下:
1.以延胡索为例,建立了中药化学成分的质谱鉴定方法。在没有对照品条件下,从成分复杂的样品中鉴定了延胡索甲素、四氢黄连碱、坎那定、别隐片碱、黄连碱、小檗碱等生物碱成分,并对延胡索中血浆中的移行成进行分析鉴定。这种方法在中药物质基础研究中具有应用价值。
2.首次通过电喷雾质谱技术,对枳壳在大鼠尿液中的代谢产物指纹图谱进行研究,提供了枳壳在大鼠尿液中不同时间段的代谢产物指纹图谱。结果表明能较好的反应枳壳活性成分在体内的变化过程。为解决中药代谢产物指纹图谱研究中出现的干扰成分过多的问题提供参考。
3.通过对碎片离子相对丰度的比较,建立了中药中同分异构成分的质谱区分方法。利用该方法可对香豆素和黄酮苷两类裂解途径相似的同分异构成分进行有效的区分。与其它方法相比,通过相对丰度的比较可以更为简便地区分同分异构体。对于解决中药同分异构成分的质谱区分问题提供新的研究思路与方法。
以上研究成果发表5篇论文,其中包括一篇SCI收录。
Mass spectrometry is an important instrument in the modern analysis of Traditional Chinese Medicine(TCM).In particularly,the development of electrospray ionization(ESI) source enhances the ionization ability,and shows the advantages of mass spectrometer in the widely applied area.But TCM is a very complex mixture containing up to hundreds or even thousands of components, which make it extremely difficult to analyze the bioactive components contained in it.However,it was just thought that TCM expressed its effects through multi-components and multi-targets.The multiple constituents were usually responsible for its therapeutic effects by synergistic and antagonistic interaction. So it needs to get simultaneous analysis of more targets to reflect the integrity of TCM and it also inhances the difficulties of the analysis in complex TCM system. The major problem was as follows:
1 The identification problem of complex constituents in TCM(in the situation of no reference substance)
2 The detection problem of metabolite fingerprint problem of TCM
3 The distinguishing problem of isomers in TCM(the isomers with similar fragment pathway)
4 The deviation of undetectable constiuents in TCM
Part one:method study on the identification of complex constituents Rhizome Corydalts(RC)
According the biosynthenic pathway of plant and the related literatures,the feature of main cores and substituted groups in different alkaloids were summaried first.By the systematic study of fragment pathways of the standard compound,the distinguished method of different type alkaloid was established.Based on it,the type of unknown compound could be characterized.Then according the feature of the alkloid structure and the fragment pathways,fourteen alkaloids in RC could be identified and one of them was found in this plant for first time.Based on the identification of the alkaloid in RC,its plasma containing constituents was detected in Auto-MS~n negtive mode.14 components in plasma after giving extract of RC.10 of them were original constituents and 4 of them were metabolic constituents.
Part two:Study of Rat urinary metabolite profile of Aurantii Fructus
Liquid chromatographic-tandem electrospray ionization ion trap mass spectrometry technique(LC-MS~n) was used to analyze rat urinary metabolite profile of TCM Aurantii Fructus(AF).According the data of MS~2 and MS~3 spectra, more than twenty metabolites were identified or tentatively characterized.They were derived from the flavonoid O-diglycosides of AF and the major metabolic pathways of them were hydrolization,glucuronidation and sulfation.The method based on LC-MS~n technique was proposed to rapidly analyze the metabolites profile in rat urine.The urine samples were collected at five different time point after the consumption of AF extract and detected by LC-ESI/MS in negative multiple reactions monitoring(MRM) mode.To our knowledge,this is the first report of the analysis of rat urinary metabolite profile of flavonoid O-diglycosides from AF.The results were very valuable to analyze the metabolic course of the bioactive constituents in AF.It also could be used for investigations of the metabolite profiles of many other TCM.
Part three:The isomer distinguishing method of flavonoid-glycosides and coumarin
Based on the LC-MS~n technique,the isomers of Psoralen and Isopsoralen, Imperatorin and Isoimperatorin,Neohesperidin and Hesperidin,Naringin and Narirutin were distinguished mainly by comparison of the relative abundance of their major fragment ions.The two pairs of coumarin isomers could be distinguished by comparing the the relative abundances of fragment ions formed by the loss of CO_2 and 2CO.For the isomers of flavonoid glycosides the relative abundance of fragment ions generated by the ring-cross cleavage of glycan was different and this could be used in distinguishing them.Although the fragmentation pathways were similar,according the tiny difference of structure, the change of relative intensity of main fragment ions could be observed.Through the further study of the fragment mechanism caused by the difference of structures, it could be used to distinguish some isomers more accurately and quickly.
Part four:The derivazation of undetectable constitunts in TCM
This part described the development of efficient derivatization approaches to facilitate mass spectrometric analysis of poor-ionizable and low molecular compounds.
For the low polar constituents,Strong-ionizable group was combined with the structure of them to make the derivated structure could be detected.The method of benzolytion and sulfation was compared and the better one sulfation was useful in the detection of TCM complex system.
The detective trouble was also happened in the the detection of monosaccharides because of their low molecular weight.Six monosaccharides were derived to make them molecular weight increased by PMP.The derived structures have high response and more fragment ions in mass spectra.It coud provided more information for the detection of monasaccharide and make the identification of them more accurate.Furthermore,for distinguishing the isomers of derivated monosacchrides structures,the method comparing relative abundance of fragment ion which proposed in the forth chart of this paper was used.The result showed that in the differentiation of the derivated monosacchrides,the method coud be also accurate and convenient.
中药及其体内样品复杂成分鉴定(无对照品的成分难于鉴定)
中药代谢产物指纹图谱检测
中药同分异构成分区分(碎裂途径相似的同分异构成分难于区分)
中药部分成分质谱响应困难
针对上述难题本论文展开以下研究:
1中药延胡索复杂成分质谱鉴定方法
本部分以中药延胡索为例,对中药复杂成分的质谱鉴定方法进行探讨,建立延胡索中生物碱成分在电喷雾质谱下的鉴定方法,并以此为基础对其在血浆中的原型成分和代谢产物进行分析。基于生物合成规律,在无对照品情况下,通过对复杂成分样品的质谱分析,鉴定了延胡索甲素、四氢黄连碱、坎那定、别隐片碱、黄连碱、小檗碱等14种生物碱成分,并对延胡索中一种新的生物碱结构进行推测。以此为基础,在无对照品的条件下,对其在血浆中原型成分和代谢产物进行分析,检测到14种移行成分,其中原形10种,代谢产物4种,主要的代谢途径为氢化和水合等还原反应。该方法简化了中药化学成分分析鉴定的过程,在中药物质基础研究中具有广泛的应用价值。
本部分首次对延胡索中四种不同类型生物碱的裂解途径的区别进行了系统的总结,在对延胡索甲素裂解途径的研究中,发现一种RDA裂解的新方式,该裂解不仅可以发生在该化合物的C环上,也可通过重排和电子转移使B环发生裂解,形成互补的碎片离子,为通过RDA裂解鉴定部分四氢原小檗碱型生物碱提供了新的指标。
2中药枳壳代谢产物质谱指纹图谱检测方法研究
本部分以中药枳壳为例,探讨其主要成分在大鼠尿样中代谢产物的指纹图谱检测方法进行研究。以电喷雾多级质谱技术为基础,依据质谱裂解行为和代谢特征相结合获取双重信息的研究思路,对大鼠灌服枳壳提取液后的尿液进行系统研究。鉴定了21种代谢产物,这些代谢产物主要来自于枳壳中的黄酮二糖苷类成分,主要的代谢途径是:水解、葡萄糖醛酸化、磺酸化以及环开裂氢化等。
在对代谢产物进行结构分析的基础上,为更好地反映不同类型代谢产物在不同时间段浓度的变化情况及相互关系,对枳壳中黄酮二糖苷类成分在大鼠尿液中代谢产物指纹图谱进行了系统研究。采用多离子选择监控模式(MRM),通过设立11个不同的区段,以各个代谢产物的分子量及主要碎片离子的双重信息为检测目标,在MRM模式下对大鼠口服枳壳后0-3、3-6、6-9、9-12、12-24h的尿液进行检测,提供了大鼠在24小时5个时间段的代谢产物指纹图谱,揭示了枳壳中黄酮二糖苷类成分在体内先水解成苷元再发生葡萄糖醛酸化和磺酸化反应的主要代谢途径。
3香豆素及黄酮苷类同分异构成分质谱区分方法
同分异构体的区分一直是质谱在中药复杂成分分析中的难题,尤其是碎裂途径相似的同分异构体,常规的质谱检测方法往往难以区分。本章通过比较主要碎片离子的相对强度,区分了四对碎裂途径相似的同分异构体:补骨脂素和异补骨脂素、欧前胡素和异欧前胡素(香豆素)、橙皮苷和新橙皮苷、柚皮苷和柚皮芸香苷(黄酮苷)。与常规的质谱区分方法不同,本文以结构的差别为线索,通过对产生相对丰度变化的碎裂机理进行深入研究,从而达到区分的目的。通过比较失去2CO和CO_2形成的碎片离子相对丰度实现了两类呋喃香豆素类成分的区分。通过比较糖裂环产生的碎片离子相对丰度区分了黄酮二糖苷类同分异构体,并对该方法在不同碎裂条件和中药复杂体系中的稳定性进行了研究。该方法简便准确,适用于中药复杂体系中同分异构成分的分析鉴定。
4中药难检测成分衍生化方法
本部分主要针对中药中低极性成分和低分子量成分进行研究,分别通过衍生上易离子化基团和增加分子量的方法解决它们在质谱检测中的困难。
难电离成分的衍生:对低极性成分采用衍生上易离子化基团的办法使其得以检测,从而解决这类成分在检测上的难题。以龙脑,薯蓣皂苷元,胆固醇三种低极性的化学成分为例,通过磺酸化(负离子模式检测)和苯甲酰化(正离子模式检测)两种方法对这几种难电离成分进行衍生,并对复方制剂丹参滴丸及龙脑对大鼠灌胃1h后的血浆样品进行磺酸衍生化,结果表明复杂的中药样品体系并未影响衍生化结果。
糖类的衍生:电喷雾质谱在低端的干扰较大,这使分子量小的各种单糖在质谱检测中比较困难。采用PMP法对六种单糖进行衍生,使衍生后的结构分子量增加,从而易于检测,并对六种单糖衍生结构的裂解途径进行总结,从而通过保留时间,碎片离子,分子量三重信息实现对单糖的结构鉴定,有利于增加单糖鉴别试验的准确性。此外,在区分单糖衍生结构的同分异构成分中,本部分延续了第四章利用碎片离子相对丰度区分同分异构体的研究思路,通过比较衍生结构失水后碎片离子相对丰度的方法,对单糖衍生结构中的同分异构成分达到了很好的区分效果。
本文创新点
本论文主要创新性研究成果如下:
1.以延胡索为例,建立了中药化学成分的质谱鉴定方法。在没有对照品条件下,从成分复杂的样品中鉴定了延胡索甲素、四氢黄连碱、坎那定、别隐片碱、黄连碱、小檗碱等生物碱成分,并对延胡索中血浆中的移行成进行分析鉴定。这种方法在中药物质基础研究中具有应用价值。
2.首次通过电喷雾质谱技术,对枳壳在大鼠尿液中的代谢产物指纹图谱进行研究,提供了枳壳在大鼠尿液中不同时间段的代谢产物指纹图谱。结果表明能较好的反应枳壳活性成分在体内的变化过程。为解决中药代谢产物指纹图谱研究中出现的干扰成分过多的问题提供参考。
3.通过对碎片离子相对丰度的比较,建立了中药中同分异构成分的质谱区分方法。利用该方法可对香豆素和黄酮苷两类裂解途径相似的同分异构成分进行有效的区分。与其它方法相比,通过相对丰度的比较可以更为简便地区分同分异构体。对于解决中药同分异构成分的质谱区分问题提供新的研究思路与方法。
以上研究成果发表5篇论文,其中包括一篇SCI收录。
Mass spectrometry is an important instrument in the modern analysis of Traditional Chinese Medicine(TCM).In particularly,the development of electrospray ionization(ESI) source enhances the ionization ability,and shows the advantages of mass spectrometer in the widely applied area.But TCM is a very complex mixture containing up to hundreds or even thousands of components, which make it extremely difficult to analyze the bioactive components contained in it.However,it was just thought that TCM expressed its effects through multi-components and multi-targets.The multiple constituents were usually responsible for its therapeutic effects by synergistic and antagonistic interaction. So it needs to get simultaneous analysis of more targets to reflect the integrity of TCM and it also inhances the difficulties of the analysis in complex TCM system. The major problem was as follows:
1 The identification problem of complex constituents in TCM(in the situation of no reference substance)
2 The detection problem of metabolite fingerprint problem of TCM
3 The distinguishing problem of isomers in TCM(the isomers with similar fragment pathway)
4 The deviation of undetectable constiuents in TCM
Part one:method study on the identification of complex constituents Rhizome Corydalts(RC)
According the biosynthenic pathway of plant and the related literatures,the feature of main cores and substituted groups in different alkaloids were summaried first.By the systematic study of fragment pathways of the standard compound,the distinguished method of different type alkaloid was established.Based on it,the type of unknown compound could be characterized.Then according the feature of the alkloid structure and the fragment pathways,fourteen alkaloids in RC could be identified and one of them was found in this plant for first time.Based on the identification of the alkaloid in RC,its plasma containing constituents was detected in Auto-MS~n negtive mode.14 components in plasma after giving extract of RC.10 of them were original constituents and 4 of them were metabolic constituents.
Part two:Study of Rat urinary metabolite profile of Aurantii Fructus
Liquid chromatographic-tandem electrospray ionization ion trap mass spectrometry technique(LC-MS~n) was used to analyze rat urinary metabolite profile of TCM Aurantii Fructus(AF).According the data of MS~2 and MS~3 spectra, more than twenty metabolites were identified or tentatively characterized.They were derived from the flavonoid O-diglycosides of AF and the major metabolic pathways of them were hydrolization,glucuronidation and sulfation.The method based on LC-MS~n technique was proposed to rapidly analyze the metabolites profile in rat urine.The urine samples were collected at five different time point after the consumption of AF extract and detected by LC-ESI/MS in negative multiple reactions monitoring(MRM) mode.To our knowledge,this is the first report of the analysis of rat urinary metabolite profile of flavonoid O-diglycosides from AF.The results were very valuable to analyze the metabolic course of the bioactive constituents in AF.It also could be used for investigations of the metabolite profiles of many other TCM.
Part three:The isomer distinguishing method of flavonoid-glycosides and coumarin
Based on the LC-MS~n technique,the isomers of Psoralen and Isopsoralen, Imperatorin and Isoimperatorin,Neohesperidin and Hesperidin,Naringin and Narirutin were distinguished mainly by comparison of the relative abundance of their major fragment ions.The two pairs of coumarin isomers could be distinguished by comparing the the relative abundances of fragment ions formed by the loss of CO_2 and 2CO.For the isomers of flavonoid glycosides the relative abundance of fragment ions generated by the ring-cross cleavage of glycan was different and this could be used in distinguishing them.Although the fragmentation pathways were similar,according the tiny difference of structure, the change of relative intensity of main fragment ions could be observed.Through the further study of the fragment mechanism caused by the difference of structures, it could be used to distinguish some isomers more accurately and quickly.
Part four:The derivazation of undetectable constitunts in TCM
This part described the development of efficient derivatization approaches to facilitate mass spectrometric analysis of poor-ionizable and low molecular compounds.
For the low polar constituents,Strong-ionizable group was combined with the structure of them to make the derivated structure could be detected.The method of benzolytion and sulfation was compared and the better one sulfation was useful in the detection of TCM complex system.
The detective trouble was also happened in the the detection of monosaccharides because of their low molecular weight.Six monosaccharides were derived to make them molecular weight increased by PMP.The derived structures have high response and more fragment ions in mass spectra.It coud provided more information for the detection of monasaccharide and make the identification of them more accurate.Furthermore,for distinguishing the isomers of derivated monosacchrides structures,the method comparing relative abundance of fragment ion which proposed in the forth chart of this paper was used.The result showed that in the differentiation of the derivated monosacchrides,the method coud be also accurate and convenient.
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