基于~1H-NMR代谢物组学技术的多基源中藏药品种质量评价研究
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摘要
中药／民族药的质量控制关系到药物临床使用的安全性和有效性。由于药材本身成分的复杂性,加上仪器分析条件、研究思路和方法的局限,中药／民族药的质量控制一直缺乏行之有效的方法。目前,中药／民族药质量控制及评价的研究角度、思路和方法需要总结和创新,以期建立一套既能反映整体观和系统性,又能体现“安全有效、科学、先进实用”等特点的中药／民族药质控方法。
中药／民族药品种的多基源性自古有之,品种的多样性与复杂性导致来源混杂、真伪难辨、优劣难评,严重制约药材的质量控制、质量标准制订、临床合理利用和新药开发。利用现代科学技术加强复杂多基源中药／民族药的品种鉴别、质量控制与评价研究,促进药材质量标准的完善与提高,是提升中药／民族药的科技水平,推动其现代化、产业化的必由之路。
目的：以常用多基源中药“黄连”及藏药“藏茵陈”为模式药物,采用代谢物组学技术研究不同品种药材的代谢物差异,寻找特征代谢标志物(metabolic markers),为黄连和藏茵陈药材的品种鉴别、质量控制及临床合理利用提供理论依据,也为当前中药／民族药的质量控制及评价提供方法学参考。
方法：
1、采用1H-NMR代谢物组学技术,建立黄连药材的整体代谢物指纹图谱,并结合主成分分析(PCA)、偏最小二乘法判别分析(PLS-DA)等方法,系统分析三个黄连品种(味连Coptis chinensis、雅连C. deltoidea和云连C. teeta)的初生和次生代谢产物差异,并找出引起差异的代谢标志物。
2、应用定量核磁共振(qNMR)技术,建立黄连药材中小檗碱、黄连碱、非洲防己碱、药根碱等6种主要生物碱成分的定量分析方法,并采用配对t检验评价qNMR与常规HPLC定量方法的一致性。
3、采用1H-NMR代谢物组学技术,同时检测分析“藏茵陈”药材的整体代谢成分,结合PLS-DA、HCA方法研究5种獐芽菜属植物(印度獐牙菜Swertia chirayita、川西獐牙菜S. mussotii、抱茎獐牙菜S. franchetiana、四数獐牙菜S.tetraptera阳高獐牙菜S. elata)的代谢物差异及其亲缘关系。
结果：
1、从黄连提取物中同时检测出16个(类)化合物,包括小檗碱、巴马汀、黄连碱、表小檗碱、非洲防己碱、药根碱、木兰花碱、绿原酸、阿魏酸、蔗糖、α-葡萄糖、β-葡萄糖、丙氨酸、不饱和脂肪酸类、饱和脂肪酸类、甾醇类。
根据PCA、PLS-DA结果,40个黄连药材样品分类为三组,每一组对应于一个品种。结合方差分析,发现了黄连碱、非洲防己碱、表小檗碱、巴马汀和脂肪酸类成分的含量在味连中最高,而云连和雅连分别含有最多的绿原酸和蔗糖。
2、成功建立了黄连药材中6种生物碱成分的qNMR定量分析方法,重复性、选择性良好,6种生物碱的平均回收率为96.93-102.39%。t检验结果显示本文建立的qNMR方法与常规的HPLC分析方法的定量结果基本一致(P>0.05)。
3、从“藏茵陈”原植物药材中同时检测出25个属于不同化学类型的代谢成分,包括(1)口山酮类成分：芒果苷、1,8-二羟基-3,5-二甲氧基口山酮、1,8-二羟基-3,7-二甲氧基口山酮、1-羟基-3,7,8-三甲氧基口山酮、1,5,8-三羟基-3-甲氧基口山酮和7-0-[a-L-吡喃鼠李糖-(1→2)-p-D-吡哺木糖]-1，8-二羟基-3-甲氧基口山酮；(2)环烯醚萜苷类成分：獐牙菜苦苷、獐牙菜苷、落干酸、龙胆苦苷；(3)五环三萜类成分：齐墩果酸；(4)黄酮类成分：异荭草苷；(5)氨基酸类成分：丙氨酸、缬氨酸；糖类成分：蔗糖、α-葡萄糖、β-葡萄糖；(6)其他类成分：胆碱、没食子酸、甲酸、醋酸、丁二酸、饱和脂肪酸类、不饱和脂肪酸类、甾醇类。
根据PLS-DA和HCA的结果,五种獐牙菜属植物被明显分为五组,齐墩果酸、芒果苷、脂肪酸类和缬氨酸的含量在印度獐牙菜药材中最高,而四数獐牙菜含有最多的龙胆苦苷和胆碱,川西獐牙菜含有最多的落干酸和β-葡萄糖,抱茎獐牙菜含有最多的獐牙菜苦苷。
结论：
1、味连、雅连和云连代谢成分有明显的差异,临床使用时要注意生物等效性。黄连碱、表小檗碱、非洲防己碱、小檗碱、巴马汀、药根碱、蔗糖、脂肪酸类和绿原酸为黄连种间差异代谢物,其中表小檗碱和蔗糖在三个品种两两之间均有明显的差异,因此为黄连品种鉴别最重要的代谢标志物。
2、qNMR方法简便、快速、准确、重复性好,可以应用于黄连药材及其他含生物碱类成分药材的质量控制与评价。
3、五种獐牙菜属植物的代谢成分具有明显的差异,不应共同作为“藏茵陈’药材的原植物来源。齐墩果酸、芒果苷、獐牙菜苦苷、龙胆苦苷、落干酸、脂肪酸类、缬氨酸、胆碱、糖类为五种獐牙菜属植物种间差异的代谢标志物,今后可作为品种鉴别、质量控制的有效指标。从化学分类学角度来说,印度獐牙菜与其他四种獐牙菜的化学亲缘关系最远,而四数獐牙菜与川西獐牙菜的亲缘关系更近,抱茎獐牙菜和高獐牙菜的亲缘关系更近。
创新点：
1、本论文融合多学科理论和技术,创新性应用1H-NMR代谢物组学技术及分析方法,从整体代谢物组(metabolome)角度探索了复杂多基源中藏药品种鉴定、质量评价和化学分类学研究的新思路和新方法。
2、本文建立了黄连药材的整体代谢物指纹图谱,结合化学计量学方法,首次从代谢物组水平上研究了黄连三个品种(味连、雅连和云连)的初生和次生代谢产物差异,并发现了种间差异的代谢标志物。
3、首次建立黄连药材中小檗碱、黄连碱、药根碱、巴马汀、非洲防己碱、表小檗碱的qNMR定量分析方法,为其质量控制与评价提供了新的手段。
4、首次检测分析了“藏茵陈”药材中的整体代谢物组,包括口山酮及其苷类、五环三萜类、环稀醚萜苷类、黄酮类、糖类、氨基酸类及有机酸类等25个成分。其中,蔗糖、胆碱、甲酸、醋酸和丁二酸为首次报道。
The quality control of traditional Chinese medicine and ethnic medicine is closely related to their safety and effectiveness in clinical use. Due to the complex chemical compositions combined with the limitations of instrumental analysis conditions, research ideas and methods, the current quality control methods are not effective for controlling the quality of traditional Chinese medicine and ethnic medicine. At present, in order to establish a suitable quality control method that not only reflects the integrity and systematization, but also has the features of "safety, effectiveness, science, advance and practicality", we must summarize and change the research ideas and methods of quality control for traditional Chinese medicine and ethnic medicine.
Traditional Chinese medicine and ethnic medicine mostly originates from various species, which leads to the difficulty for distinguishing the identity and evaluating the quality of crude drugs. Species diversity also seriously hampers the quality control, quality standards development and clinical rational use of medicinal material. Therefore, it is very important to strengthen the research of species identification, quality control and quality evaluation for traditional Chinese medicine and ethnic medicine from various species by using modern science and technology. These studies are necessary to heighten the technological level of traditional Chinese medicine and ethnic medicine, and promote the process of their modernization and industrialization.
Purposes:
In this paper, Rhizoma Coptidis and "Zangyinchen", two broadly used multi-species medicinal plants, were used as the research objects. The aims of this study were to evaluate the differences of the overall metabolites for the two medicinal materials from various species, and to find out the characteristic metabolic markers by means of1H NMR-based metabolomics. These studies can provide not only a theoretical basis for the species identification, quality control and clinical rational use of Rhizoma Coptidis and "Zangyinchen", but also a new research ideas and methods for the quality control and/or quality evaluation of traditional Chinese medicine and ethnic medicine.
Methods:
1. A1H NMR-based metabolomics protocol coupled with multivariate statistical analysis (e.g., principal component analysis and partial least squares discriminant analysis) was applied to establish the metabolic fingerprinting of Rhizoma Coptidis, to evaluate the differences of the three species (Coptis chinensis, C. deltoidea and C. teeta) for their primary and secondary metabolites, and to identify potential metabolic markers that could be responsible for the discrimination of the three species.
2. A rapid, simple and accurate quantitative nuclear magnetic renonance (qNMR) method was developed for simultaneous determination of berberine, jatrorrhizine, epiberberine, coptisine, palmatine and columbamine in Rhizoma Coptidis. Moreover, paired t-test was performed to compare the quantitative data obtained by the'H NMR with those obtained through a HPLC-DAD method.
3. A1H NMR-based metabolomics method coupled with multivariate statistical analysis (e.g., partial least squares discriminant analysis and hierarchical cluster analysis) was applied to simultaneously analyze the overall metabolites of "Zangyinchen", and to study the phylogenetic relationship of the five Swertia species (Swertia chirayita, S. mussotii, S. franchetiana, S. tetraptera and S. elata) and their differences in the primary and secondary metabolites.
Results:
1. Approximately16metabolites were identified in the methanol extract of Rhizoma Coptidis including berberine, palmatine, coptisine, epiberberine, columbamine, jateorrhizine, magnoflorine, chlorogenic acid, ferulic acid, sucrose, a-glucose, β-glucose, alanine, unsaturated fatty acids, saturated fatty acids and sterols.
By combining PCA, PLS-DA and ANOVA results, we found that the40samples of Rhizoma Coptidis could be clearly classified into three groups according to different species, respectively. Palmatine, coptisine, epiberberine, columbamine and fatty acids contents were highest in C. chinensis, whereas C. deltoidea and C. teeta showed the highest levels of sucrose and chlorogenic acid, respectively.
2. A quantitative1H NMR method having good linearity, precision, repeatability and accuracy was successfully applied for simultaneous determination of six protoberberine alkaloids in Rhizoma Coptidis. The average recoveries were between96.93%and102.39%with RSD values of less than2.33%for all the six compounds. The results of the paired t-test showed that there are good agreements between the1H NMR and HPLC-DAD methods for their quantitative results.
3. A broad range of metabolites belonging to different chemical types were detected from "Zangyinchen" by means of1H NMR spectroscopy, including (1) xanthones:mangiferin,1,8-dihydroxy-3,5-dimethoxy xanthone,1,8-dihydroxy-3,7-dimethoxy xanthone,1-hydroxy-3,7,8-trimethoxy xanthone,1,5,8-trihydroxy-3-methoxy xanthone,7-O-[a-L-rhamnopyranosyl-(1→2)-β-D-xylopyranosyl]-1,8-dihydroxy-3-methoxy xanthone;(2) iridoid glycosides:swertiamarin, sweroside, gentiopicrin, loganic acid;(3) pentacyclic triterpenoids:oleanolic acid;(4) flavonoids: isoorientin;(5) amino acids:alanine, valine;(5) sugars:sucrose, a-glucose, β-glucose;(6) others: gallic acid, choline, formic acid, acetic acid, succinic acid, saturated fatty acids, unsaturated fatty acids, sterols.
By combining PCA, PLS-DA and ANOVA results, we found that all samples of "Zangyinchen" could be clearly classified into five groups according to different species, respectively. Oleanolic acid, mangiferin, fatty acids and valine contents were highest in S. chirayita, whereas S. tetraptera showed the highest levels of gentiopicroside and choline, S. mussotii showed the highest levels of loganic acid and β-glucose, S. franchetiana showed the highest level of swertiamarin.
Conclusions:
1. Metabolites of C. chinensis, C. deltoidea and C. teeta have significant differences, and so it was important to show solicitude for their bioequivalence in clinical use. In addition, the critical markers responsible for the discrimination of different Rhizoma Coptidis species were found to be palmatine, coptisine, epiberberine, jateorrhizine, columbamine, berberine, sucrose, fatty acids and chlorogenic acid. Among them, epiberberine and sucrose are the most important metabolic markers as their contents have significant differences between any two of the three species.
2. The qNMR method is simple, fast, accurate and reproducible, which can be applied for the quality control and/or quality evaluation of Rhizoma Coptidis or other herbs containing alkaloids.
3. Metabolites of S. chirayita, S. mussotii, S. franchetiana, S. tetraptera and S. elata have significant differences, thus they should not be together as the original plant source of the "Zangyinchen". The critical markers responsible for the discrimination of different "Zangyinchen" species were found to be oleanolic acid, mangiferin, swertiamarin, gentiopicroside, loganic acid, fatty acids, valine, choline and sugars. These metabolites can be effective as the indicators for the species identification and quality control of "Zangyinchen". In addition, from the chemotaxonomic point of view, S. chirayita has the farthest phylogenetic relationship with the other four Swertia. whereas S. mussotii has a closer phylogenetic relationship with S. tetraptera and S. franchetiana has a closer phylogenetic relationship with S. elata.
Innovations:
1. In this study, by integration of multidisciplinary theories and techniques, we applied the1H NMR-based metabolomic technologies and analysis methods to study the species identification, quality evaluation and chemical taxonomy of multi-species traditional Chinese medicine and ethnic medicine from the perspective of the overall metabolome.
2. This paper has established the metabolic fingerprinting of Rhizoma Coptidis. In addition, by the combination of chemometric methods, we studied the difference of primary and secondary metabolites of the three species (C. chinensis, C. deltoidea and C. teeta) from the metabolome level for the first time.
3. Quantitative1H NMR (qNMR) method was first developed for simultaneous determination of berberine, jatrorrhizine, epiberberine, coptisine, palmatine and columbamine in Rhizoma Coptidis, which provides a new mean for the quality control and/or quality evaluation of Rhizoma Coptidis.
4. The overall metabolites present in "Zangyinchen" were simultaneously detected for the first time including xanthones and their glycosides, pentacyclic triterpenoids, iridoid glycosides, flavonoids, sugars, amino acids and organic acids. Among them, sucrose, choline, formic acid, acetic acid and succinic acid were reported for the first time in "Zangyinchen"
中药／民族药品种的多基源性自古有之,品种的多样性与复杂性导致来源混杂、真伪难辨、优劣难评,严重制约药材的质量控制、质量标准制订、临床合理利用和新药开发。利用现代科学技术加强复杂多基源中药／民族药的品种鉴别、质量控制与评价研究,促进药材质量标准的完善与提高,是提升中药／民族药的科技水平,推动其现代化、产业化的必由之路。
目的：以常用多基源中药“黄连”及藏药“藏茵陈”为模式药物,采用代谢物组学技术研究不同品种药材的代谢物差异,寻找特征代谢标志物(metabolic markers),为黄连和藏茵陈药材的品种鉴别、质量控制及临床合理利用提供理论依据,也为当前中药／民族药的质量控制及评价提供方法学参考。
方法：
1、采用1H-NMR代谢物组学技术,建立黄连药材的整体代谢物指纹图谱,并结合主成分分析(PCA)、偏最小二乘法判别分析(PLS-DA)等方法,系统分析三个黄连品种(味连Coptis chinensis、雅连C. deltoidea和云连C. teeta)的初生和次生代谢产物差异,并找出引起差异的代谢标志物。
2、应用定量核磁共振(qNMR)技术,建立黄连药材中小檗碱、黄连碱、非洲防己碱、药根碱等6种主要生物碱成分的定量分析方法,并采用配对t检验评价qNMR与常规HPLC定量方法的一致性。
3、采用1H-NMR代谢物组学技术,同时检测分析“藏茵陈”药材的整体代谢成分,结合PLS-DA、HCA方法研究5种獐芽菜属植物(印度獐牙菜Swertia chirayita、川西獐牙菜S. mussotii、抱茎獐牙菜S. franchetiana、四数獐牙菜S.tetraptera阳高獐牙菜S. elata)的代谢物差异及其亲缘关系。
结果：
1、从黄连提取物中同时检测出16个(类)化合物,包括小檗碱、巴马汀、黄连碱、表小檗碱、非洲防己碱、药根碱、木兰花碱、绿原酸、阿魏酸、蔗糖、α-葡萄糖、β-葡萄糖、丙氨酸、不饱和脂肪酸类、饱和脂肪酸类、甾醇类。
根据PCA、PLS-DA结果,40个黄连药材样品分类为三组,每一组对应于一个品种。结合方差分析,发现了黄连碱、非洲防己碱、表小檗碱、巴马汀和脂肪酸类成分的含量在味连中最高,而云连和雅连分别含有最多的绿原酸和蔗糖。
2、成功建立了黄连药材中6种生物碱成分的qNMR定量分析方法,重复性、选择性良好,6种生物碱的平均回收率为96.93-102.39%。t检验结果显示本文建立的qNMR方法与常规的HPLC分析方法的定量结果基本一致(P>0.05)。
3、从“藏茵陈”原植物药材中同时检测出25个属于不同化学类型的代谢成分,包括(1)口山酮类成分：芒果苷、1,8-二羟基-3,5-二甲氧基口山酮、1,8-二羟基-3,7-二甲氧基口山酮、1-羟基-3,7,8-三甲氧基口山酮、1,5,8-三羟基-3-甲氧基口山酮和7-0-[a-L-吡喃鼠李糖-(1→2)-p-D-吡哺木糖]-1，8-二羟基-3-甲氧基口山酮；(2)环烯醚萜苷类成分：獐牙菜苦苷、獐牙菜苷、落干酸、龙胆苦苷；(3)五环三萜类成分：齐墩果酸；(4)黄酮类成分：异荭草苷；(5)氨基酸类成分：丙氨酸、缬氨酸；糖类成分：蔗糖、α-葡萄糖、β-葡萄糖；(6)其他类成分：胆碱、没食子酸、甲酸、醋酸、丁二酸、饱和脂肪酸类、不饱和脂肪酸类、甾醇类。
根据PLS-DA和HCA的结果,五种獐牙菜属植物被明显分为五组,齐墩果酸、芒果苷、脂肪酸类和缬氨酸的含量在印度獐牙菜药材中最高,而四数獐牙菜含有最多的龙胆苦苷和胆碱,川西獐牙菜含有最多的落干酸和β-葡萄糖,抱茎獐牙菜含有最多的獐牙菜苦苷。
结论：
1、味连、雅连和云连代谢成分有明显的差异,临床使用时要注意生物等效性。黄连碱、表小檗碱、非洲防己碱、小檗碱、巴马汀、药根碱、蔗糖、脂肪酸类和绿原酸为黄连种间差异代谢物,其中表小檗碱和蔗糖在三个品种两两之间均有明显的差异,因此为黄连品种鉴别最重要的代谢标志物。
2、qNMR方法简便、快速、准确、重复性好,可以应用于黄连药材及其他含生物碱类成分药材的质量控制与评价。
3、五种獐牙菜属植物的代谢成分具有明显的差异,不应共同作为“藏茵陈’药材的原植物来源。齐墩果酸、芒果苷、獐牙菜苦苷、龙胆苦苷、落干酸、脂肪酸类、缬氨酸、胆碱、糖类为五种獐牙菜属植物种间差异的代谢标志物,今后可作为品种鉴别、质量控制的有效指标。从化学分类学角度来说,印度獐牙菜与其他四种獐牙菜的化学亲缘关系最远,而四数獐牙菜与川西獐牙菜的亲缘关系更近,抱茎獐牙菜和高獐牙菜的亲缘关系更近。
创新点：
1、本论文融合多学科理论和技术,创新性应用1H-NMR代谢物组学技术及分析方法,从整体代谢物组(metabolome)角度探索了复杂多基源中藏药品种鉴定、质量评价和化学分类学研究的新思路和新方法。
2、本文建立了黄连药材的整体代谢物指纹图谱,结合化学计量学方法,首次从代谢物组水平上研究了黄连三个品种(味连、雅连和云连)的初生和次生代谢产物差异,并发现了种间差异的代谢标志物。
3、首次建立黄连药材中小檗碱、黄连碱、药根碱、巴马汀、非洲防己碱、表小檗碱的qNMR定量分析方法,为其质量控制与评价提供了新的手段。
4、首次检测分析了“藏茵陈”药材中的整体代谢物组,包括口山酮及其苷类、五环三萜类、环稀醚萜苷类、黄酮类、糖类、氨基酸类及有机酸类等25个成分。其中,蔗糖、胆碱、甲酸、醋酸和丁二酸为首次报道。
The quality control of traditional Chinese medicine and ethnic medicine is closely related to their safety and effectiveness in clinical use. Due to the complex chemical compositions combined with the limitations of instrumental analysis conditions, research ideas and methods, the current quality control methods are not effective for controlling the quality of traditional Chinese medicine and ethnic medicine. At present, in order to establish a suitable quality control method that not only reflects the integrity and systematization, but also has the features of "safety, effectiveness, science, advance and practicality", we must summarize and change the research ideas and methods of quality control for traditional Chinese medicine and ethnic medicine.
Traditional Chinese medicine and ethnic medicine mostly originates from various species, which leads to the difficulty for distinguishing the identity and evaluating the quality of crude drugs. Species diversity also seriously hampers the quality control, quality standards development and clinical rational use of medicinal material. Therefore, it is very important to strengthen the research of species identification, quality control and quality evaluation for traditional Chinese medicine and ethnic medicine from various species by using modern science and technology. These studies are necessary to heighten the technological level of traditional Chinese medicine and ethnic medicine, and promote the process of their modernization and industrialization.
Purposes:
In this paper, Rhizoma Coptidis and "Zangyinchen", two broadly used multi-species medicinal plants, were used as the research objects. The aims of this study were to evaluate the differences of the overall metabolites for the two medicinal materials from various species, and to find out the characteristic metabolic markers by means of1H NMR-based metabolomics. These studies can provide not only a theoretical basis for the species identification, quality control and clinical rational use of Rhizoma Coptidis and "Zangyinchen", but also a new research ideas and methods for the quality control and/or quality evaluation of traditional Chinese medicine and ethnic medicine.
Methods:
1. A1H NMR-based metabolomics protocol coupled with multivariate statistical analysis (e.g., principal component analysis and partial least squares discriminant analysis) was applied to establish the metabolic fingerprinting of Rhizoma Coptidis, to evaluate the differences of the three species (Coptis chinensis, C. deltoidea and C. teeta) for their primary and secondary metabolites, and to identify potential metabolic markers that could be responsible for the discrimination of the three species.
2. A rapid, simple and accurate quantitative nuclear magnetic renonance (qNMR) method was developed for simultaneous determination of berberine, jatrorrhizine, epiberberine, coptisine, palmatine and columbamine in Rhizoma Coptidis. Moreover, paired t-test was performed to compare the quantitative data obtained by the'H NMR with those obtained through a HPLC-DAD method.
3. A1H NMR-based metabolomics method coupled with multivariate statistical analysis (e.g., partial least squares discriminant analysis and hierarchical cluster analysis) was applied to simultaneously analyze the overall metabolites of "Zangyinchen", and to study the phylogenetic relationship of the five Swertia species (Swertia chirayita, S. mussotii, S. franchetiana, S. tetraptera and S. elata) and their differences in the primary and secondary metabolites.
Results:
1. Approximately16metabolites were identified in the methanol extract of Rhizoma Coptidis including berberine, palmatine, coptisine, epiberberine, columbamine, jateorrhizine, magnoflorine, chlorogenic acid, ferulic acid, sucrose, a-glucose, β-glucose, alanine, unsaturated fatty acids, saturated fatty acids and sterols.
By combining PCA, PLS-DA and ANOVA results, we found that the40samples of Rhizoma Coptidis could be clearly classified into three groups according to different species, respectively. Palmatine, coptisine, epiberberine, columbamine and fatty acids contents were highest in C. chinensis, whereas C. deltoidea and C. teeta showed the highest levels of sucrose and chlorogenic acid, respectively.
2. A quantitative1H NMR method having good linearity, precision, repeatability and accuracy was successfully applied for simultaneous determination of six protoberberine alkaloids in Rhizoma Coptidis. The average recoveries were between96.93%and102.39%with RSD values of less than2.33%for all the six compounds. The results of the paired t-test showed that there are good agreements between the1H NMR and HPLC-DAD methods for their quantitative results.
3. A broad range of metabolites belonging to different chemical types were detected from "Zangyinchen" by means of1H NMR spectroscopy, including (1) xanthones:mangiferin,1,8-dihydroxy-3,5-dimethoxy xanthone,1,8-dihydroxy-3,7-dimethoxy xanthone,1-hydroxy-3,7,8-trimethoxy xanthone,1,5,8-trihydroxy-3-methoxy xanthone,7-O-[a-L-rhamnopyranosyl-(1→2)-β-D-xylopyranosyl]-1,8-dihydroxy-3-methoxy xanthone;(2) iridoid glycosides:swertiamarin, sweroside, gentiopicrin, loganic acid;(3) pentacyclic triterpenoids:oleanolic acid;(4) flavonoids: isoorientin;(5) amino acids:alanine, valine;(5) sugars:sucrose, a-glucose, β-glucose;(6) others: gallic acid, choline, formic acid, acetic acid, succinic acid, saturated fatty acids, unsaturated fatty acids, sterols.
By combining PCA, PLS-DA and ANOVA results, we found that all samples of "Zangyinchen" could be clearly classified into five groups according to different species, respectively. Oleanolic acid, mangiferin, fatty acids and valine contents were highest in S. chirayita, whereas S. tetraptera showed the highest levels of gentiopicroside and choline, S. mussotii showed the highest levels of loganic acid and β-glucose, S. franchetiana showed the highest level of swertiamarin.
Conclusions:
1. Metabolites of C. chinensis, C. deltoidea and C. teeta have significant differences, and so it was important to show solicitude for their bioequivalence in clinical use. In addition, the critical markers responsible for the discrimination of different Rhizoma Coptidis species were found to be palmatine, coptisine, epiberberine, jateorrhizine, columbamine, berberine, sucrose, fatty acids and chlorogenic acid. Among them, epiberberine and sucrose are the most important metabolic markers as their contents have significant differences between any two of the three species.
2. The qNMR method is simple, fast, accurate and reproducible, which can be applied for the quality control and/or quality evaluation of Rhizoma Coptidis or other herbs containing alkaloids.
3. Metabolites of S. chirayita, S. mussotii, S. franchetiana, S. tetraptera and S. elata have significant differences, thus they should not be together as the original plant source of the "Zangyinchen". The critical markers responsible for the discrimination of different "Zangyinchen" species were found to be oleanolic acid, mangiferin, swertiamarin, gentiopicroside, loganic acid, fatty acids, valine, choline and sugars. These metabolites can be effective as the indicators for the species identification and quality control of "Zangyinchen". In addition, from the chemotaxonomic point of view, S. chirayita has the farthest phylogenetic relationship with the other four Swertia. whereas S. mussotii has a closer phylogenetic relationship with S. tetraptera and S. franchetiana has a closer phylogenetic relationship with S. elata.
Innovations:
1. In this study, by integration of multidisciplinary theories and techniques, we applied the1H NMR-based metabolomic technologies and analysis methods to study the species identification, quality evaluation and chemical taxonomy of multi-species traditional Chinese medicine and ethnic medicine from the perspective of the overall metabolome.
2. This paper has established the metabolic fingerprinting of Rhizoma Coptidis. In addition, by the combination of chemometric methods, we studied the difference of primary and secondary metabolites of the three species (C. chinensis, C. deltoidea and C. teeta) from the metabolome level for the first time.
3. Quantitative1H NMR (qNMR) method was first developed for simultaneous determination of berberine, jatrorrhizine, epiberberine, coptisine, palmatine and columbamine in Rhizoma Coptidis, which provides a new mean for the quality control and/or quality evaluation of Rhizoma Coptidis.
4. The overall metabolites present in "Zangyinchen" were simultaneously detected for the first time including xanthones and their glycosides, pentacyclic triterpenoids, iridoid glycosides, flavonoids, sugars, amino acids and organic acids. Among them, sucrose, choline, formic acid, acetic acid and succinic acid were reported for the first time in "Zangyinchen"
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