黄连化学成分的分离及其降糖活性研究
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摘要
黄连为常见传统中草药之一,临床上多用于清热解毒的治疗。现代药理研究表明黄连有抗菌、消炎、抗癌、降压、降糖及抗氧化等作用。其主要化学成分为生物碱,如小檗碱、黄连碱、表小檗碱、巴马汀、药根碱等,其中小檗碱含量较高,约6%-10%。小檗碱被认为是黄连的主要活性成分。很多有关黄连的研究通常都以小檗碱为对象进行,但小檗碱在很多植物中均存在,含量也并非黄连中最高,黄连通常以煎剂或粉剂形式用药,与小檗碱相比,某些功效表现更优,所以小檗碱不能代替黄连。为了弄清黄连化学成分,了解黄连药效的物质基础,为黄连进一步综合开发利用做好铺垫,本课题对黄连化学成分进行了系统分离,并对各组分的降糖和抗氧化活性进行了研究,实验方法与结果如下：
1.黄连化学成分的分离
首先用液液分配色谱中的高速逆流色谱(HSCCC)技术在CHCl3-MeOH-0.2M HCl体系中分离黄连浸膏,大致划分黄连化学成分的极性范围。结果显示,除几种主要生物碱外,黄连中大部分成分是亲水性化合物,含量约50%。同时用HSCCC法从黄连浸膏中一次分离得到6个黄连主要生物碱(小檗碱、黄连碱、巴马汀、表小檗碱、药根碱和非洲防己碱),化合物纯度均大于90%。
其次用溶剂分部提取黄连浸膏,并对各提取部位进行柱色谱分离纯化。实验结果为石油醚提取物含量约占浸膏5%,氯仿提取物约10%,正丁醇提取物约70%。用传统柱色谱技术从氯仿和正丁醇部位分离得到14个已知化合物,分别为：小檗碱、小檗胺、巴马汀、黄连碱、小檗红碱、表小檗碱、木兰碱、groenlandicine、阿魏酸、胆碱、药根碱、非洲防己碱、8-氧小檗碱和8-氧黄连碱。其中胆碱是第一次从该属植物中分离得到。
在HPLC色谱图中指认了小檗碱、黄连碱、表小檗碱、药根碱及巴马汀以外的3个色谱峰,分别为阿魏酸、木兰碱和groenlandicine。用HPLC-DAD法测定了各色谱峰的大致含量。
2.降糖活性研究
黄连降糖在临床上有悠久的历史。为了考察黄连降糖活性物质,本文比较了各组分促进HepG2细胞葡萄糖消耗效果,并检测化合物之间是否有协同降糖作用。结果表明,各组分细胞降糖活性效果以黄连总碱最强,而浸膏次之,主要生物碱以外的组分降糖活性较弱。在实验浓度范围内,几乎所有的组分均能在一定程度上促进HepG2细胞葡萄糖消耗,并呈现剂量依赖关系。比较各个化合物在3μM时促进细胞降糖的效果,结果显示小檗碱降糖效果最为明显,与同剂量阳性对照二甲双胍相当,能显著促进细胞吸收葡萄糖；黄连碱和药根碱其次,也具有较强的促进细胞降糖活性；表小檗碱、非洲防己碱、小檗红碱和阿魏酸的活性相近；胆碱的活性表现较弱。几种主要生物碱之间有协同细胞降糖作用,而小檗碱分别与胆碱、阿魏酸也有显著的协同细胞降糖作用。与同剂量的小檗碱相比,100mg·L-1胆碱与38mg·L-1小檗碱混合后,细胞对葡萄糖的消耗增加34%,存活率上升到75%。当小檗碱与阿魏酸的质量比为100：1时,二者有显著地协同作用。动物实验中各组分的表现与细胞实验结果基本一致。动物实验比较黄连各组分(浸膏、总碱、主要生物碱外的亲水性组分)对四氧嘧啶糖尿病小鼠的降糖效果。动物实验说明各组分均对四氧嘧啶糖尿病大鼠的氧化应激指标SOD、MDA、GSH有一定的改善作用,但混合生物碱表现最为显著。
3.体外抗氧化活性研究
黄连在很多中药及其复方中用于糖尿病并发症的治疗,而并发症与抗氧化活性有密切的关系。本文用体外抗氧化实验考察了黄连的抗氧化效果。用比色法测定黄连中各化合物清除超氧阴离子、羟自由基、过氧化氢等活性氧的效果,用荧光法测定清除线粒体和细胞中活性氧的效果。结果显示在实验浓度范围内几乎所有化合物均有不同程度抗氧化活性；总体上小檗红碱、groenlandicine和黄连碱活性较高,优于小檗碱。
Rhizoma Coptidis is one of traditional medicinal plants, often used in treatment of clearing heat and detoxicating. Modern pharmacology studies showed it owned many activities, such as antimicrobial, anti-inflammation, anticancer, antihypertension, antihyperglycemic, antioxidant, and so forth. Its main constituents are alkaloids, shuch as berberine, coptistine, epiberberine, palmatine, jatrorrhizine. Of them, berberine had the highest mass ratio in Rhizoma Coptidis, about6%-10%. Many studies showed that berberine was main active constituent of Rhizoma Coptidis, but berberine cann't take the place of Rhizoma Coptidis, one reason was that beberine existed in many plants, another one was that the content of berberine from Rhizoma Coptidis wasn't the highest in all plants. In Chinese traditional medicinal study, Rhizoma Coptidis often was used by apozem and powder in clinic remedy, and some reports suggested that it showed some better pharmacological effect than berberine. In order to clarify material base of pharmacological effect derived from Rhizoma Coptidis, we made some study as follows:
1. Study on chemical constituents from Rhizoma Coptidis
To study polar of constituents from Rhizoma Coptidis by High Speed Counter Current Chromatography (HSCCC). HSCCC is liquid-liquid distribution chromatography technology. Rhizoma Coptidis extracts was isolated in CHCl3-MeOH-0.2MHCl olvent system by HSCCC. The result showed that most of constituents from Rhizoma Coptidis were hydrophilic compounds, about50%ass ratio of alcohol extracts. Six main alkaloids were isolated in one run by HSCCC, purify of them were all above85%.
Rhizoma Coptidis extracts was firstly extracted by different polar solvents, petroleum ether, chloroform, and n-butyl alcohol. Petroleum ether extracts had little. Petroleum extracts, chloroform extracts and n-butyl alcohol extracts occupied respectively5%,10%, and70%ass ratio of Rhizoma Coptidis alcohol extracts. Then slovent extracts were separated by traditional solum chromatography technology. From them,14compounds were isolated and identified by TLC, HPLC, NMR and MS. They were berberine, berbamine, palmatine, coptisine, berberubine, epiberberine, magnoflorine, groenlandicine, ferulic acid, choline, jatrorrhizine, columbamine, oxyberberine, and8-oxocoptisine. Choline was the first time isolated from coptidis plants.
Rhizoma Coptidis extracts was analysised with the method of content determination in2010Chinese Pharmacopoeia (2010edition).8compounds were identified in fingerprint of HPLC. Ferulic acid, magnoflorine and groenlandicine were determined by quantitative analysis with diode array detector.
2. Antihyperglycemic effect of constituents from Rhizoma Coptidis
HepG2cells is similar to human liver cells. Effect of glucose metabolism resulted from different constituents was determined by the glucose consumption in HepG2cells and alloxan-induced diabetes. Almost all compounds can increase glucose consumption in HepG2cells, and had dose-dependent relationship within test concentration. In3μM centration, berberine had the strongest activity, similar to positive control metformin, secondly, coptisine and jatrorrhizine also can promote glucose consumption in cells, epiberberine, columbamine and berberubine showed similar effect to ferulic acid, choline showed little activity. Main alkaloids had interaction glucose-lowering effect on HepG2cells, so do berberine and ferulic acid or choline. Compared with same dose of berberine, berberine38mg-L-in combination with choline100mg-L"1can make glucose consumption increase by34%nd elevate cell livability up to75%n HepG2cells. Berberine and ferulic acid had obvious synergistic glucose-lowering effect on HepG2cells as their mass ratio was100:1. Total alkaloids showes better activity than Rhizoma Coptidis ethanol extracts. Constituents except for main alkaloids had more little effect. Animal experiments had same effect as cells assay.
3. Antioxidant effect of constituents from Rhizoma Coptidis in vitro
The antioxidant effect of compounds from Rhizoma Coptidis was evaluated by colorimetric method on scavenging superoxide anion, hydroxyl free radical and hydrogen peroxide in vitro. ROS generated in mitochondria and HepG2cells was determined by fluorescence method. The result suggested almost compouds had antioxidant activities within test concentration. As a whole, berberubine, groenlandicine and coptisine has higher activities than berberine.
1.黄连化学成分的分离
首先用液液分配色谱中的高速逆流色谱(HSCCC)技术在CHCl3-MeOH-0.2M HCl体系中分离黄连浸膏,大致划分黄连化学成分的极性范围。结果显示,除几种主要生物碱外,黄连中大部分成分是亲水性化合物,含量约50%。同时用HSCCC法从黄连浸膏中一次分离得到6个黄连主要生物碱(小檗碱、黄连碱、巴马汀、表小檗碱、药根碱和非洲防己碱),化合物纯度均大于90%。
其次用溶剂分部提取黄连浸膏,并对各提取部位进行柱色谱分离纯化。实验结果为石油醚提取物含量约占浸膏5%,氯仿提取物约10%,正丁醇提取物约70%。用传统柱色谱技术从氯仿和正丁醇部位分离得到14个已知化合物,分别为：小檗碱、小檗胺、巴马汀、黄连碱、小檗红碱、表小檗碱、木兰碱、groenlandicine、阿魏酸、胆碱、药根碱、非洲防己碱、8-氧小檗碱和8-氧黄连碱。其中胆碱是第一次从该属植物中分离得到。
在HPLC色谱图中指认了小檗碱、黄连碱、表小檗碱、药根碱及巴马汀以外的3个色谱峰,分别为阿魏酸、木兰碱和groenlandicine。用HPLC-DAD法测定了各色谱峰的大致含量。
2.降糖活性研究
黄连降糖在临床上有悠久的历史。为了考察黄连降糖活性物质,本文比较了各组分促进HepG2细胞葡萄糖消耗效果,并检测化合物之间是否有协同降糖作用。结果表明,各组分细胞降糖活性效果以黄连总碱最强,而浸膏次之,主要生物碱以外的组分降糖活性较弱。在实验浓度范围内,几乎所有的组分均能在一定程度上促进HepG2细胞葡萄糖消耗,并呈现剂量依赖关系。比较各个化合物在3μM时促进细胞降糖的效果,结果显示小檗碱降糖效果最为明显,与同剂量阳性对照二甲双胍相当,能显著促进细胞吸收葡萄糖；黄连碱和药根碱其次,也具有较强的促进细胞降糖活性；表小檗碱、非洲防己碱、小檗红碱和阿魏酸的活性相近；胆碱的活性表现较弱。几种主要生物碱之间有协同细胞降糖作用,而小檗碱分别与胆碱、阿魏酸也有显著的协同细胞降糖作用。与同剂量的小檗碱相比,100mg·L-1胆碱与38mg·L-1小檗碱混合后,细胞对葡萄糖的消耗增加34%,存活率上升到75%。当小檗碱与阿魏酸的质量比为100：1时,二者有显著地协同作用。动物实验中各组分的表现与细胞实验结果基本一致。动物实验比较黄连各组分(浸膏、总碱、主要生物碱外的亲水性组分)对四氧嘧啶糖尿病小鼠的降糖效果。动物实验说明各组分均对四氧嘧啶糖尿病大鼠的氧化应激指标SOD、MDA、GSH有一定的改善作用,但混合生物碱表现最为显著。
3.体外抗氧化活性研究
黄连在很多中药及其复方中用于糖尿病并发症的治疗,而并发症与抗氧化活性有密切的关系。本文用体外抗氧化实验考察了黄连的抗氧化效果。用比色法测定黄连中各化合物清除超氧阴离子、羟自由基、过氧化氢等活性氧的效果,用荧光法测定清除线粒体和细胞中活性氧的效果。结果显示在实验浓度范围内几乎所有化合物均有不同程度抗氧化活性；总体上小檗红碱、groenlandicine和黄连碱活性较高,优于小檗碱。
Rhizoma Coptidis is one of traditional medicinal plants, often used in treatment of clearing heat and detoxicating. Modern pharmacology studies showed it owned many activities, such as antimicrobial, anti-inflammation, anticancer, antihypertension, antihyperglycemic, antioxidant, and so forth. Its main constituents are alkaloids, shuch as berberine, coptistine, epiberberine, palmatine, jatrorrhizine. Of them, berberine had the highest mass ratio in Rhizoma Coptidis, about6%-10%. Many studies showed that berberine was main active constituent of Rhizoma Coptidis, but berberine cann't take the place of Rhizoma Coptidis, one reason was that beberine existed in many plants, another one was that the content of berberine from Rhizoma Coptidis wasn't the highest in all plants. In Chinese traditional medicinal study, Rhizoma Coptidis often was used by apozem and powder in clinic remedy, and some reports suggested that it showed some better pharmacological effect than berberine. In order to clarify material base of pharmacological effect derived from Rhizoma Coptidis, we made some study as follows:
1. Study on chemical constituents from Rhizoma Coptidis
To study polar of constituents from Rhizoma Coptidis by High Speed Counter Current Chromatography (HSCCC). HSCCC is liquid-liquid distribution chromatography technology. Rhizoma Coptidis extracts was isolated in CHCl3-MeOH-0.2MHCl olvent system by HSCCC. The result showed that most of constituents from Rhizoma Coptidis were hydrophilic compounds, about50%ass ratio of alcohol extracts. Six main alkaloids were isolated in one run by HSCCC, purify of them were all above85%.
Rhizoma Coptidis extracts was firstly extracted by different polar solvents, petroleum ether, chloroform, and n-butyl alcohol. Petroleum ether extracts had little. Petroleum extracts, chloroform extracts and n-butyl alcohol extracts occupied respectively5%,10%, and70%ass ratio of Rhizoma Coptidis alcohol extracts. Then slovent extracts were separated by traditional solum chromatography technology. From them,14compounds were isolated and identified by TLC, HPLC, NMR and MS. They were berberine, berbamine, palmatine, coptisine, berberubine, epiberberine, magnoflorine, groenlandicine, ferulic acid, choline, jatrorrhizine, columbamine, oxyberberine, and8-oxocoptisine. Choline was the first time isolated from coptidis plants.
Rhizoma Coptidis extracts was analysised with the method of content determination in2010Chinese Pharmacopoeia (2010edition).8compounds were identified in fingerprint of HPLC. Ferulic acid, magnoflorine and groenlandicine were determined by quantitative analysis with diode array detector.
2. Antihyperglycemic effect of constituents from Rhizoma Coptidis
HepG2cells is similar to human liver cells. Effect of glucose metabolism resulted from different constituents was determined by the glucose consumption in HepG2cells and alloxan-induced diabetes. Almost all compounds can increase glucose consumption in HepG2cells, and had dose-dependent relationship within test concentration. In3μM centration, berberine had the strongest activity, similar to positive control metformin, secondly, coptisine and jatrorrhizine also can promote glucose consumption in cells, epiberberine, columbamine and berberubine showed similar effect to ferulic acid, choline showed little activity. Main alkaloids had interaction glucose-lowering effect on HepG2cells, so do berberine and ferulic acid or choline. Compared with same dose of berberine, berberine38mg-L-in combination with choline100mg-L"1can make glucose consumption increase by34%nd elevate cell livability up to75%n HepG2cells. Berberine and ferulic acid had obvious synergistic glucose-lowering effect on HepG2cells as their mass ratio was100:1. Total alkaloids showes better activity than Rhizoma Coptidis ethanol extracts. Constituents except for main alkaloids had more little effect. Animal experiments had same effect as cells assay.
3. Antioxidant effect of constituents from Rhizoma Coptidis in vitro
The antioxidant effect of compounds from Rhizoma Coptidis was evaluated by colorimetric method on scavenging superoxide anion, hydroxyl free radical and hydrogen peroxide in vitro. ROS generated in mitochondria and HepG2cells was determined by fluorescence method. The result suggested almost compouds had antioxidant activities within test concentration. As a whole, berberubine, groenlandicine and coptisine has higher activities than berberine.
引文
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