基于谱-效关系及肠道菌转化的桔梗总皂苷镇咳祛痰药效物质阐释研究

Our previous study showed that it is very important to explain the effective substances of total saponins from Platycodi radix based on prototype active compounds, metabolic active compounds and their one-to-many and many-to-one metabolic networks, as the total saponins from Platycodi radix possesses great value for development of new modern medicine with high safety and efficacy for cough and expectoration treatment. Furthermore, the explanation is also very necessary for the standard revision of Platycodi radix. However, the effective materials research of traditional Chinese medicine with antitussive and expectorant effects is mainly dependent on animal models. It needs much amount of sample and seriously limited the development of new modern medicine.. In this work, the spectrum-effective relationships method was selected to reduce the amount requirement of prototype compounds and provide guidance information for separation, concentration and screening of prototype active compounds, the intestinal microbiota biotransformation method together with the spectrum-effective relationships were applied to concentrate the extracts of traditional Chinese medicine for the active metabolites research, the intestinal microbiota biotransformation method was used to reduce the sample amount requirement for metabolism research to clarify the metabolic network of prototype and metabolic active components of traditional Chinese medicine. Hence, the limitation of animal models for the explanations of effective substances will be overcome, and the effective materials of total saponins from Platycodi radix could be not only clarified but also be explained using these methods.. This work could provide material and theory basis for total saponins of Platycodi radix on developmentof new modern antitussive and expectorant medicines for cough and expectoration treatment as well as the standard revision of Platycodi radix, and it also put up new methods and ideas to explain effective materials of other traditional Chinese medicine with antitussive and expectorant effects.

课题组前期研究表明根据原形与代谢活性成分及二者一对多、多对一的代谢网络阐释桔梗总皂苷镇咳祛痰药效物质，对基于其开发现代化新药保障咳嗽咳痰的安全有效防治及桔梗药材标准的修订极为必要。但当前镇咳祛痰中药药效物质研究主要依赖动物模型，样品用量大，严重束缚药效物质阐释。本项目基于谱-效关系缩小原形成分研究目标，进而导向富集目标成分并验证其活性以阐明桔梗皂苷原形活性成分；利用肠道菌转化富集桔梗总皂苷代谢产物并基于谱-效关系及原形活性成分基原阐明桔梗皂苷镇咳祛痰代谢活性成分；采用肠道菌转化降低桔梗皂苷原形活性成分代谢研究用量并结合代谢活性成分阐明二者一对多、多对一的代谢网络，拟突破动物模型研究镇咳祛痰药效物质的束缚，快速高效阐释而不仅仅阐明桔梗总皂苷镇咳祛痰药效物质。本研究可为桔梗总皂苷现代化镇咳祛痰新药的开发及桔梗药材标准的修订奠定物质与理论基础，并为其它镇咳祛痰中药药效物质阐释提供新方法新思路。

基于原形与代谢活性成分及二者一对多、多对一的代谢网络阐释桔梗总皂苷镇咳祛痰药效物质，对基于其开发现代化新药保障咳嗽咳痰的安全有效防治具有重要意义。肠道菌转化与谱效关系联用新方法是筛选中药活性成分研究的有力工具。课题组基于谱效关系共筛选出10个与桔梗总皂苷镇咳活性相关原形成分，16个与桔梗总皂苷祛痰活性相关原形成分。其中Platycodin D、Platycoside G3和 Platycodin D3等3个桔梗皂苷原形成分兼具镇咳祛痰活性。将桔梗总皂苷经肠道菌转化，基于谱效关系共筛选出11个与镇咳活性相关的桔梗总皂苷肠道菌转化产物成分，12个与祛痰活性相关桔梗总皂苷肠道菌转化产物成分。其中8个转化产物成分兼具镇咳祛痰活性。以10个桔梗皂苷单体成分进行肠道菌转化，研究其转化产物成分及转化规律。结果发现一个单体成分可以产生多种转化产物成分，而不同的单体成分可产生多种相同的肠道菌转化产物成分。根据其转化规律，以相同母核为依据，通过反向追踪法，课题组构建了桔梗皂苷原形成分与桔梗总皂苷转化产物活性成分的一对多、多对一网络。同时，代谢组学研究结果表明，桔梗总皂苷及其转化产物均可以通过调控亚油酸代谢、花生四烯酸代谢和甘油磷脂代谢发挥镇咳活性，可通过调控花生四烯酸代谢发挥祛痰活性。这一结果进一步提示桔梗总皂苷在体内真正起效的成分可能是其肠道菌转化产物成分。最后，本课题组选用桔梗皂苷D进行了镇咳祛痰药效研究，验证了本课题研究方法的可靠性。从整体看，课题组所构建的桔梗皂苷原形活性成分与转化产物活性成分之间的一对多、多对一网络，在很大程度上成功阐释了桔梗总皂苷镇咳祛痰药效物质，为桔梗总皂苷现代化镇咳祛痰新药的开发奠定了物质与理论基础，并为其它镇咳祛痰中药药效物质阐释提供了新方法新思路。