整合代谢组学与定性代谢流技术研究五子衍宗丸治疗少弱精子症的药效物质基础及作用机制

Wuzi-Yanzong-Wan (WZYZW), a classical traditional Chinese medicine (TCM) prescription is widely used to treat oligoasthenozoospermia. However, the therapeutic basis of WZYZW as well as its action mechanism for oligoasthenozoospermia has been still unclear yet. Recent study indicated that oligoasthenozoospermia is highly associated with multiple metabolic pathways, which suggested that WZYZW may prevent oligoasthenozoospermia through regulatory metabolizability. In this work, an advanced strategy based on the integration of Metabonomics and qualitative metabolic flow technology was used to for systematically screening and identifying the metabolites of drug action as well as demonstrating the time-effect relationships of WZYZW for improving sperm quality. Meanwhile，the main constituents of WZYZW in rat serum were also detected to analyze its correlation between the constituents in vivo and the metabolites of drug action,and determine the potential effective compounds for therapeutic effect, subsequently, the pharmacokinetic of the main active constituents will be studied. The pharmacokinetic-pharmacodynamic ( PK-PD) model will be developed for the evaluation of the dose-time and time-effect relationships of the potential effective compounds of WZYZW on oligoasthenozoospermia.Then radically clarify the material therapeutic basis of WZYZW, the dose-time and time-effect relationships as well as its action mechanism for oligoasthenozoospermia, which can provide data to support the clinical application of WZYZW and to discover innovative constituents from WZYZW.

五子衍宗丸是中医治疗少弱精子症首选方，其药效物质和作用机制尚不清楚。新研，少弱精子症与多条代谢途径高度关联，生理、病理与药理内在统一提示：药物可能通过调节代谢治疗少弱精子症，课题组根据中医药理论和临床实践初步证实了其调控代谢行为。本研究拟以代谢组学与定性代谢流整合技术为研究策略，首先在整体动物层面确定药物作用的代谢产物并预测通路，然后在离体细胞层面阐明药物作用的代谢通路并揭示药物对上述代谢产物效应的经时变化特征；运用中药血清药物化学方法分析和表征药物体内成分；采用“谱效关系”方法建立药物体内成分与代谢产物的相关性，确定药效物质并进行药代动力学研究；应用PK-PD模型建立药物药效动力学与药代学行为的关联，揭示其量效时关系特征。从而阐明五子衍宗丸治疗少弱精子症的药效物质、作用机制及量效时关系，为临床应用奠定夯实的生物学及化学基础，为其它经典名方的活性成分和作用机制研究提供有益参考。

男性不育发病率持续上升及其对人口的影响是重要的公共卫生问题，少弱精症是男性不育的主要临床表型之一，缺乏药物治疗方案一直是少弱精症治疗的主要障碍。因此，如何发现新的少弱精症药物治疗策略是目前仍待解决的重要科学问题。本课题从代谢组和基因组两个层面对中医治疗少弱精症的经典名方五子衍宗丸的药效成分和作用机制开展了系统的研究，取得了一定进展。并在此基础上，综合利用中药学、化学、基因组学、生物信息学等学科前沿交叉技术，从五子衍宗丸的化学成分群中发现了一种具有显著增强动物精子数量、活力、空间运动和授精能力的活性成分五味子乙素，其可显著激活睾丸中三条生殖信号通路包括配子生成、减数分裂和精子发育通路中的基因表达，发挥生精作用。药动学研究显示，其口服后可迅速入血并到达靶器官睾丸，表现出良好的成药性。该研究首次发现并证实了五味子乙素的生精活性，揭示了其基因调控机制，具有重要科学的意义和临床转化价值，可望为解决男性不育相关社会问题作出重要贡献，预期亦可产生重大经济效益。