Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Jinan University, Guangzhou, China.
Key Laboratory of Hainan Trauma and Disaster Rescue, The First Affiliated Hospital of Hainan Medical University, Haikou, China.
Rapid Commun Mass Spectrom. 2021 Sep 30;35(18):e9157. doi: 10.1002/rcm.9157.
Characterizing the functional mechanism of quality control marker (Q-marker) was of great importance in revealing the primary pharmacological mechanism of herbs or the other complex system, and drug-related metabolites always contribute to the pharmacological functions. Cortex Phellodendri was used as a core herb in the treatment of diabetes mellitus (DM). As a Q-marker of Cortex Phellodendri, the role of phellodendrine in DM was still unclear. Thus, the characterization of phellodendrine-related metabolites in vivo and the subsequent induced functional mechanism exerted great importance in elucidating the anti-DM mechanism of Cortex Phellodendri.
An ultra-high-performance liquid chromatography-coupled time-of-flight mass spectrometry (UHPLC/Q-TOF MS) method was developed to profile metabolites of phellodendrine in rats. The potential pharmacological mechanism against DM was predicted by network pharmacology.
A total of 19 phellodendrine-related metabolites were screened out in rats for the first time. Among them, M4, M5, M9, and M12 were regarded as the primary metabolites. Meanwhile, phase I metabolic reactions of hydroxylation, demethylation, and isomerization and phase II reactions of glucuronidation and sulfation occurred to phellodendrine; glucuronidation and hydroxylation were the two main metabolic reactions. Moreover, the potential targets of phellodendrine and three main metabolites (M4, M5, and M12) were predicted by a network pharmacological method, and they mainly shared 52 targets, including PDE5A, CHRNA3, SIGMAR1, F3, ESR1, DRD1, DRD2, DRD3, and DRD4. Furthermore, Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that calcium signaling pathway, cGMP-PKG signaling pathway, and cAMP signaling pathway were regarded as the core mechanism of phellodendrine to treat DM.
The metabolic feature of phellodendrine in vivo was revealed for the first time, and its anti-DM mechanism information for further pharmacological validations was also supplied. It also gave a direction to further elucidation of pharmacological mechanism of Cortex Phellodendri in treating DM.
表征质量控制标志物（Q-marker）的功能机制对于揭示草药或其他复杂系统的主要药理机制非常重要，而药物相关代谢物通常有助于药理作用。黄柏被用作治疗糖尿病（DM）的核心草药。作为黄柏的 Q-marker，小檗碱在 DM 中的作用尚不清楚。因此，体内小檗碱相关代谢物的特征及其随后诱导的功能机制对于阐明黄柏的抗 DM 机制具有重要意义。
建立了超高效液相色谱-飞行时间质谱（UHPLC/Q-TOF MS）法对大鼠中小檗碱的代谢物进行分析。通过网络药理学预测潜在的抗 DM 药理机制。
首次在大鼠中筛选出 19 种小檗碱相关代谢物，其中 M4、M5、M9 和 M12 被认为是主要代谢物。同时，小檗碱发生了羟化、去甲基化和异构化的 I 相代谢反应以及葡萄糖醛酸化和硫酸化的 II 相反应；葡萄糖醛酸化和羟化是两种主要的代谢反应。此外，通过网络药理学方法预测了小檗碱和三种主要代谢物（M4、M5 和 M12）的潜在靶点，它们主要共享 52 个靶点，包括 PDE5A、CHRNA3、SIGMAR1、F3、ESR1、DRD1、DRD2、DRD3 和 DRD4。此外，京都基因与基因组百科全书通路分析表明，钙信号通路、cGMP-PKG 信号通路和 cAMP 信号通路被认为是小檗碱治疗 DM 的核心机制。
首次揭示了小檗碱在体内的代谢特征，并为进一步的药理验证提供了其抗 DM 机制信息。这也为进一步阐明黄柏治疗 DM 的药理机制提供了方向。
