Zhang Fengxiang, Cui ShuangShuang, Li Ziting, Yuan Yulinlan, Li Chang, Li Ruiman
Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Jinan University Guangzhou 510632 China
Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University Guangzhou 510632 China.
RSC Adv. 2020 Sep 21;10(57):34847-34858. doi: 10.1039/d0ra06382g. eCollection 2020 Sep 16.
The prototypes and metabolites formed from the use of traditional Chinese medicines (TCM) are typically the cause of both side side-effects and therapeutic results. Therefore, the characterization of substances and the determination of functional changes are of great importance for clinical applications. Secoisolariciresinol-diglycoside (SDG), one major compound in flaxseeds, was used as a potential drug to treat tumors in the clinic; however, the metabolism information and functional changes of SDG were limited, which limited its application. In this study, an integrated strategy based on metabolite profiling and network pharmacology was applied to explore the metabolism feature and functional changes of SDG. As a result, a total of 28 metabolites were found in rats, including 14 in plasma, 22 in urine, 20 in feces, 7 in the heart, 14 in the liver, 8 in the spleen, 10 in the lungs, 14 in the kidneys, and 4 in the brain. Among them, M8, M13 and M26 were the main metabolites of SDG in rats and 24 were characterized for the first time. The metabolic reactions contained phase I reactions of demethylation, dehydroxylation, deglycosylation, arabinosylation and glycosylation, and phase II reactions of glucuronidation and sulfation were also observed. Notably, the arabinosylation and glycosylation were found in SDG for the first time. Meanwhile, 121 targets of SDG and its metabolites were found, PRKCB was the main target of SDG, and the metabolites of SDG mainly targeted HSP90A1, IL6, AKT1, MAPK3, MTOR, PIK3CA, SRC, ESR1, AR, PIK3CB, and PIK3CB. The difference of targets between SDG and its metabolites could result in its additional functional pathways of neurotrophin signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway or indications of anti-prostate cancer. This work provided a new insight for exploring the mechanism and therapy indications of drugs.
中药使用过程中形成的原型和代谢产物通常是副作用和治疗效果的起因。因此，物质表征和功能变化的测定对于临床应用至关重要。开环异落叶松脂素二葡萄糖苷（SDG）是亚麻籽中的一种主要化合物，在临床上被用作治疗肿瘤的潜在药物；然而，SDG的代谢信息和功能变化有限，这限制了其应用。在本研究中，采用了基于代谢物谱分析和网络药理学的综合策略来探索SDG的代谢特征和功能变化。结果，在大鼠中总共发现了28种代谢产物，包括血浆中的14种、尿液中的22种、粪便中的20种、心脏中的7种、肝脏中的14种、脾脏中的8种、肺中的10种、肾脏中的14种以及大脑中的4种。其中，M8、M13和M26是大鼠中SDG的主要代谢产物，24种是首次被表征。代谢反应包括去甲基化、去羟基化、去糖基化、阿拉伯糖基化和糖基化的I相反应，同时也观察到了葡萄糖醛酸化和硫酸化的II相反应。值得注意的是，阿拉伯糖基化和糖基化是首次在SDG中发现。同时，发现了SDG及其代谢产物的121个靶点，PRKCB是SDG的主要靶点，SDG的代谢产物主要靶向HSP90A1、IL6、AKT1、MAPK3、MTOR、PIK3CA、SRC、ESR1、AR、PIK3CB和PIK3CB。SDG与其代谢产物之间靶点的差异可能导致其神经营养因子信号通路、PI3K-Akt信号通路、HIF-1信号通路的额外功能途径或抗前列腺癌的适应症。这项工作为探索药物的作用机制和治疗适应症提供了新的见解。
