基于肠道菌群的特女珍胺靶向羧酸酯酶治疗结直肠癌的药动药效研究及分子机制。
Gut microbiota-based pharmacokinetic-pharmacodynamic study and molecular mechanism of specnuezhenide in the treatment of colorectal cancer targeting carboxylesterase.
发表日期：2023 Sep
作者：
Hang Yu, Hui Xu, Xinyu Yang, Zhengwei Zhang, Jiachun Hu, Jinyue Lu, Jie Fu, Mengmeng Bu, Haojian Zhang, Zhao Zhai, Jingyue Wang, Jiandong Jiang, Yan Wang
来源：
Journal of Pharmaceutical Analysis
摘要：
特女贞苷（SNZ）是女贞子的主要成分之一，具有抗炎、抗氧化、抗肿瘤作用。 SNZ的生物利用度低，难以解释其药理作用机制。本研究探讨了肠道菌群在SNZ代谢和药代动力学特征中的作用及其药理学意义。 SNZ 可以被肠道微生物组快速代谢，并且发现了 SNZ 的两种肠道细菌代谢物：红景天苷和酪醇。此外，羧酸酯酶可能是介导其代谢的主要肠道细菌酶。同时，在SNZ与肝微粒体或肝匀浆的培养体系中未发现代谢，表明肠道菌群是参与SNZ代谢的主要部分。此外，药代动力学研究表明，在肠道微生物群存在的情况下，可以在血浆中检测到红景天苷和酪醇。有趣的是，口服SNZ的结直肠肿瘤小鼠模型中肿瘤的发展受到抑制，这表明SNZ表现出抑制肿瘤生长的潜力，组织分布研究表明红景天苷和酪醇可以分布在肿瘤组织中。同时，SNZ调节肠道菌群和真菌群的结构，这可能是SNZ抗肿瘤活性的机制。此外，SNZ 在体外和体内刺激肠道菌群分泌短链脂肪酸。未来，针对肠道微生物以及天然产物与肠道微生物之间的相互作用可能会导致新药的发现和开发。© 2023 作者。
Specnuezhenide (SNZ) is among the main components of Fructus Ligustri Lucidi, which has anti-inflammation, anti-oxidation, and anti-tumor effect. The low bioavailability makes it difficult to explain the mechanism of pharmacological effect of SNZ. In this study, the role of the gut microbiota in the metabolism and pharmacokinetics characteristics of SNZ as well as the pharmacological meaning were explored. SNZ can be rapidly metabolized by the gut microbiome, and two intestinal bacterial metabolites of SNZ, salidroside and tyrosol, were discovered. In addition, carboxylesterase may be the main intestinal bacterial enzyme that mediates its metabolism. At the same time, no metabolism was found in the incubation system of SNZ with liver microsomes or liver homogenate, indicating that the gut microbiota is the main part involved in the metabolism of SNZ. In addition, pharmacokinetic studies showed that salidroside and tyrosol can be detected in plasma in the presence of gut microbiota. Interestingly, tumor development was inhibited in a colorectal tumor mice model administered orally with SNZ, which indicated that SNZ exhibited potential to inhibit tumor growth, and tissue distribution studies showed that salidroside and tyrosol could be distributed in tumor tissues. At the same time, SNZ modulated the structure of gut microbiota and fungal group, which may be the mechanism governing the antitumoral activity of SNZ. Furthermore, SNZ stimulates the secretion of short-chain fatty acids by intestinal flora in vitro and in vivo. In the future, targeting gut microbes and the interaction between natural products and gut microbes could lead to the discovery and development of new drugs.© 2023 The Authors.