Liu Xiaoxuan, Wang Qiaoxia, Chen Meng, Tao Jiayue, Wang Jing, Liu Siqi, Hou Jincai, Li Dan, Wang Rufeng
School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 102488, China.
School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 102488, China.
J Ethnopharmacol. 2023 May 23;308:116303. doi: 10.1016/j.jep.2023.116303. Epub 2023 Feb 24.
Changan Granule (CAG) is a Chinese patent drug developed based on an empirical prescription in accordance with the formulation theory of Traditional Chinese Medicine. The prescription is composed of eight herbal drugs which have been traditionally used by Chinese people for a long history. It has effects of invigorating spleen and supplementing qi, as well as regulating liver and ceasing diarrhea, and is indicated for the treatment of irritable bowel syndrome (IBS).
This study was aimed to investigate the interaction between CAG and its main components and cytochrome P450 (CYP450) enzymes so as to characterize the major metabolites and metabolic enzymes and evaluate the safety concerns to its clinical use.
Both in vivo and in vitro experiments using such as diarrhea-predominant IBS (IBS-D) rat model, HepG2 cells, and human liver microsomes (HLM) were carried out to investigate the interaction between CAG and its main components and CYP450 enzymes. Real-time quantitative PCR (qPCR), ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and cocktail probes were employed to qualitatively or quantitatively measure the metabolites and metabolic enzymes.
CAG inhibited the enzyme activities of CYP1A2, CYP2E1, CYP2D6, CYP2C9, and CYP3A4 and the mRNA expressions of CYP2E1, CYP2C9, CYP3A4, and CYP2D6 in vitro. CAG down-regulated the increased expression of CYP1A2 and up-regulated the decreased expression of CYP3A1 in vivo. Twenty-two metabolites were characterized from the main components of CAG after incubation with HLM in vitro. CYP2D6, CYP2E1, CYP3A4 and CYP2C9 were identified as the characteristic metabolic enzymes.
This study provides a reference for clinical application of CAG in safety. CAG and CYP450 enzymes are interacted. CAG is mainly metabolized by CYP2E1 and CYP2D6. The expression of CYP2E1 and CYP2D6 are more susceptible to be influenced by CAG in comparison with that of CYP3A4, CYP2C9 and CYP1A2. It implies the potential risk of interaction when CAG is taken together with the drugs metabolized by CYP2E1 and CYP2D6.
肠安颗粒（CAG）是一种基于经验方并按照中医方剂理论研制的中成药。该方剂由八味草药组成，这些草药在中国有着悠久的使用历史。它具有健脾益气、疏肝止泻的功效，用于治疗肠易激综合征（IBS）。
本研究旨在探讨CAG及其主要成分与细胞色素P450（CYP450）酶之间的相互作用，以确定主要代谢产物和代谢酶，并评估其临床使用的安全性问题。
采用腹泻型肠易激综合征（IBS-D）大鼠模型、HepG2细胞和人肝微粒体（HLM）进行体内和体外实验，以研究CAG及其主要成分与CYP450酶之间的相互作用。采用实时定量PCR（qPCR）、超高效液相色谱-串联质谱（UPLC-MS/MS）和鸡尾酒探针定性或定量测定代谢产物和代谢酶。
CAG在体外抑制CYP1A2、CYP2E1、CYP2D6、CYP2C9和CYP3A4的酶活性以及CYP2E1、CYP2C9、CYP3A4和CYP2D6的mRNA表达。CAG在体内下调CYP1A2的上调表达并上调CYP3A1的下调表达。体外与HLM孵育后，从CAG的主要成分中鉴定出22种代谢产物。CYP2D6、CYP2E1、CYP3A4和CYP2C9被确定为特征性代谢酶。
本研究为CAG的临床安全应用提供了参考。CAG与CYP450酶存在相互作用。CAG主要由CYP2E1和CYP2D6代谢。与CYP3A4、CYP2C9和CYP1A2相比，CAG对CYP2E1和CYP2D6表达的影响更敏感。这意味着CAG与由CYP2E1和CYP2D6代谢的药物合用时存在相互作用的潜在风险。
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