新加密氨酸和人类细胞染色体P450的相互作用 in silico 和 in vitro
Xiu Chen1, Xiaoyi Pan1, Jieping Zhao1
1Institute of Drug Metabolism and Pharmaceutical Analysis, Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
新加密氨酸 (NCTS) 是由CYP2C8和CYP2C9酶代谢的. 此外,NCTS还会诱导CYP2B6和CYP3A4的表达,影响药物开发和临床使用.
科学领域:
- 药理学 药理学 是一个学科.
- 药物新陈代谢 药物新陈代谢
- 自然产品 化学 化学
背景情况:
- 来自Salviae Miltiorrhizae Radix et Rhizoma的Neocryptotanshinone (NCTS) 显示出潜在的低血糖和抗炎作用.
- 了解NCTS与细胞染色体P450s (CYPs) 的相互作用对于其治疗发展至关重要.
研究的目的:
- 通过人类肝脏显微体 (HLM) 调查NCTS的代谢.
- 确定NCTS对CYP酶表达的监管作用.
- 阐明NCTS-CYP相互作用背后的机制.
主要方法:
- 人类肝脏显微体 (HLMs) 化试验用于识别NCTS代谢物.
- 酶动力学和抑制研究,以评估NCTS对CYP活性的影响.
- 主要人类肝细胞和记者基因测试用于评估NCTS诱导的CYP表达和PXR激活.
- 分子对接模拟以预测NCTS与CYP和PXR结合.
主要成果:
- 在HLM中,NCTS主要由CYP2C9 (65%) 和CYP2C8 (35%) 代谢.
- NCTS对CYP1A2,CYP2C8和CYP2C9 (IC50>30μM) 的抑制作用较弱.
- 通过孕前X受体 (PXR) 激活,NCTS显著诱导了人肝细胞中CYP2B6和CYP3A4的表达.
结论:
- NCTS通过CYP2C9和CYP2C8.8进行显著的代谢.
- NCTS可以诱导CYP2B6和CYP3A4的表达,可能会影响同时服用药物的新陈代谢.
- 这些发现对于预测药物相互作用和指导NCTS临床应用至关重要.
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