Identification of Cytochrome P450 (CYP) Isoforms involved in the Metabolism of Corynoline, and Assessment of its Herb-Drug Interactions
Identification of Cytochrome P450 (CYP) Isoforms involved in the Metabolism of Corynoline, and Assessment of its Herb-Drug Interactions
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参与 Corynoline 代谢的细胞色素 P450 (CYP) 亚型的鉴定及其草药-药物相互作用的评估
DOI：
10.1002/ptr.3255
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发表时间：
2011-02-01
影响因子：
7.2
通讯作者：
Yang, Ling
中科院分区：
文献类型：
--
作者：
Fang, Zhong-Ze;Zhang, Yan-Yan;Yang, Ling
Corynoline是从Corynoline属植物中分离得到的一种异喹啉类生物碱，具有抑制乙酰胆碱酯酶、抑制细胞粘附、抗真菌和细胞毒等多种药理作用。本研究主要集中在其代谢及基于代谢的中草药相互作用。在NADPH存在下，将紫堇灵与人肝微粒体（HLM）孵育后，形成两种代谢产物（M-1和M-2）。化学抑制实验和重组CYP异构体的测定表明，CYP 2C 9主要参与M-1的形成，CYP 3A 4主要催化M-2的产生。在检测的7种主要的β-受体亚型中，紫堇碱对CYP 3A 4和CYP 2C 9的活性显示出强烈的抑制作用，IC 50分别为3.3 +/- 0.9 μ M和31.5 +/- 0.5 μ M。动力学分析表明，紫堇灵对CYP 3A 4的抑制最适合于非竞争性方式，Ki为3.2 μ M，而紫堇灵对CYP 2C 9的抑制最适合于竞争性方式，Ki为6.3 μ M。此外，Corynoline对CYP 3A 4表现出时间依赖性抑制（TDI）。灭活动力学参数（K-I和k（inact））分别计算为6.8 μ M和0.07 min（-1）。这些数据对紫堇碱及含紫堇碱中药的应用具有重要意义。版权所有（C）2010约翰威利父子有限公司
Corynoline, an isoquinoline alkaloid isolated from the genus Corydalis, has been demonstrated to show multiple pharmacological effects including inhibition of acetylcholinesterase, inhibition of cell adhesion, fungitoxic and cytotoxic activity. The present study focused on its metabolism and metabolism-based herb drug interactions. After corynoline was incubated with human liver microsomes (HLMs) in the presence of NADPH, two metabolites (M-1 and M-2) were formed. Chemical inhibition experiments and assays with recombinant CYP isoforms showed that CYP2C9 was mainly involved in the formation of M-1 and CYP3A4 mainly catalysed the production of M-2. Among seven major CYP isoforms tested, corynoline showed strong inhibitory effects on the activities of CYP3A4 and CYP2C9, with an IC50 of 3.3 +/- 0.9 mu M and 31.5 +/- 0.5 mu M, respectively. Kinetic analysis showed that inhibition of CYP3A4 by corynoline was best fit to a noncompetitive manner with K-i of 3.2 mu M, while inhibition of CYP2C9 by corynoline was best fit to a competitive manner with K-i of 6.3 mu M. Additionally, corynoline exhibited time-dependent inhibition (TDI) toward CYP3A4. The inactivation kinetic parameters (K-I and k(inact)) were calculated to be 6.8 mu M and 0.07 min(-1), respectively. These data are of significance for the application of corynoline and corynoline-containing herbs. Copyright (C) 2010 John Wiley & Sons, Ltd.