水芹中的脱氧鬼臼毒素对人 CYP2C9 和 CYP3A4 的抑制作用。

Inhibitory effects of deoxypodophyllotoxin from Anthriscus sylvestris on human CYP2C9 and CYP3A4.

机构信息

Doping Control Center, Korea Institute of Science and Technology, Chungryang, Seoul 130-650, Korea.

出版信息

Planta Med. 2010 May;76(7):701-4. doi: 10.1055/s-0029-1240657. Epub 2009 Dec 3.

PMID:19960413

Abstract

Deoxypodophyllotoxin (DPT) is a bioactive compound of Anthriscus sylvestris (Apiaceae). In the present study, the inhibition of cytochrome P450 (CYP) by DPT was evaluated in human liver microsomes (HLM) and the baculovirus-insect cell-expressed human CYPs using a cocktail probe assay. When a mixture of specific CYP substrates was incubated with DPT in HLM, CYP2C9-catalyzed diclofenac 4-hydroxylation and CYP3A4-catalyzed midazolam 1-hydroxylation were strongly inhibited by DPT, with IC (50) values of 6.3 and 9.2 microM, respectively. The Lineweaver-Burke plots for the inhibition of CYP2C9 and CYP3A4 in HLM and baculovirus-insect cell-expressed human CYPs were consistent with a competitive type of inhibition. From these results, DPT was characterized to be a competitive inhibitor of CYP2C9 and CYP3A4, with K(i) values of 3.5 and 10.8 microM in HLM and 24.9 and 3.5 microM in baculovirus-insect cell-expressed human CYPs, respectively.

摘要

脱氧鬼臼毒素（DPT）是土木香（伞形科）的一种生物活性化合物。在本研究中，采用鸡尾酒探针法，在人肝微粒体（HLM）和杆状病毒-昆虫细胞表达的人细胞色素 P450（CYP）中评估了 DPT 对细胞色素 P450（CYP）的抑制作用。当用 DPT 孵育含有特定 CYP 底物的混合物时，DPT 强烈抑制 CYP2C9 催化的双氯芬酸 4-羟化和 CYP3A4 催化的咪达唑仑 1-羟化，IC（50）值分别为 6.3 和 9.2 microM。HLM 和杆状病毒-昆虫细胞表达的人细胞色素 P450 中 CYP2C9 和 CYP3A4 的抑制的 Lineweaver-Burke 图谱与竞争性抑制一致。根据这些结果，DPT 被鉴定为 CYP2C9 和 CYP3A4 的竞争性抑制剂，在 HLM 和杆状病毒-昆虫细胞表达的人细胞色素 P450 中的 K（i）值分别为 3.5 和 10.8 microM 和 24.9 和 3.5 microM。