Selective Inhibitory Effect of Osthenol on Human Cytochrome 2C8

Bulletin of the Korean Chemical Society

Pil Joung Cho¹ 

[1] BK21 Plus KNU MultiOmics based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences Kyungpook National University Daegu 41566 Republic of Korea

关键词: Osthenol;    Furanocoumarin;    CYP2C8;    Paclitaxel;    Human liver microsomes;   

DOI  :  10.1002/bkcs.11479

学科分类：化学（综合）

来源: Korean Chemical Society

【 摘 要 】

Osthenol is a furanocoumarin with anti‐tumor, anti‐inflammatory, and anti‐viral activity. It is present in various citrus juices and fruits; however, its inhibitory effects on cytochrome P450 (CYP) enzyme activity, in the context of herb–drug interaction (HDI) prediction, have not been previously studied. In this study, osthenol was chemically synthesized in order to identify potential HDIs. Its inhibitory effect on eight CYP isoforms and the underlying mechanism of inhibition were investigated by using cocktail assays and liquid chromatography‐tandem mass spectrometry in pooled human liver microsomes. The inhibitory effect of osthenol on CYP2C8‐catalyzed paclitaxel hydroxylation was selective and dose‐dependent, but not time‐dependent. The IC50 value was 2.8 μM. Additionally, osthenol displayed mixed mode inhibition with a relatively low Ki value of 0.96 μM, which is indicative of the potential for HDIs with co‐administered CYP2C8 substrates. To the best of our knowledge, this is the first report of selective inhibition of CYP2C8 by osthenol.

【 授权许可】

Unknown