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Selective Inhibitory Effect of Osthenol on Human Cytochrome 2C8
Author(s) -
Cho Pil Joung,
Nam WoongShik,
Lee Doohyun,
Lee Taeho,
Lee Sangkyu
Publication year - 2018
Publication title -
bulletin of the korean chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.237
H-Index - 59
ISSN - 1229-5949
DOI - 10.1002/bkcs.11479
Subject(s) - chemistry , cytochrome p450 , inhibitory postsynaptic potential , furanocoumarin , ic50 , pharmacology , microsome , context (archaeology) , cyp3a4 , hydroxylation , biochemistry , enzyme , in vitro , biology , paleontology , neuroscience
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 IC 50 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.