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KMID : 0613820130230091126
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Journal of Life Science
2013 Volume.23 No. 9 p.1126 ~ p.1132
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Inhibitory Potential of Thelephoric Acid on CYP2J2 Activities in Human Liver Microsomes
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Wu Zhexue
Lee Bo-ram
Song Kyung-Sik
Liu Kwang-Hyeon
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Abstract
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Cytochrome P450 2J2 (CYP2J2) is an enzyme mainly found in human extrahepatic tissues, with predominant expression in the cardiovascular system. CYP2J2 plays important roles in the metabolism of endogenous metabolites and therapeutic drugs, such as arachidonic acid, astemizole, ebastine, and terfenadine. CYP2J2 is also overexpressed in human cancer tissues and cancer cell lines and may represent a potential target for therapy of human cancers. In this study, 10 natural products obtained from plants and microorganisms were screened as potential CYP2J2 inhibitors. Among them, thelephoric acid showed strong inhibition of astemizole O-demethylation activity (IC_50=3.23μM) in a dose-dependent manner. Evaluation of the substrate dependency of the inhibitory activity of thelephoric acid showed that it strongly inhibited CYP2J2-mediated ebastine hydroxylation (IC_50=5.32μM) and terfenadine hydroxylation (IC_50=3.27μM) in a substrate nondependent manner. The present data suggest that this compound might be a potential candidate for further evaluation for anticancer activity.
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KEYWORD
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Thelephoric acid, CYP2J2, screening, drug-interaction, cytochrome P450
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