C5-Hydroxylation of liquiritigenin is catalyzed selectively by CYP1A2

Abstract

1. Liquiritigenin (7,4′-dihydroxyflavone), the primary active component of a traditional Chinese medicine Glycyrrhizae radix, has a wide range of pharmacological activities. Six oxidative metabolites of liquiritigenin (7,3′,4′-trihydroxyflavone, a hydroxyl quinine metabolite, two A-ring dihydroxymetabolites, 7,4′-dihydroxyflavone, and 7-hydroxychromone) have been detected in rat liver microsomes (RLMs), and one CYP3A4-catalyzed metabolite (7,4′-dihydroxyflavone) has been identified in human liver microsomes (HLMs) recently.

2. In this study, a novel mono-hydroxylated metabolite was detected in reaction catalyzed by HLMs, and was identified as 4′,5,7-trihydroxyflavanone by comparing the tandem mass spectra and the chromatographic retention time with that of the standard compound.

3. Significant difference in CL_int (9-fold) was found between these two oxidative pathways of liquiritigenin, and C5-hydroxylation pathway was identified as the major oxidative metabolism of liquiritigenin.

4. The study with chemical selective inhibitor, cDNA-expressed human CYPs, correlation assay, and kinetic study demonstrated that CYP1A2 was the specific isozyme responsible for the C5-hydroxylation metabolism of liquiritigenin in HLMs.

Keywords::

• Liquiritigenin
• cytochrome P450
• human liver microsomes
• metabolism

Acknowledgements

We thank the help and advice of Dr. Yu-Qi He, Shanghai University of Traditional Chinese Medicine.

Declaration of interest

The authors report no conflict of interest.