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Drug Metabolism and Disposition Fast Forward
First published on July 30, 2007; DOI: 10.1124/dmd.107.017012

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Received for publication June 11, 2007.
Revised July 13, 2007.
Accepted for publication July 27, 2007.

Identification of new flavone-8-acetic acid metabolites using mouse microsomes and comparison with human microsomes

Minh Hien Pham 1, Nicolas Auzeil 2, Anne Regazzetti 2, Daniel Dauzonne 3, Annabelle Dugay 2, Marie-Claude Menet 2, Daniel Scherman 1, Guy G. Chabot 1*

1 Faculty of Pharmacy, University Paris Descartes, Laboratory of chemical and genetic pharmacology 2 Faculty of Pharmacy, University Paris Descartes, Service de Chimie Analytique 3 Institut Curie, Section Recherche UMR 176

* Address correspondence to: E-mail: guy.chabot{at}univ-paris5.fr

Abstract

Flavone-8-acetic acid (FAA) is a potent anticancer agent in mouse but has not shown activity in humans. Because FAA metabolism could play a role in this interspecies difference, our aim was to identify the metabolites formed in vitro using mouse microsomes and compare to human microsomes. Mouse microsomes produced 6 metabolites as detected by reversed-phase high-performance liquid chromatography-mass spectrometry. Three metabolites were identified as the 3'-, 4'-, or 6-hydroxy-FAA, by comparison with retention times, UV and MS spectra of standards. Two metabolites presented a molecular weight of 296 (FAA=280) indicating the presence of one oxygen, but did not correspond to any monohydroxylated FAA derivative. These two metabolites were identified as epoxides because they were sensitive to epoxide hydrolase. The position of the oxygen was determined by the formation of the corresponding phenols under soft acidic conditions: one epoxide yielded the 3'- and 4'-hydroxy-FAA, thus corresponding to the 3',4'-epoxy-FAA, whereas the other epoxide yielded the 5- and 6-hydroxy-FAA, thus identifying the 5,6-epoxy-FAA. The last metabolite was assigned to the 3',4'-dihydrodiol-FAA because of its molecular weight (314) and sulfuric acid dehydration that indicated that the 3' and 4' positions were involved. Compared to mouse microsomes, human microsomes (2 pools and 15 individual microsomes) were unable to metabolize FAA to a significant extent. In conclusion, we have identified 6 new FAA metabolites formed by mouse microsomes, whereas human microsomes could not metabolize this flavonoid to a significant extent. The biological importance of the new metabolites identified herein remains to be evaluated.


Key words: anticancer agents, cytochrome P450 catalyzed oxidations, endoplasmic reticulum, HPLC, human CYP enzymes, liver microsomes, metabolite identification, microsomes, structure elucidation




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