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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: dmd.107.017012v1 35/11/2023    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pham, M. H. Articles by Chabot, G. G. Search for Related Content PubMed PubMed Citation Articles by Pham, M. H. Articles by Chabot, G. G.

Identification of New Flavone-8-Acetic Acid Metabolites Using Mouse Microsomes and Comparison with Human Microsomes

Institut National de la Santé et de la Recherche Médicale U640, Centre National de la Recherche Scientifique UMR8151, Université Paris Descartes, Faculté de Pharmacie, Laboratoire de Pharmacologie Chimique et Génétique (M.H.P., D.S., G.G.C.) and Plateau Spectrométrie de Masse (IFR 71), Service de Chimie Analytique, Paris, France (N.A., A.R., A.D., M.-C.M.); AP-HP, Hôpital Européen Georges Pompidou, Département de Pharmacologie et de Toxicologie, Paris, France (M.H.P.); Ecole Nationale Supérieure de Chimie, Paris, France (D.S.); and Centre National de la Recherche Scientifique, UMR176, Institut Curie, Centre de Recherche, Paris, France (D.D.).

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 compared with those in human microsomes. Mouse microsomes produced six metabolites as detected by reversed-phase high-performance liquid chromatography-mass spectrometry (MS). Three metabolites were identified as the 3'-, 4'-, or 6-hydroxy-FAA, by comparison with retention times and 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 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 with mouse microsomes, human microsomes (2 pools and 15 individual microsomes) were unable to metabolize FAA to a significant extent. In conclusion, we have identified six 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.