title: Metabolism of Flavone-8-acetic Acid in Mice.
abstract: Flavone-8-acetic acid (FAA) is a potent antivascular agent in mice but not in humans. Assuming that FAA was bioactivated in mice, we previously demonstrated that 6-OH-FAA was formed from FAA by mouse microsomes but not by human microsomes; its antivascular activity was 2.1- to 15.9-fold stronger than that of FAA, and its antivascular activity was mediated through the Ras homolog gene family (Rho) protein kinase A (RhoA) pathway. The present work aimed to study FAA metabolism in order to verify if 6-OH-FAA is formed in mice. Using synthesized standards and high-performance liquid chromatography (HPLC) coupled with ultraviolet (UV) detection and mass spectrometry (MS) analysis, we herein demonstrated, for the first time, that in vitro FAA and its monohydroxylated derivatives could directly undergo phase II metabolism forming glucuronides, and two FAA epoxides were mostly scavenged by NAC and GSH forming corresponding adducts. FAA was metabolized in mice. Several metabolites were formed, in particular 6-OHFAA. The antitumor activity of 6-OH-FAA in vivo is worthy of investigation.
authors.affiliation: Chemical, Genetic and Imaging Pharmacology Laboratory, Faculty of Pharmacy, Chimie ParisTech, Paris Descartes University, Sorbonne Paris Cité, INSERM U1022, CNRS UMR8151, Paris, France Medical Oncology and Cellular Therapy Department, Tenon Hospital, Public Assistance Hospitals of Paris, Alliance for Cancer Research, Paris, France Laboratory of Therapeutic Drug Monitoring, Platform for Peptidomic, Metabolomic and Drug Measurements, Saint Antoine Hospital, Paris, France minh-hien.pham@aphp.fr.
authors.forename: Minh Hien
authors.initials: MH
authors.lastname: Pham
authors.affiliation: Platform of Mass spectrometry, Faculty of Pharmacy (IFR 71), University Paris Descartes, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Auzeil
authors.affiliation: Platform of Mass spectrometry, Faculty of Pharmacy (IFR 71), University Paris Descartes, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Regazzetti
authors.affiliation: Chemical, Genetic and Imaging Pharmacology Laboratory, Faculty of Pharmacy, Chimie ParisTech, Paris Descartes University, Sorbonne Paris Cité, INSERM U1022, CNRS UMR8151, Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Scherman
authors.affiliation: Chemical, Genetic and Imaging Pharmacology Laboratory, Faculty of Pharmacy, Chimie ParisTech, Paris Descartes University, Sorbonne Paris Cité, INSERM U1022, CNRS UMR8151, Paris, France.
authors.forename: Johanne
authors.initials: J
authors.lastname: Seguin
authors.affiliation: Chemical, Genetic and Imaging Pharmacology Laboratory, Faculty of Pharmacy, Chimie ParisTech, Paris Descartes University, Sorbonne Paris Cité, INSERM U1022, CNRS UMR8151, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mignet
authors.affiliation: Department of Research, Institute Curie, CNRS UMR3666, INSERM U1143, Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Dauzonne
authors.affiliation: Chemical, Genetic and Imaging Pharmacology Laboratory, Faculty of Pharmacy, Chimie ParisTech, Paris Descartes University, Sorbonne Paris Cité, INSERM U1022, CNRS UMR8151, Paris, France.
authors.forename: Guy G
authors.initials: GG
authors.lastname: Chabot
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification* / Q000378:metabolism* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D005419:Flavonoids / Q000302:isolation & purification* / Q000378:metabolism* / Q000627:therapeutic use; D020719:Glucuronides / Q000096:biosynthesis / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D020719:Glucuronides; C049328:flavone acetic acid; D005978:Glutathione
keywords: FAA; Flavone-8-acetic acid; in vivo; mice; phase II metabolism