title: Identification and induction of cytochrome P450s involved in the metabolism of flavone-8-acetic acid in mice.
abstract: The metabolism of flavone-8-acetic acid (FAA) has been hypothesized to be partly responsible for its potent anticancer activity in mice. The purpose of this study was to identify the mouse enzymes involved in FAA Phase I metabolism and evaluate their possible induction in vivo by FAA. Mouse microsomes metabolized FAA into 6 metabolites: 3',4'-dihydrodiol-FAA, 5,6-epoxy-FAA, 4'-OH-FAA, 3'-OH-FAA, 3',4'-epoxy-FAA and 6-OH-FAA. Using Cyp-specific inhibitors (furafylline, Cyp1a2; α-naphthoflavone, Cyp1b1; tranylcypromine, Cyp2b9; quercetin, Cyp2c29; quinidine, 2d9; diethyldithiocarbamate, Cyp2e1; ketoconazole, Cyp3a11), the formation of 5,6-epoxy-FAA was mainly attributed to Cyps 1a2, 1b1, 2b9, 2c29 and 2e1, whereas the 3',4'-epoxy-FAA was formed by Cyps 2b9 and 3a11. The 4'-OH-FAA was generated by Cyps 1a2, 1b1, 2b9 and 2e1, and the 6-OH-FAA was formed by Cyps 1b1 and 2c9. Using the epoxide scavenger N-acetyl cysteine, 4'-OH-FAA, 3'-OH-FAA and 6-OH-FAA were shown to derive partly from non enzymatic isomerisation of their corresponding epoxides. The specific epoxide hydrolase inhibitor elaidamide allowed the confirmation that 3',4'-dihydrodiol-FAA was formed via the epoxide hydrolase. FAA treatment in vivo in mice led to a significant increase in the hepatic expression of Cyp1a2 (1.9-fold), 2e1 (2.1-fold), 2b10 (3.2-fold), 2d9 (2.3-fold) and 3a11 (2.2-fold), as evaluated by qRT-PCR. In conclusion, several Cyps were shown to be involved in FAA metabolism, particularly Cyps 3a11 and 2b9 which were responsible for the formation of the principal metabolites (5,6-epoxy-FAA, 3',4'-epoxy-FAA), and that FAA could induce the expression of several Cyps after in vivo administration. The possible implication of these enzymes in the in vivo anticancer activity of FAA in mice is discussed.
authors: Université Paris Descartes; Faculté des Sciences Pharmaceutiques et Biologiques; Institut National de la Santé et de la Recherche Médicale (Inserm U1022), Paris, F-75006 France.
authors: Minh Hien
authors: MH
authors: Pham
authors: Hervé
authors: H
authors: Rhinn
authors: Nicolas
authors: N
authors: Auzeil
authors: Anne
authors: A
authors: Regazzetti
authors: Djamel Eddine
authors: DE
authors: Harami
authors: Daniel
authors: D
authors: Scherman
authors: Guy G
authors: GG
authors: Chabot
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004790:Enzyme Induction; D004851:Epoxide Hydrolases / Q000502:physiology; D005260:Female; D005419:Flavonoids / Q000378:metabolism*; D006900:Hydroxylation; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism
chemical_list: D005419:Flavonoids; C049328:flavone acetic acid; D003577:Cytochrome P-450 Enzyme System; D004851:Epoxide Hydrolases; D000111:Acetylcysteine