1. Fisetin disposition and metabolism in mice: Identification of geraldol as an active metabolite. : Fisetin disposition and metabolism in mice
- Author
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Daniel Scherman, Nicolas Auzeil, Yasmine Touil, François Boulinguez, Hanane Saighi, Anne Regazzetti, Guy G. Chabot, Unité de pharmacologie chimique et génétique et d'imagerie (UPCGI - UMR 8151 / UMR_S 1022 ), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC), Laboratoire de Chimie et Toxicologie Analytique et Cellulaire (EA 4463), Université Paris Descartes - Paris 5 (UPD5), Inserm, CNRS, Institut National du Cancer (INCa), and Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP) - Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)
- Subjects
Flavonols ,Metabolite ,Angiogenesis Inhibitors ,Pharmacology ,Biochemistry ,MESH : Flavonoids ,Carcinoma, Lewis Lung ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,MESH: Glucuronides ,Cell Movement ,MESH: Collagen ,MESH : Cell Movement ,MESH : Female ,MESH: Animals ,MESH: Endothelial Cells ,geraldol ,MESH : Laminin ,MESH: Cell Movement ,MESH: Angiogenesis Inhibitors ,MESH : Cell Survival ,0303 health sciences ,MESH: Carcinoma, Lewis Lung ,MESH : Flavones ,MESH: Laminin ,Biological activity ,MESH : Proteoglycans ,3. Good health ,MESH : Antineoplastic Agents ,Drug Combinations ,MESH : Drug Combinations ,MESH: Cell Survival ,MESH: Proteoglycans ,030220 oncology & carcinogenesis ,cytotoxicity ,Female ,Proteoglycans ,Collagen ,Glucuronide ,pharmacokinetics ,MESH: Cell Line, Tumor ,Cell Survival ,fisetin ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Antineoplastic Agents ,MESH : Mice, Inbred C57BL ,MESH : Glucuronides ,03 medical and health sciences ,Glucuronides ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Pharmacokinetics ,MESH: Mice, Inbred C57BL ,In vivo ,MESH : Carcinoma, Lewis Lung ,Cell Line, Tumor ,MESH : Mice ,MESH : Angiogenesis Inhibitors ,MESH : Neoplasm Transplantation ,Animals ,MESH: Mice ,Active metabolite ,030304 developmental biology ,MESH: Drug Combinations ,Flavonoids ,MESH : Cell Line, Tumor ,MESH : Endothelial Cells ,MESH: Flavones ,Endothelial Cells ,Flavones ,In vitro ,Mice, Inbred C57BL ,chemistry ,MESH : Collagen ,Flavonoid ,MESH: Antineoplastic Agents ,MESH : Animals ,Laminin ,metabolism ,MESH: Female ,MESH: Flavonoids ,MESH: Neoplasm Transplantation ,Neoplasm Transplantation ,Fisetin - Abstract
International audience; Although the natural flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) has been recently identified as an anticancer agent with antiangiogenic properties in mice, its in vivo pharmacokinetics and metabolism are presently not characterized. Our purpose was to determine the pharmacokinetics and metabolism of fisetin in mice and determine the biological activity of a detected fisetin metabolite. After fisetin administration of an efficacious dose of 223 mg/kg i.p. in mice, the maximum fisetin concentration reached 2.5 μg/ml at 15 min and the plasma concentration declined biphasically with a rapid half-life of 0.09 h and a terminal half-life of 3.1h. Three metabolites were detected, one of which was a glucuronide of fisetin (M1), whereas another glucuronide (M2) was a glucuronide of a previously unknown fisetin metabolite (M3). HPLC-MS/MS analysis indicated that M3 was a methoxylated metabolite of fisetin (MW=300 Da). The UV spectrum of M3 was identical to that of fisetin and standard 3,4',7-trihydroxy-3'-methoxyflavone (geraldol). In addition, because M3 co-eluted with standard geraldol in 4 different chromatographic ternary gradient conditions, M3 was therefore assigned to geraldol. Of interest, this metabolite was shown to achieve higher concentrations than fisetin in Lewis lung tumors. We also compared the cytotoxic and antiangiogenic activities of fisetin and geraldol in vitro and it was found that the latter was more cytotoxic than the parent compound toward tumor cells, and that it could also inhibit endothelial cells migration and proliferation. In conclusion, these results suggest that fisetin metabolism plays an important role in its in vivo anticancer activities.
- Published
- 2011