title: Accumulation and metabolism of the anticancer flavonoid 5,7-dimethoxyflavone compared to its unmethylated analog chrysin in the Atlantic killifish.
abstract: The use of dietary flavonoids as potential chemopreventive agents is a concept of increasing interest. Recent findings indicate that methylated flavones have the advantage of increased metabolic stability. One such compound, the naturally-occurring 5,7-dimethoxyflavone (5,7-DMF), has been shown to be a potential chemopreventive agent in human cancer originating from the liver, mouth, esophagus and lung. As bioavailability is a key issue for potential in vivo effects, the tissue accumulation and biliary elimination of 5,7-DMF and its non-methylated analog chrysin were examined in a small fish model (Fundulus heteroclitus). The fish were exposed to 5,7-DMF, chrysin or vehicle control (DMSO<0.01%) in seawater for 8h. Toxicity was not observed at the 5microM exposure level. Tissues and bile were harvested and analyzed by HPLC and LC/MS for quantitation and identification of parent compound and metabolites. 5,7-DMF accumulated 20-fold to 100-fold in all tissues examined, with the highest accumulation in liver and brain, whereas chrysin was barely detectable in any tissues except the liver. The bile of chrysin-exposed fish contained very low concentrations of unchanged chrysin but high concentrations of two glucuronic acid conjugates. In the bile of 5,7-DMF-exposed fish, the parent compound was detectable in significant amounts along with glucuronic acid conjugates of O-demethylated 5,7-DMF. In conclusion, our study demonstrated high tissue accumulation and limited metabolism of 5,7-DMF compared to chrysin in vivo, making this flavone a promising chemopreventive molecule.
authors.affiliation: Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: Petra A
authors.initials: PA
authors.lastname: Tsuji
authors.forename: Richard N
authors.initials: RN
authors.lastname: Winn
authors.forename: Thomas
authors.initials: T
authors.lastname: Walle
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001646:Bile / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004121:Dimethyl Sulfoxide / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000378:metabolism*; D020723:Glucuronic Acid / Q000378:metabolism; D006801:Humans; D007695:Killifishes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D013058:Mass Spectrometry; D008745:Methylation; D012623:Seawater; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D016588:Anticarcinogenic Agents; D005419:Flavonoids; C060298:5,7-dimethoxyflavone; C043561:chrysin; D020723:Glucuronic Acid; D004121:Dimethyl Sulfoxide