title: Metabolites of galangin by 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible cytochrome P450 1A1 in human intestinal epithelial Caco-2 cells and their antagonistic activity toward aryl hydrocarbon receptor.
abstract: Galangin, a dietary flavonoid, inhibited cytochrome P450 1A1 (CYP1A1) expression induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). This inhibitory activity remained after permeating human intestinal epithelial Caco-2 cell monolayers, but was reduced when galangin permeated TCDD-pretreated Caco-2 cells. The present study tested whether TCDD affected the intestinal metabolism of flavonoids. LC-MS/MS analyses showed that galangin and two galangin glucuronoconjugates were reduced 0.7-fold, whereas kaempferol (a galangin oxidate) and kaempferol glucuronoconjugate were increased 1.5-fold by permeating TCDD-pretreated Caco-2 cells, as compared to untreated Caco-2 cells. An assay using recombinant human CYP1A1 and the CYP1A1 inhibitor alpha-naphthoflavone revealed that CYP1A1 oxidized galangin to kaempferol. These results indicated that galangin was metabolized to kaempferol by TCDD-inducible CYP1A1 in Caco-2 cells. A previous study revealed that kaempferol had much weaker inhibitory activity than galangin toward TCDD-induced CYP1A1 expression. Therefore, the oxidative metabolism of galangin to kaempferol in TCDD-pretreated Caco-2 cells implicated reduction in the inhibitory activity of galangin.
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. mikage417@hotmail.co.jp
authors.forename: Mika
authors.initials: M
authors.lastname: Hamada
authors.forename: Hideo
authors.initials: H
authors.lastname: Satsu
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ashida
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Sugita-Konishi
authors.forename: Makoto
authors.initials: M
authors.lastname: Shimizu
mesh_terms: D018938:Caco-2 Cells; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005419:Flavonoids / Q000378:metabolism* / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008658:Inactivation, Metabolic; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D044949:Kaempferols / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism* / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D005419:Flavonoids; D044949:Kaempferols; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C037032:galangin; C006552:kaempferol; D019363:Cytochrome P-450 CYP1A1