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.

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.