Cytochrome P450 CYP1 metabolism of hydroxylated flavones and flavonols: Selective bioactivation of luteolin in breast cancer cells

Natural flavonoids with methoxy substitutions are metabolized by CYP1 enzymes to yield the corresponding demethylated products. The present study aimed to characterize the metabolism and further antiproliferative activity of the hydroxylated flavonoids apigenin, luteolin, scutellarein, kaempferol and quercetin in CYP1 recombinant enzymes and in the CYP1 expressing cell lines MCF7 and MDA-MB-468, respectively. Apigenin was converted to luteolin and scutellarein, whereas kaempferol was metabolized only to quercetin by recombinant CYP1 enzymes. Luteolin metabolism yielded 6 hydroxyluteolin only by recombinant CYP1B1, whereas CYP1A1 and CYP1A2 were not capable of metabolizing this compound. Molecular modeling demonstrated that CYP1B1 favored the A ring orientation of apigenin and luteolin to the heme group compared with CYP1A1. The IC50 of the compounds luteolin, scutellarein and 6 hydroxyluteolin was significantly lower in MDA-MB-468, MCF7 and MCF10A cells compared with that of apigenin. Similarly, the IC50 of quercetin in MDA-MB-468 cells was significantly lower compared with that of kaempferol. The most potent compound was luteolin in MDA-MB-468 cells (IC50 = 2 +/- 0.3 mu M). In the presence of the CYP1-inhibitors alpha-napthoflavone and/or acacetin, luteolin activation was lessened. Taken collectively, the data demonstrate that the metabolism of hydroxylated flavonoids by cytochrome P450 CYP1 enzymes, notably CYP1A1 and CYP1B1, can enhance their antiproliferative activity in breast cancer cells. In addition, this antiproliferative activity is attributed to the combined action of the parent compound and the corresponding CYP1 metabolites.