Comparative α-Naphthoflavone and β-Naphthoflavone Inhibits the Formation of a Carcinogenic Estrogen Metabolite

Abstract

17b-Estradiol (E2) is hydrolyzed to 2-hydroxy-E2 and 4-hydroxy-E2 (4-OH-E2) via cytochrome P450 (CYP) 1B1. In estrogen target tissues including the mammary gland, ovaries and uterus, CYP1B1 is highly expressed, and 4-OH-E2 is predominantly formed in cancerous tissues. In the present study, we investigated the inhibitory activity of a-naphthoflavone and b-naphthoflavone against CYP1B1 using estrogen E2 as substrate in vitro to reveal structure-activity relationship between structure of flavonoids and inhibition. The results showed that a-naphthoflavone and b-naphthoflavone possessed inhibitory activity against CYP1B1-mediated E2 and the inhibition of a-naphthoflavone was stronger than b-naphthoflavone. By kinetic analyses, a-naphthoflavone displayed uncompetitive inhibition, while b-naphthoflavone displayed mixed inhibition. Taken together, the data suggested that the benzo at A ring of flavonoids play a prominent role in CYP1B1 inhibition, especially 7,8-benzo is better than 5,6-benzo. This study may help to reveal the relationship between the structure of flavonoids and the inhibition CYP1B1 for discovering new drugs in cancer therapy and prevention.17b-Estradiol 2-OH-E2 2-Hydroxy-17b-estradiol 4-OH-E2 4-Hydroxy-17b-estradiol CYP1B1 Cytochrome P450 (CYP) 1B1 D 6 -E1 D 6 -Estrone IC50 50 % Inhibition