A hydroxylated flavonol, fisetin inhibits the formation of a carcinogenic estrogen metabolite

- Fisetin inhibits the formation of a carcinogenic estrogen metabolite.
- Reveal one of fisetin anti-cancer mechanisms.
- Reveal the relationship between the structure of flavonoids and the inhibition CYP1B1.

Fisetin can be found in a wide variety of plants and possesses strong efficacy against many cancers. 17β-Estradiol (E2) is hydrolyzed to 4-hydroxy-E2 (4-OHE2) via cytochrome P450 (CYP) 1B1 in vivo. In estrogen target tissues including the mammary gland, ovaries, and uterus, CYP1B1 is highly expressed, and 4-OHE2 is predominantly formed in cancerous tissues. Herein, we investigated the inhibitory activity of fisetin and flavone against CYP1B1 using estrogen E2 as substrate in vitro to reveal structure-activity relationship between structure of flavonoids and inhibition. The results showed that fisetin possessed inhibitory effect on CYP1B1 activity. Compared with flavone, the inhibition of fisetin was stronger. The Vmax and Ki values were 1.950 ± 0.157 pmol/μg protein/min and 4.925 ± 0.689 nM for fisetin and 2.277 ± 0.231 pmol/μg protein/min and 9.148 ± 2.150 nM for flavone, respectively. By kinetic analyses, both fisetin and flavone displayed mixed inhibition. Taken together the data suggested that fisetin is able to inhibit the formation of carcinogenic 4-OHE2 from E2, which reveals one of its anti-cancer mechanisms and helps to reveal the relationship between the structure of flavonoids and the inhibition CYP1B1 for discovering new drugs in cancer therapy and prevention.

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