Dietary flavonoids in cancer therapy and prevention: substrates and inhibitors of cytochrome P450 CYP1 enzymes.

Flavonoids are polyphenolic compounds that have attracted the attention of the scientific community as the hallmark molecules responsible for cancer prevention by a plethora of different mechanisms. One of their most important characteristics, responsible for their cancer preventive properties, is their interaction with cytochrome P450 CYP1 enzymes. Flavonoids have traditionally been described as CYP1 inhibitors due to the inhibition of carcinogenic product formation and consequent blockage of the initiation stage of carcinogenesis. However, mounting evidence indicate that flavonoids are also capable of acting as CYP1 substrates, undergoing bioactivation to more antiproliferative agents within cancer cells. In this review, a comprehensive summary of the two models is presented. Structural features responsible for CYP1 inhibition or substrate turnover are discussed and limitations as well as discrepancies between procarcinogen-activating and 7-ethoxyresorufin-inhibition assay systems are further explored in vitro and in vivo. Moreover, a thorough investigation of the substrate specificity of flavonoids for the active site of CYP1 enzymes is undertaken. Finally, issues concerning the bioavailability and metabolic fate of these compounds in vivo are addressed. Ultimately, the mode of flavonoid action, in terms of CYP1 inhibition or CYP1-mediated bioactivation, is dependent on the lipophilicity or hydrophilicity of each compound. The degree of hydroxylation or methoxylation of the A and B rings is the major factor which determines the accessibility to the tumor site, in terms of hepatic and intestinal metabolism, and the introduction of the molecules to the CYP1 active site, respectively.