Comparative Inhibition of Human Cytochromes P450 1A1 and 1A2 by Flavonoids

Flavonoids are a class of dietary phytochemicals that modulate various biological activities. The effects of flavone and five hydroxylated derivatives on the methoxyresorufin O -demethylase activity catalyzed by cDNA-expressed human cytochromes P450 (CYP)1A1 and 1A2 were examined. Flavone was a less potent inhibitor of CYP1A1 (IC50 = 0.14 μM) than CYP1A2 (IC50 = 0.066 μM). Four hydroxylated flavone derivatives (3-hydroxy-, 5-hydroxy-, 7-hydroxy-, and 3,7-dihydroxyflavone) were also potent inhibitors of CYP1A1 (IC50 < 0.1 μM) and CYP1A2 (IC50 < 0.3 μM). For CYP1A1, 7-hydroxyflavone exhibited a competitive mode of inhibition, with a Ki value of 0.015 μM and 6-fold selectivity for CYP1A1 over CYP1A2. 3,5,7-Trihydroxyflavone (galangin) showed the highest potency toward CYP1A2. The inhibition by galangin of the methoxyresorufin O -demethylase activity of CYP1A2 was mixed-type, with a Ki value of 0.008 μM. Galangin showed 5-fold selectivity in its inhibition of CYP1A2 over CYP1A1. The results indicate that some flavonoids have high potencies and selectivities for inhibition of CYP1A isozymes. This may have important implications for cancer prevention, as well as other pharmacological and toxicological effects of these compounds.