Spectral perturbation of human microsomal cytochrome P-450 by flavonoid binding

Aromatase is the cytochrome P-450 complex responsible for oestrogen biosynthesis in vivo. Inhibitors of this enzyme complex might therefore serve to modulate oestrogen-dependent processes by interfering with the production of oestrogens. Thus, these agents may be useful in reproductive processes and in treating oestrogen-dependent disease states such as breast and endometrial cancer. We have demonstrated that inhibitors such as the naturally occurring flavonoids having 5,7-dihydroxy substituents can bind to human placental cytochrome P-450 with affinity comparable to their ability to inhibit aromatization of androstenedione and testosterone to oestradiol and oestrone, respectively. It appears that the mechanism of this inhibition requires the flavonoid to bind to the active site of the cytochrome P-450 without prior generation of metabolic intermediate products. Our data also suggest that the presently known differences in potency of inhibition of cytochrome P-450-mediated aromatization of steroids by different hydroxylated derivatives of 5,7-dihydroxyflavones may arise from their different binding affinity to the enzyme, particularly those compounds hydroxylated in the C3 position in ring C of the flavonoid nucleus.