MOLECULAR-BASIS OF THE INHIBITION OF HUMAN AROMATASE (ESTROGEN SYNTHETASE) BY FLAVONE AND ISOFLAVONE PHYTOESTROGENS - A SITE-DIRECTED MUTAGENESIS STUDY

Flavone and isoflavone phytoestrogens are plant chemicals and are know n to be competitive inhibitors of cytochrome P450 aromatase with respe ct to the androgen substrate. Aromatase is the enzyme that converts an drogen to estrogen; therefore, these plans chemicals are thought to be capable of modifying the estrogen level in women. In this study, the inhibition profiles of four flavones [chrysin (5,7-dihydroxyflavone), 7,8-dihydroxyflavone baicalein (5,6,7-trihydroxyflavone), and galangin (3,5,7-trihydroxyflavone)], two isoflavones [genistein (4',5,7-trihyd roxyisoflavone) and biochanin A (5,7-dihydroxy-4'-methoxyisoflavone)], one flavanone [naringenin (4',5,7-trihydroxyflavanone)], and one naph thoflavone (alpha-naphthoflavone) on the wild-type and six human aroma tase mutants (I133Y, P308F, D309A, T310S, I395F, and I474Y) were deter mined. In combination with computer modeling the binding characteristi cs and the structure requirement for flavone and isoflavone phytoestro gens to inhibit human aromatase were obtained. These compounds were fo und to bind to the active site of aromatase in an orientation in which rings A and C mimic rings D and C of the androgen substrate, respecti vely. This study also provides a molecular basis as to why isoflavones are significantly poorer inhibitors of aromatase than flavones.