Inhibition of 17β-Hydroxysteroid Oxidoreductase by Flavonoids in Breast and Prostate Cancer Cells (44237)

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Abstract

Abstract.

Several flavonoids and isoflavonoids were found to inhibit 17β-oxidoreduction of estrogens by the purified 17β-HSOR type 1, or in cell lines expressing 17β-HSOR type 1 enzyme (T-47D breast cancer cells) or type 2 (PC-3 prostate cancer cells). The structural demands for the inhibition of estrone (E1) reduction and estradiol (E2) oxidation catalyzed by 17β-HSOR types 1 and 2, respectively, were not identical. Flavones, flavanones, and isoflavones hydroxylated at both the double ring (positions 5 and 7) and ring B (position 4′) were the most potent inhibitors of E1 reduction in T-47D cells, and by the purified type 1 enzyme whereas flavones hydroxylated at positions 3, 5, and 7 of rings A and C, with or without a hydroxyl group in ring B, were capable of inhibiting E2 oxidation in PC-3 cells. Change to flavanone structure, or hydroxylation at position 3 of ring C of flavones, or methylation of the hydroxyl group at position 4′ of ring B of flavones and isoflavones reduced or abolished their inhibitory activity on E1 reduction in T-47D cells. On the contrary, hydroxyl group at position 3 of flavones (flavonol structure) markedly increased the inhibition of E2 oxidation in PC-3 cells. Thus, changes in the number and location of hydroxyl groups may discriminate inhibition of E1 reduction and E2 oxidation. Some of the differences may be due to differences in pharmacokinetics of these compounds in T-47D and PC-3 cells. Inhibition of 17β-HSORs could lead to an alteration in the availability of the highly active endogenous estrogen, but the effects of these compounds in vivo cannot be predicted on the basis of these results alone. Some of these compounds (isoflavones) are estrogenic per se, and they may replace endogenous estrogens, whereas flavones are only very weakly estrogenic or nonestrogenic. Regarding prevention or treatment of estrogen-related diseases, apigenin, coumestrol, and genistein raise special interest.

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