Flavonoids and related structures (e.g., flavones, isoflavones, flavanones, catechins) exert various biological effects, including anticarcinogenic, antioxidant and (anti-)estrogenic effects, and modulation of sex hormone homeostasis. A key enzyme in the synthesis of estrogens from androgens is aromatase (cytochrome P45019; CYP19). We investigated the effects of various natural and synthetic flavonoids on the catalytic activity and promoter-specific expression of aromatase in H295R human adrenocortical carcinoma cells. Natural flavones were consistently more potent inhibitors than flavanones. IC50 values for 7-hydroxyflavone, chrysin, and apigenin were 4,7, and 20 μ M, respectively; for the flavanones 7-hydroxyflavanone and naringenin the IC50 values were 65 and 85 ♂, respectively. The steroidal aromatase inhibitor (positive control) 4-hydroxyandrostenedione had an IC50 of 20 nM. The inhibition by apigenin and naringenin coincided with some degree of cytotoxicity at 100 μM. The natural flavonoid derivative rotenone (IC50 0.3 μM) was the most potent aromatase inhibitor tested. Several synthetic flavonoid and structurally related quinolin-4-one analogs inhibited aromatase activity. The most potent inhibitor was 4′-tert-butyl-quinolin-4-one (IC50 2 μM), followed by two 2-pyridinyl-substituted alpha-naphthoflavones (IC50s 5 and > 30 μM).The two 2-pyridinyl-substituted gamma-naphthoflavones consistently produced biphasic concentration-response curves, causing about 1.5-fold aromatase induction at concentrations below 1 μM and inhibition above that level (IC50s 7 and > 30 μM). The natural flavone quercetin and isoflavone genistein induced aromatase activity 4- and 2.5-fold induction, respectively, at 10 μM. This coincided with increased intracellular cAMP concentrations and increased levels of the cAMP-dependent pII and to a lesser extent 1.3 promoter-specific aromatase transcripts. These results shed light on the structure-activity relationships for aromatase inhibition as well as mechanisms of induction in human H295R cells.
- Endocrine disruption
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