ToxSci Advance Access originally published online on August 19, 2004
Toxicological Sciences 2004 82(1):70-79; doi:10.1093/toxsci/kfh257
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Toxicological Sciences vol. 82 no. 1 © Society of Toxicology 2004; all rights reserved.
Induction and Inhibition of Aromatase (CYP19) Activity by Natural and Synthetic Flavonoid Compounds in H295R Human Adrenocortical Carcinoma Cells
* Institute for Risk Assessment Sciences (IRAS), Utrecht University, 3508 TD, Utrecht, The Netherlands; Department of Environmental Toxicology, and Department of Chemistry, University of California, Davis, California 95616
Received June 2, 2004; accepted August 9, 2004
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 P450 19; 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 µM, respectively; for the flavanones 7-hydroxyflavanone and naringenin the IC50 values were 65 and 85 µM, 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.
Key Words: H295R; flavonoids; quinolin-4-ones; catechins; aromatase; endocrine disruption; induction; inhibition; transcription.
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