ToxSci Advance Access published online on August 19, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh257
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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1 Institute for Risk Assessment Sciences (IRAS), Utrecht University, PO Box 80176, 3508 TD, Utrecht, The Netherlands
* To whom correspondence should be addressed. E-mail: t.sanderson{at}iras.uu.nl.
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 they 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 (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 mechanism of induction in human H295R cells.
Accepted August 9, 2004
Endocrine Toxicology
Induction and Inhibition of Aromatase (CYP19) Activity by Natural and Synthetic Flavonoid Compounds in H295R Human Adrenocortical Carcinoma Cells
2 Department of Environmental Toxicology, University of California, Davis, CA, USA
3 Department of Chemistry, University of California, Davis, CA, USA
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