Chrysin

Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study.
Kao YC, Zhou C, Sherman M, Laughton CA, Chen S.
Environ Health Perspect. 1998 Feb;106(2):85-92.

 Flavone and isoflavone phytoestrogens are plant chemicals and are known to be competitive inhibitors of cytochrome P450 aromatase with respect to the androgen substrate. Aromatase is the enzyme that converts androgen to estrogen; therefore, these plant 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-trihydroxyisoflavone) and biochanin A (5,7-dihydroxy-4-methoxyisoflavone)], one flavanone [naringenin (4, 5,7-trihydroxyflavanone)], and one naphthoflavone (alpha-naphthoflavone) on the wild-type and sixhuman aromatase mutants (I133Y, P308F, D309A, T310S, I395F, and I474Y) were determined. In combination with computer modeling, the binding characteristics and the structure requirement for flavone and isoflavone phytoestrogens to inhibit human aromatase were obtained. These compounds were found 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, respectively. This study also provides a molecular basis as to why isoflavones are significantly poorer inhibitors of aromatase than flavones.
PMID: 9435150

  Effects of flavonoids on aromatase activity, an in vitro study.
Pelissero C, Lenczowski MJ, Chinzi D, Davail-Cuisset B, Sumpter JP, Fostier A.
J Steroid Biochem Mol Biol. 1996 Feb;57(3-4):215-23.

 In the study, the inhibitory effect of flavonoids, including isoflavonic phytoestrogens, on the ovarianaromatase enzyme complex from the rainbow trout, Oncorhynchus mykiss, was assessed in vitro. Some of the compounds tested on fish were also tested on human placental aromatase activityas a comparison between the two sources of enzyme. It was found that flavone, dl-aminoglutethimide, apigenin, quercetin, 7,4′- dihydroxyflavone, alpha-naphthoflavone and equol were potent inhibitors of the ovarian aromatase activity in rainbow trout. Relative potencies (RP) of these compounds compared to flavone (assigned an effect of 1) were, respectively, 19.0, 8.7, 5.3, 3.7, 3.2 and 0.9. Two other phytoestrogens, namely biochanin A and genistein, slightly inhibited aromatase activity. Finally, 7-hydroxyflavone, formononetin, daidzein, coumestrol, chrysin, flavanone and estradiol-17beta did not inhibit ovarian aromatase activity at doses up to 1000 microM. Experiments on human placental aromatase showed inhibitory effects of dl-aminoglutethimide, flavone, flavanone and equol with RP values of 2.8. 1, 1.5 and 0.4, respectively. These results are in accordance with previous studies. The influence of the experimental procedure on IC50 values and RP is discussed. PMID: 8645631

  Inhibition of human estrogen synthetase (aromatase) by flavones.
Kellis JT Jr, Vickery LE.
Science. 1984 Sep 7;225(4666):1032-4.

 Several naturally occurring and synthetic flavones were found to inhibit the aromatization of androstenedione and testosterone to estrogens catalyzed by human placental and ovarian microsomes. These flavones include (in order of decreasing potency) 7,8-benzoflavone, chrysin, apigenin, flavone, flavanone, and quercetin; 5,6-benzoflavone was not inhibitory. 7,8-Benzoflavone and chrysin were potent competitive inhibitors and induced spectral changes in the aromatasecytochrome P-450 indicative of substrate displacement. Flavones may thus compete with steroids in their interaction with certain monooxygenases and thereby alter steroid hormone metabolism. PMID: 6474163

  Inhibition of aromatase activity by flavonoids.
Jeong HJ, Shin YG, Kim IH, Pezzuto JM.
Arch Pharm Res. 1999 Jun;22(3):309-12

 In searching for potent cancer chemopreventive agents from synthetic or natural products, 28 randomly selected flavonoids were screened for inhibitory effects against partially purified aromatase prepared from human placenta. Over 50% of the flavonoids significantly inhibited aromatase activity, with greatest activity being demonstrated with apigenin (IC50: 0.9 microg/mL), chrysin (IC50: 1.1 microg/mL), and hesperetin (IC50: 1.0 microg/mL). PMID: 10403137

  Aromatase inhibition by synthetic lactones and flavonoids in human placental microsomes and breast fibroblasts–a comparative study.
van Meeuwen JA, Nijmeijer S, Mutarapat T, Ruchirawat S, de Jong PC, Piersma AH, van
den Berg M.
Toxicol Appl Pharmacol. 2008 May 1;228(3):269-76

 Interference of exogenous chemicals with the aromatase enzyme can be useful as a tool to identify chemicals that could act either chemopreventive for hormone-dependent cancer or adverse endocrine disruptive. Aromatase is the key enzyme in the biosynthesis of steroids, as it converts androgens to estrogens. Certain flavonoids, plant derived chemicals, are known catalyticaromatase inhibitors. Various systems are in use to test aromatase inhibitory properties of compounds. Commonly used are microsomes derived from ovary or placental tissue characterized by high aromatase activity. To a lesser extent whole cell systems are used and specifically cell systems that are potential target tissue in breast cancer development. In this study aromataseinhibitory properties of fadrozole, 8-prenylnaringenin and a synthetic lactone (TM-7) were determined in human placental microsomes and in human primary breast fibroblasts. In addition, apigenin, chrysin, naringenin and two synthetic lactones (TM-8 and TM-9) were tested in human microsomes only. Comparison of the aromatase inhibitory potencies of these compounds between the two test systems showed that the measurement of aromatase inhibition in human placental microsomes is a good predictor of aromatase inhibition in human breast fibroblasts. PMID: 18201740