| Molecular Basis of the Inhibition of Human Aromatase (Estrogen Synthetase) by Flavone and Isoflavone Phytoestrogens: A Site-directed Mutagenesis Study Yeh-Chih Kao,
1
Changbao Zhou,
1
Mark Sherman,
2
Charles A. Laughton,
3
and Shiuan Chen
1
Divisions of
1
Immunology; and
2
Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010 USA
3
CRC Biomolecular Structure Unit, Institute of Cancer Research, Sutton, Surrey, United Kingdom Abstract
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 (  -naphthoflavone) on the wild-type and six human 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. Key words : aromatase, aromatase inhibitors, computer modeling, cytochrome P450, estrogen synthesis, flavone, isoflavone, phytoestrogens, site-directed mutagenesis. Environ Health Perspect 106:85-92 (1998) . [Online 21 January 1998] http://ehpnet1.niehs.nih.gov/docs/1998/106p85-92kao/ abstract.html Address correspondence to S. Chen, Division of Immunology, Beckman Research Institute of the City of Hope, 1450 E. Duarte Road, Duarte, CA 91010 USA. This research was supported by the American Cancer Society (grant BE-192) and National Institutes of Health (grants CA44735 and ES08258) . Received 7 July 1997 ; accepted 26 September 1997.
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