Molecular Basis of the Inhibition of Human Aromatase (Estrogen Synthetase) by Flavone and Isoflavone Phytoestrogens: A Site-Directed Mutagenesis Study

Abstract

JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org.. The National Institute of Environmental Health Sciences (NIEHS) and Brogan & Partners are collaborating with JSTOR to digitize, preserve and extend access to Environmental Health Perspectives.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 (a-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 signifirntly 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. //ehpnetlniehs.nih.gov/docs/1998/106p85-92kao/abstract.html As pointed out by Henderson (1) in 1993, one of the most dramatic features of breast cancer is the disparity in incidence rates between highly westernized and nonwesternized countries. Women born and raised in the UnitedStates are at least five times as likely to get breast cancer as women born and raised in Japan. But Japanese women increase their risk if they live in rapidly westernizing Japanese cities or emigrate and live in the United States. As is true with coronary heart disease, differences in diet are thought to be a major underlying factor in the different incidence rates of breast cancer, particularly among postmenopausal women. The U.S. Environmental Protection Agency (EPA) anticipates filling at least one position in the Office of Economy and Environment. The individual will conduct original research on environmental health issues. Individuals with an interest in conducting policyrelevant an...

Chrysin enhances antioxidants and oxidative stress in L-NAME-induced hypertensive rats

“…Chrysin (5,7-dihydroxy flavones structure shown in Figure 1) is a naturally occurring flavone contained in flowers such as the blue passion flower (Passiflora caerulea) and the Indian trumpet flower, as well as in edible items such as mushroom, [8] honey and propolis. [9] Chrysin has been found to possess antioxidant, [10] anti-allergic, [11] anti-inflammatory, [12] anti-cancer, [13] antiestrogenic, [14] anxiolytic [15] and antihypertensive [16] properties.…”

Effects of chrysin on free radicals and enzymatic antioxidants in Nω-nitro-l-arginine methyl ester: Induced hypertensive rats

“…Chrysin (5,7-dihydroxy flavones; structure shown in Figure 1) is a naturally occurring flavone present in flowers such as the blue passion flower (Passiflora caerulea) and the Indian trumpet flower, as well as in edible items such as mushroom, [4] honey, and propolis. [5] Chrysin has been found to possess antioxidant, [6] anti-allergic, [7] anti-inflammatory, [8] anti-cancer, [9] antiestrogenic, [10] anxiolytic, [11] and antihypertensive [12] properties. The prospective adverse reactions of chrysin have not been studied well yet.…”

Effects on chrysin on lipid and xenobiotic metabolizing enzymes in l-NAME-induced hypertension

“…Chrysin (5,7-dihydroxy flavone, structure shown in Figure 1) is a naturally occurring flavone present in flowers such as blue passion flower (Passiflora caerulea) and the Indian trumpet flower, as well as in edible items such as mushroom, [11] honey, and propolis. [12] Chrysin has been found to possess antioxidant, [13] anti-allergic, [14] anti-inflammatory, [15] anti-cancer, [16] antiestrogenic, [17] anxiolytic, [18] and antihypertensive [19,20] properties. However, there are no scientific reports available on the effects of chrysin on l-NAME-induced hypertensive rats.…”