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.
The study concluded that Flavones are stronger inhibitors of aromatase than isoflavones.
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 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.
Y C Kao, C Zhou, M Sherman, C A Laughton, and S Chen. Selected References
These references are in PubMed. This may not be the complete list of references from this article.
• Henderson M. Current approaches to breast cancer prevention. Science. 1993 Jan 29;259(5095):630–631. [PubMed]
• Martin PM, Horwitz KB, Ryan DS, McGuire WL. Phytoestrogen interaction with estrogen receptors in human breast cancer cells. Endocrinology. 1978 Nov;103(5):1860–1867. [PubMed]
• Kagawa Y. Impact of Westernization on the nutrition of Japanese: changes in physique, cancer, longevity and centenarians. Prev Med. 1978 Jun;7(2):205–217. [PubMed]
• London S, Willett W. Diet and the risk of breast cancer. Hematol Oncol Clin North Am. 1989 Dec;3(4):559–576. [PubMed]
• Kaldas RS, Hughes CL., Jr Reproductive and general metabolic effects of phytoestrogens in mammals. Reprod Toxicol. 1989;3(2):81–89. [PubMed]
• Howe GR, Hirohata T, Hislop TG, Iscovich JM, Yuan JM, Katsouyanni K, Lubin F, Marubini E, Modan B, Rohan T, et al. Dietary factors and risk of breast cancer: combined analysis of 12 case-control studies. J Natl Cancer Inst. 1990 Apr 4;82(7):561–569. [PubMed]
• Block G, Patterson B, Subar A. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer. 1992;18(1):1–29. [PubMed]
• Lippman ME, Dickson RB, Kasid A, Gelmann E, Davidson N, McManaway M, Huff K, Bronzert D, Bates S, Swain S, et al. Autocrine and paracrine growth regulation of human breast cancer. J Steroid Biochem. 1986 Jan;24(1):147–154. [PubMed]
• Bates SE, Davidson NE, Valverius EM, Freter CE, Dickson RB, Tam JP, Kudlow JE, Lippman ME, Salomon DS. Expression of transforming growth factor alpha and its messenger ribonucleic acid in human breast cancer: its regulation by estrogen and its possible functional significance. Mol Endocrinol. 1988 Jun;2(6):543–555. [PubMed]
• Santner SJ, Chen S, Zhou D, Korsunsky Z, Martel J, Santen RJ. Effect of androstenedione on growth of untransfected and aromatase-transfected MCF-7 cells in culture. J Steroid Biochem Mol Biol. 1993 Mar;44(4-6):611–616. [PubMed]
• Yue W, Zhou D, Chen S, Brodie A. A new nude mouse model for postmenopausal breast cancer using MCF-7 cells transfected with the human aromatase gene. Cancer Res. 1994 Oct 1;54(19):5092–5095. [PubMed]
• Tekmal RR, Ramachandra N, Gubba S, Durgam VR, Mantione J, Toda K, Shizuta Y, Dillehay DL. Overexpression of int-5/aromatase in mammary glands of transgenic mice results in the induction of hyperplasia and nuclear abnormalities. Cancer Res. 1996 Jul 15;56(14):3180–3185. [PubMed]
• Kellis JT, Jr, Vickery LE. Inhibition of human estrogen synthetase (aromatase) by flavones. Science. 1984 Sep 7;225(4666):1032–1034. [PubMed]
• Ibrahim AR, Abul-Hajj YJ. Aromatase inhibition by flavonoids. J Steroid Biochem Mol Biol. 1990 Oct;37(2):257–260. [PubMed]
• Adlercreutz H, Bannwart C, Wähälä K, Mäkelä T, Brunow G, Hase T, Arosemena PJ, Kellis JT, Jr, Vickery LE. Inhibition of human aromatase by mammalian lignans and isoflavonoid phytoestrogens. J Steroid Biochem Mol Biol. 1993 Feb;44(2):147–153. [PubMed]
• Campbell DR, Kurzer MS. Flavonoid inhibition of aromatase enzyme activity in human preadipocytes. J Steroid Biochem Mol Biol. 1993 Sep;46(3):381–388. [PubMed]
• Wang C, Mäkelä T, Hase T, Adlercreutz H, Kurzer MS. Lignans and flavonoids inhibit aromatase enzyme in human preadipocytes. J Steroid Biochem Mol Biol. 1994 Aug;50(3-4):205–212. [PubMed]
• Zhou DJ, Pompon D, Chen SA. Structure-function studies of human aromatase by site-directed mutagenesis: kinetic properties of mutants Pro-308—-Phe, Tyr-361—-Phe, Tyr-361—-Leu, and Phe-406—-Arg. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):410–414. [PMC free article] [PubMed]
• Zhou DJ, Korzekwa KR, Poulos T, Chen SA. A site-directed mutagenesis study of human placental aromatase. J Biol Chem. 1992 Jan 15;267(2):762–768. [PubMed]
• Kadohama N, Yarborough C, Zhou D, Chen S, Osawa Y. Kinetic properties of aromatase mutants Pro308Phe, Asp309Asn, and Asp309Ala and their interactions with aromatase inhibitors. J Steroid Biochem Mol Biol. 1992 Dec;43(7):693–701. [PubMed]
• Chen S, Zhou D. Functional domains of aromatase cytochrome P450 inferred from comparative analyses of amino acid sequences and substantiated by site-directed mutagenesis experiments. J Biol Chem. 1992 Nov 5;267(31):22587–22594. [PubMed]
• Kadohama N, Zhou D, Chen S, Osawa Y. Catalytic efficiency of expressed aromatase following site-directed mutagenesis. Biochim Biophys Acta. 1993 May 13;1163(2):195–200. [PubMed]
• Chen S, Zhou D, Swiderek KM, Kadohama N, Osawa Y, Hall PF. Structure-function studies of human aromatase. J Steroid Biochem Mol Biol. 1993 Mar;44(4-6):347–356. [PubMed]
• Zhou D, Cam LL, Laughton CA, Korzekwa KR, Chen S. Mutagenesis study at a postulated hydrophobic region near the active site of aromatase cytochrome P450. J Biol Chem. 1994 Jul 29;269(30):19501–19508. [PubMed]
• Kao YC, Cam LL, Laughton CA, Zhou D, Chen S. Binding characteristics of seven inhibitors of human aromatase: a site-directed mutagenesis study. Cancer Res. 1996 Aug 1;56(15):3451–3460. [PubMed]
• Laughton CA, Zvelebil MJ, Neidle S. A detailed molecular model for human aromatase. J Steroid Biochem Mol Biol. 1993 Mar;44(4-6):399–407. [PubMed]
• Gunning P, Leavitt J, Muscat G, Ng SY, Kedes L. A human beta-actin expression vector system directs high-level accumulation of antisense transcripts. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4831–4835. [PMC free article] [PubMed]
• Zhou DJ, Pompon D, Chen SA. Stable expression of human aromatase complementary DNA in mammalian cells: a useful system for aromatase inhibitor screening. Cancer Res. 1990 Nov 1;50(21):6949–6954. [PubMed]
• Graham-Lorence S, Amarneh B, White RE, Peterson JA, Simpson ER. A three-dimensional model of aromatase cytochrome P450. Protein Sci. 1995 Jun;4(6):1065–1080. [PMC free article] [PubMed]
• Poulos TL, Finzel BC, Gunsalus IC, Wagner GC, Kraut J. The 2.6-A crystal structure of Pseudomonas putida cytochrome P-450. J Biol Chem. 1985 Dec 25;260(30):16122–16130. [PubMed]
• Ravichandran KG, Boddupalli SS, Hasermann CA, Peterson JA, Deisenhofer J. Crystal structure of hemoprotein domain of P450BM-3, a prototype for microsomal P450’s. Science. 1993 Aug 6;261(5122):731–736. [PubMed]
• Hasemann CA, Ravichandran KG, Peterson JA, Deisenhofer J. Crystal structure and refinement of cytochrome P450terp at 2.3 A resolution. J Mol Biol. 1994 Mar 4;236(4):1169–1185. [PubMed]
• Cupp-Vickery JR, Poulos TL. Structure of cytochrome P450eryF involved in erythromycin biosynthesis. Nat Struct Biol. 1995 Feb;2(2):144–153. [PubMed]
• Chen S, Deng PS, Swiderek K, Li M, Chan SI. Interaction of flavones and their bromoacetyl derivatives with NAD(P)H:quinone acceptor oxidoreductase. Mol Pharmacol. 1995 Feb;47(2):419–424. [PubMed]
• Das A, Wang JH, Lien EJ. Carcinogenicity, mutagenicity and cancer preventing activities of flavonoids: a structure-system-activity relationship (SSAR) analysis. Prog Drug Res. 1994;42:133–166. [PubMed]
• Collins BM, McLachlan JA, Arnold SF. The estrogenic and antiestrogenic activities of phytochemicals with the human estrogen receptor expressed in yeast. Steroids. 1997 Apr;62(4):365–372. [PubMed]
• Liu XF, Liu ML, Iyanagi T, Legesse K, Lee TD, Chen SA. Inhibition of rat liver NAD(P)H:quinone acceptor oxidoreductase (DT-diaphorase) by flavonoids isolated from the Chinese herb scutellariae radix (Huang Qin). Mol Pharmacol. 1990 Jun;37(6):911–915. [PubMed]
• Medina JH, Paladini AC, Wolfman C, Levi de Stein M, Calvo D, Diaz LE, Peña C. Chrysin (5,7-di-OH-flavone), a naturally-occurring ligand for benzodiazepine receptors, with anticonvulsant properties. Biochem Pharmacol. 1990 Nov 15;40(10):2227–2231. [PubMed]
• CHENG E, STORY CD, YODER L, HALE WH, BURROUGHS W. Estrogenic activity of isoflavone derivatives extracted and prepared from soybean oil meal. Science. 1953 Aug 7;118(3058):164–165. [PubMed]
• Adlercreutz H, Fotsis T, Lampe J, Wähälä K, Mäkelä T, Brunow G, Hase T. Quantitative determination of lignans and isoflavonoids in plasma of omnivorous and vegetarian women by isotope dilution gas chromatography-mass spectrometry. Scand J Clin Lab Invest Suppl. 1993;215:5–18. [PubMed]
• Adlercreutz CH, Goldin BR, Gorbach SL, Höckerstedt KA, Watanabe S, Hämäläinen EK, Markkanen MH, Mäkelä TH, Wähälä KT, Adlercreutz T. Soybean phytoestrogen intake and cancer risk. J Nutr. 1995 Mar;125(3 Suppl):757S–770S. [PubMed]
• Barnes S. Effect of genistein on in vitro and in vivo models of cancer. J Nutr. 1995 Mar;125(3 Suppl):777S–783S. [PubMed]