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Suppression of aromatase (estrogen synthetase) by red wine phytochemicals

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Abstract

Estrogen promotes the proliferation of breast cancer cells. Aromatase is the enzyme that converts androgen to estrogen. In tumors, the expression of aromatase is upregulated compared to surrounding non-cancerous tissue. In this study, we found that wine contains phytochemicals that are capable of suppressing aromatase. Red wine was shown to be much more effective than white wine in the suppression of aromatase activity. Whole wine, lyophilized wine, and heat-treated extracts were examined for aromatase inhibition in a human placenta microsomal assay. C18 Sep-Pak cartridge (Waters Co.) separation of red wine extracts under an increasing acetonitrile (ACN) gradient found that the most active components were in the 20% ACN fraction, in that they inhibited the wild-type human placenta aromatase, wild-type porcine placenta and blastocyst aromatase in a dose-dependent fashion. The 20% ACN active fraction was heat stable and inhibited aromatase in a non-competitive manner. The aromatase-inhibitory action of red wine extracts was also examined with a transgenic mouse model in which aromatase is over-expressed in the mammary tissues. It was found that the intake of the 20% ACN fraction by gavage completely abrogated aromatase-induced hyperplasia and other changes in the mammary tissue. This is the first report demonstrating that wine, especially red wine, contains phytochemicals that can inhibit aromatase.

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References

  1. Zeigler RG: A review of epidemiologic evidence that carotenoids reduce the risk of cancer. J Nutr 119: 116-122, 1989

    Google Scholar 

  2. Zeigler RG: Vegetables, fruit and carotenoids and risk of cancer. Am J Clin Nutr 53: 251S-259S, 1991

    Google Scholar 

  3. Gaziano JM, Hennekens CH: Update on dietary antioxidants and cancer. Pathol Biol 44: 42-45, 1996

    Google Scholar 

  4. Renaud S, de Lorgeril M: Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 53: 22-26, 1992

    Google Scholar 

  5. Nigdikar SV, Williams NR, Griffin BA, Howard AN: Consumption of red wine polyphenols reduces the susceptibility of low-density lipoproteins to oxidation in vivo. Am J Clin Nutr 68: 258-265, 1998

    Google Scholar 

  6. Das DK, Sato M, Ray PS, Maulik G, Engelman RM, Bertelli AA, Bertelli A: Cardioprotection of red wine: role of polyphenolic antioxidants. Drugs Exp Clin Res 25: 115-120, 1999

    Google Scholar 

  7. Lairon D, Amiot MJ: Flavonoids in food and natural antioxidants in wine. Curr Opin Lipid 10: 23-28, 1999

    Google Scholar 

  8. Paganga G, Miller N, Rice-Evans CA: The polyphenolic content of fruit and vegetables and their antioxidant activities. Free Radic Res 30: 153-162, 1999

    Google Scholar 

  9. Schorah CJ: Micronutrients, vitamins, and cancer risk. Vitamins and Hormones. 57: 1-23, 1999

    Google Scholar 

  10. Frankel EN, Kanner J, German JB, Parks E, Kinsella JE: Inhibition of oxidation of human low-density lipoprote in by phenolic substances in red wine. Lancet 341: 454-457, 1993

    Google Scholar 

  11. Renaud S, Ruff JC: Effects of alcohol on platelet functions. Clin Chim Acta 246: 77-89, 1995

    Google Scholar 

  12. Donovan JL, Bell JR, Kasim-Karakas S, Berman JB, Walzem RL, Hansen RJ, Waterhouse AL: Catech in is present as metabolites in human plasma after consumption of red wine. J Nutr 129: 1662-1668, 1999

    Google Scholar 

  13. Frankel EN, Waterhouse AL, Teissedre PL: Principal phenolic phytochemicals in selected California wines and their antioxidant activity in inhibiting oxidation of human low-density lipoproteins. J Agric Food Chem 43: 890-894, 1995

    Google Scholar 

  14. Haslam E: Practical Polyphenolics. Cambridge University Press, Cambridge, 1998

    Google Scholar 

  15. Brouillard R, George F, Fougerousse A: Polyphenols produced during red wine ageing. Biofactors 6: 403-410, 1997

    Google Scholar 

  16. Esteban J, Warsi Z, Haniu M, Hall P, Shively JE, Chen S: Detection of intratumoral aromatase in breast carcinomas. An immunohistochemical study with clinicopathologic correlation. Am J Pathol 140: 337-343, 1992

    Google Scholar 

  17. Bulun SE, Price TM, Mahendroo MS, Aitken J, Simpson ER: A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. J Clin Endocrinol Metab 77: 1622-1628, 1993

    Google Scholar 

  18. Sasano H, Nagura H, Harada N, Goukon Y, Kimura M: Immunolocalization of aromatase and other steroidogenic enzymes in human breast disorders. Hum Pathol 25: 530-535, 1994

    Google Scholar 

  19. Santen RJ, Martel H, Hoagland M, Naftolin F, Roa L, Harada N, Hafer L, Zaino R, Santner SJ: Stromal spindle cells contain aromatase in human breast tumors. J Clin Endocrinol Metab 79: 627-632, 1994

    Google Scholar 

  20. Lu Q, Nakmura J, Savinov A, Yue W, Weisz J, Dabbs DJ, Wolz G, Brodie A: Expression of aromatase prote in and messenger ribonucleic acid in tumor epithelial cells and evidence of functional significance of locally produced estrogen in human breast cancers. Endocrinology 137: 3061-3068, 1996

    Google Scholar 

  21. Harada N: Aberrant expression of aromatase in breast cancer tissues. J Ster Biochem Mol Biol 77: 1622-1628, 1997

    Google Scholar 

  22. 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 Ster Biochem Mol Biol 44: 611-616, 1993

    Google Scholar 

  23. 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 54: 5092-5095, 1994

    Google Scholar 

  24. Sun XZ, Zhou D, Chen S: Autocrine and paracrine actions of breast tumor aromatase. A three-dimensional cell culture study involving aromatase transfected MCF-7 and T-47D cells. J Ster Biochem Mol Biol 63: 29-36, 1997

    Google Scholar 

  25. Tekmal RR, Ramachandra N, Gubba S, Durgam VR, Mantione J, Toda K, Shizuta Y, Dillehay DL: Overexpression on int-5/aromatase in mammary glands of transgenic mice results in the induction of hyperplasia and nuclear abnormalities. Cancer Res 56: 3180-3185, 1996

    Google Scholar 

  26. Yue W, Wang JP, Halmilton CJ, Demers LM, Santen RJ: In situ aromatization enhances breast tumor estradiol levels and cellular proliferation. Cancer Res 58: 927-932, 1998

    Google Scholar 

  27. Kartin PM, Horwitz KB, Ryan DS, McGuire WL: Phytoestrogen interaction with estrogen receptors in human breast cells. Endocrinology 103: 1860-1867, 1978

    Google Scholar 

  28. Adlercreutz H, Nousavi Y, Loukovaara M, Hamalainen E. Lignans, isoflavones, sex hormone metabolism and breast cancer. In: Hockberg RB, Naftolin F (eds) The New Biology of Steroid Hormones. Raven Press, New York, 1991, pp 145-154

    Google Scholar 

  29. Whitten PL, Naftolin F: Dietary estrogens: a biologically active background for estrogen action. In: Hockberg RB, Naftolin F (eds) The New Biology of Steroid Hormones. Raven Press, New York, 1991, pp 145-154

    Google Scholar 

  30. Kellis JT Jr., Vickery LE: Inhibition of human estrogen synthetase (aromatase) by flavones. Science 225: 1032-1034, 1984

    Google Scholar 

  31. Ibrahim A-R, Abul-Hajj YJ: Aromatase inhibition by flavonoids. J Ster Biochem Mol Biol 37: 257-260, 1990

    Google Scholar 

  32. Adlercreutz H, Bannwart C, Wahala K, Makela T, Brunow G, Hase T, Arosemena PJ, Kellis JT, Vickery LE: Inhibition of human aromatase by mammalian lignans and isoflavonoid phytoestrogens. J Ster Biochem Mol Biol 44: 147-153, 1993

    Google Scholar 

  33. Campbell DR, Kurzer MS: Flavonoid inhibition of aromatase enzyme activity in human preadipocytes. J Ster Biochem Mol Bio 46: 381-388, 1993

    Google Scholar 

  34. Wang C, Makela T, Hase T, Adlercreutz H, Kurzer MS: Lignans and flavonoids inhibit aromatase enzyme in human preadipocytes. J Ster Biochem Mol Biol 50: 205-212, 1994

    Google Scholar 

  35. Pelissero C, Lenczowski MJ, Chinzi D, Davail-Cuisset B, Sumpter JP, Fostier A: Effects of flavonoids on aromatase activity, an in vitro study. J Ster Biochem Mol Biol 57: 215-223, 1996

    Google Scholar 

  36. Kao Y-C, Zhao C, Sherman M, Laughton CA, Chen S: Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: a sitedirected mutagenesis study. Environ Health Perspect 106: 85-92, 1998

    Google Scholar 

  37. Chen S, Sun X-Z, Kao Y-C, Kwon A, Zhou D, Eng E: Suppression of breast cancer cell growth with grape juice. Pharm Biology 36 Suppl: 53-61, 1998

    Google Scholar 

  38. Zhou D, Pompon D, Chen S: Stable expression of human aromatase cDNA in mammalian cells-a useful system for aromatase inhibitor screening. Cancer Res 50: 6949-6954, 1990

    Google Scholar 

  39. Thompson EA Jr., Siiteri PK: Utilization of oxygen and reduced nicotinamide adenine dinucleotide phosphate by human placental microsomes during aromatization of androstenedione. J Biol Chem 249: 5364-5372, 1974

    Google Scholar 

  40. Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248-254, 1976

    Google Scholar 

  41. Brodie A, Lu Q, Yue W, Wang J, Liu Y: Intratumoral aromatase model: the effects of letrozole (CGS 20267). Breast Cancer Res Treat 49: S23-26, S33-37, 1998

    Google Scholar 

  42. Lu Q, Yue W, Wang J, Liu Y, Long B, Brodie A: The effects of aromatase inhibitors and antiestrogens in the nude mouse model. Breast Cancer Res Treat 50: 63-71, 1998

    Google Scholar 

  43. Brodie A, Lu Q, Liu Y, Long B: Aromatase inhibitors and their antitumor effects in model systems. Endocr Relat Cancer 6: 205-210, 1999

    Google Scholar 

  44. Lu Q, Liu Y, Long BJ, Grigoryev D, Gimbel M, Brodie A: The effects of combining aromatase inhibitors with antiestrogens on tumor growth in a nude mouse model for breast cancer. Breast Canc Res Treat 57: 183-192, 1999

    Google Scholar 

  45. Hobbs WR, Rall TW, Verdoorn TA: Hypnotics and sedatives; ethanol. In: Hardman JG, Limbard LE, Molinoff PB, Ruddon RW, Gilman AG (eds) Goodman & Gilman's The Pharmacological Basis of Therapeutics. McGraw-Hill, New York, 1996, pp 361-397

    Google Scholar 

  46. Weiner FR, Czaja MJ, Zern MA: Ethanol and the liver. In: Arias IM, Jakoby WB, Popper H, Schachter D, Shafritz DA (eds) The Liver: Biology and Pathobiology. Raven Press, New York, 1988, p 1181

    Google Scholar 

  47. Markham KR: Techniques of flavonoid identification. In Rubery, JETAPH (ed) Biological Techniques Series. Academic Press, New York, 1982, pp 216-219

    Google Scholar 

  48. Bohm BA: Extraction, Purification, and Identification of Flavonoids. Harwood Academic Publishers, Amsterdam, 1998, pp 175-242

    Google Scholar 

  49. Kao Y-C, Cam LL, Laughton CA, Zhou D, Chen S: Binding characteristics of seven inhibitors of human aromatase: a site-directed mutagenesis study. Cancer Res 56: 3451-3460, 1996

    Google Scholar 

  50. Chan WK, Nguyen LT, Miller VP, Harris RZ: Mechanismbased inactivation of human cytochrome P450 3A4 by grapefruit juice and red wine. Life Sci 62: P L135-142, 1998

    Google Scholar 

  51. Gaido K, Dohme L, Wang F, Chen I, Blankvoort B, Ramamoorthy, Safe S: Comparative estrogenic activity of wine extracts and organochlorine pesticide residues in food. Environ Health Persp Suppl 6: 1347-1351, 1998

    Google Scholar 

  52. Gill J: The effects of moderate alcohol consumption on female hormone levels and reproductive function. Alcohol and Alcoholism 35: 417-423, 2000

    Google Scholar 

  53. Gorins A: Causal interactions of estrogens and alcohol in cancer of the breast. Presse Med 29: 670-672, 2000

    Google Scholar 

  54. Adami HO, Lund E, Bergstrom R, Meirik O: Cigarette smoking, alcohol consumption and risk of breast cancer in young women. Br J Cancer 58: 832-837, 1988

    Google Scholar 

  55. Gapstur SM, Potter JD, Sellers TA, Folsom AR: Increased risk of breast cancer with alcohol consumption in postmenopausal women. Am J Epidemiol 136: 1221-1231, 1991

    Google Scholar 

  56. Katsouyanni K, Trichopoulou A, Stuver S, Vassilaros S, Papadiamantis Y, Bournas N, Skarpou N, Mueller N, Trichopoulos D: Ethanol and breast cancer an association that may be both confounded and causal. Int J Cancer 58: 356-361, 1994

    Google Scholar 

  57. Viel JF, Perarnau JM, Challier B, Faivre-Nappez I: Alcohol calories, red wine consumption, and breast cancer among premenopausal women. Eur J Epidemiol 13: 639-643, 1997

    Google Scholar 

  58. Ferraroni M, Decarli A, Willet WC, Marubine E: Alcohol and breast cancer risk: a case-control study from northern Italy. Int J Epidemiol 20: 859-864, 1991

    Google Scholar 

  59. Freudenheim JL, Marshall JR, Graham S, Laughlin R, Vena JE, Swanson M, Ambrosone C, Nemoto T: Lifetime alcohol consumption and risk of breast cancer. Nutr Cancer 23: 1-11, 1995

    Google Scholar 

  60. Rosenberg L, Palmer JR, Miller DR, Clarke EA, Shapiro S: A case-control study of alcoholic beverage consumption and breast cancer. Am J Epidemiol 131: 6-14, 1990

    Google Scholar 

  61. Vachon CL, Kushi LH, Cerhan JR, Kuni C, Sellers TA: Association of diet and mammographic breast density in the minnesota breast cancer family cohort. Cancer Epidemiol Biomark Prev 9: 151-160, 2000

    Google Scholar 

  62. Longnecker, MP: Alcoholic beverage consumption in relation to risk of breast cancer: meta-analysis and review. Cancer Causes Control 5: 73-82, 1994

    Google Scholar 

  63. Clifford AJ, Powers TJ, Ebeler SE, Ebeler JD, Bills ND, Hinrichs SH: Delayed tumor onset in transgenic mice fed an amino acid based diet supplemented with red wine solids. FASEB J 8: A720, 1994

    Google Scholar 

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Eng, E.T., Williams, D., Mandava, U. et al. Suppression of aromatase (estrogen synthetase) by red wine phytochemicals. Breast Cancer Res Treat 67, 133–146 (2001). https://doi.org/10.1023/A:1010641102147

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