Phytoestrogenic Potential of Cyclopia Extracts and Polyphenols

Abstract

Cyclopia Vent. species, commonly known as honeybush, are endemic to Southern Africa. The plant is traditionally used as an herbal tea but several health benefits have recently been recorded. This minireview presents an overview of polyphenols found in Cyclopia and focusses on the phytoestrogenic potential of selected polyphenols and of extracts prepared from the plant.

Key words

Fabaceae - Cyclopia - phytoestrogen - ER binding - ERE promoter reporter assay - E-screen - uterotrophic assay

• References

• 1 Joubert E, Gelderblom WC, Louw A, de Beer D. South African herbal teas: Aspalathus linearis, Cyclopia spp. and Athrixia phylicoides – a review. J Ethnopharmacol 2008; 119: 376-412
• 2 Schutte A. Systematics of the genus Cyclopia Vent. (Fabaceae, Podalyrieae). Edinburgh J Bot 1997; 54: 125-170
• 3 Joubert E, Joubert ME, Bester C, de Beer D, De Lange JH. Honeybush (Cyclopia spp.): From local cottage industry to global markets – the catalytic and supporting role of research. S Afr J Bot 2011; 77: 887-907
• 4 Watt JM, Breyer-Brandwijk MG. The medicinal and poisonous plants of southern and eastern Africa. London: E. & S. Livingstone; 1962
• 5 Ferreira D, Kamara BI, Brandt EV, Joubert E. Phenolic compounds from Cyclopia intermedia (honeybush tea). 1. J Agric Food Chem 1998; 46: 3406-3410
• 6 Kamara BI, Brandt EV, Ferreira D, Joubert E. Polyphenols from honeybush tea (Cyclopia intermedia). J Agric Food Chem 2003; 51: 3874-3879
• 7 Kamara BI, Brand DJ, Brandt EV, Joubert E. Phenolic metabolites from honeybush tea (Cyclopia subternata). J Agric Food Chem 2004; 52: 5391-5395
• 8 Joubert E, Richards ES, Van der Merwe JD, De Beer D, Manley M, Gelderblom WC. An effect of species variation and processing on phenolic composition and in vitro antioxidant activity of aqueous extracts of Cyclopia spp. (honeybush tea). J Agric Food Chem 2008; 56: 954-963
• 9 Hubbe ME. Evaluation of antioxidant and free radical scavenging activities of honeybush tea (Cyclopia). Stellenbosch: Stellenbosch University; 2000
• 10 Marnewick J, Joubert E, Joseph S, Swanevelder S, Swart P, Gelderblom W. Inhibition of tumour promotion in mouse skin by extracts of rooibos (Aspalathus linearis) and honeybush (Cyclopia intermedia), unique South African herbal teas. Cancer Lett 2005; 224: 193-202
• 11 Sissing L, Marnewick J, de Kock M, Swanevelder S, Joubert E, Gelderblom W. Modulating effects of rooibos and honeybush herbal teas on the development of esophageal papillomas in rats. Nutr Cancer 2011; 63: 600-610
• 12 Muller CJF, Joubert E, Gabuza K, de Beer D, Louw J, Fey SJ. Assessment of the antidiabetic potential of an aqueous extract of honeybush (Cyclopia intermedia) in streptozotocin and obese insulin resistant wistar rats. In: Rasooli I, ed. Phytochemicals – bioactivities and impact on health. Rijeka: In Tech; 2011: 313-332
• 13 Mose Larsen P, Fey SJ, Louw J, Joubert L. Anti-diabetic extract of honeybush.. US Patent 20110045108, 2012
• 14 Rood B. Uit die veldapteek. Kaapstad: Tafelberg; 1994
• 15 Kokotkiewicz A, Luczkiewicz M, Sowinski P, Glod D, Gorynski K, Bucinski A. Isolation and structure elucidation of phenolic compounds from Cyclopia subternata Vogel (honeybush) intact plant and in vitro cultures. Food Chem 2012; 133: 1373-1382
• 16 de Beer D, Joubert E. Development of HPLC method for Cyclopia subternata phenolic compound analysis and application to other Cyclopia spp. J Food Comp Anal 2010; 23: 289-297
• 17 De Beer D, Schulze AS, Joubert E, De Villiers A, Malherbe CJ, Stander MA. Food ingredient extracts of Cyclopia subternata (honeybush): variation in phenolic composition and antioxidant capacity. Molecules 2012; 17: 14602-14624
• 18 Hattori M, Shu YZ, El-Sedawy AI, Namba T, Kobashi K, Tomimori T. Metabolism of homoorientin by human intestinal bacteria. J Nat Prod 1988; 51: 874-878
• 19 Sanugul K, Akao T, Li Y, Kakiuchi N, Nakamura N, Hattori M. Isolation of a human intestinal bacterium that transforms mangiferin to norathyriol and inducibility of the enzyme that cleaves a C-glucosyl bond. Biol Pharm Bull 2005; 28: 1672-1678
• 20 Nakamura K, Nishihata T, Jin JS, Ma CM, Komatsu K, Iwashima M, Hattori M. The C-glucosyl bond of puerarin was cleaved hydrolytically by a human intestinal bacterium strain PUE to yield its aglycone daidzein and an intact glucose. Chem Pharm Bull (Tokyo) 2011; 59: 23-27
• 21 Shanle EK, Xu W. Endocrine disrupting chemicals targeting estrogen receptor signaling: identification and mechanisms of action. Chem Res Toxicol 2011; 24: 6-19
• 22 Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Strom A, Treuter E, Warner M, Gustafsson JA. Estrogen receptors: how do they signal and what are their targets. Physiol Rev 2007; 87: 905-931
• 23 Kortenkamp A, Martin O, Faust M, Evans R, McKinley R, Orton F, Rosivatz E. State of the art assessment of endocrine disruptors. Final Rep 2011; 2011: 1-135
• 24 EDSTAC. Endocrine disruptor screening and testing advisory committee final report, 1998. Washington: US Environmental Protection Agency; 1998
• 25 Saarinen NM, Bingham C, Lorenzetti S, Mortensen A, Makela S, Penttinen P, Sorensen IK, Valsta LM, Virgili F, Vollmer G, Warri A, Zierau O. Tools to evaluate estrogenic potency of dietary phytoestrogens: a consensus paper from the EU Thematic Network “Phytohealth” (QLKI-2002–2453). Genes Nutr 2006; 1: 143-158
• 26 Soto AM, Maffini MV, Schaeberle CM, Sonnenschein C. Strengths and weaknesses of in vitro assays for estrogenic and androgenic activity. Best Pract Res Clin Endocrinol Metab 2006; 20: 15-33
• 27 Dobbins LL, Brain RA, Brooks BW. Comparison of the sensitivities of common in vitro and in vivo assays of estrogenic activity: application of chemical toxicity distributions. Environ Toxicol Chem 2008; 27: 2608-2616
• 28 Fang H, Tong W, Perkins R, Soto AM, Prechtl NV, Sheehan DM. Quantitative comparisons of in vitro assays for estrogenic activities. Environ Health Perspect 2000; 108: 723-729
• 29 Patisaul HB, Jefferson W. The pros and cons of phytoestrogens. Front Neuroendocrinol 2010; 31: 400-419
• 30 Verhoog NJD, Joubert E, Louw A. Screening of four Cyclopia (honeybush) species for putative phyto-oestrogenic activity by oestrogen receptor binding assays. S Afr J Sci 2007; 103: 13-21
• 31 de Cremoux P, This P, Leclercq G, Jacquot Y. Controversies concerning the use of phytoestrogens in menopause management: bioavailability and metabolism. Maturitas 2010; 65: 334-339
• 32 Verhoog NJ, Joubert E, Louw A. Evaluation of the phytoestrogenic activity of Cyclopia genistoides (honeybush) methanol extracts and relevant polyphenols. J Agric Food Chem 2007; 55: 4371-4381
• 33 Liu L, Xu DM, Cheng YY. Distinct effects of naringenin and hesperetin on nitric oxide production from endothelial cells. J Agric Food Chem 2008; 56: 824-829
• 34 Promberger A, Dornstauder E, Frühwirth C, Schmid ER, Jungbauer A. Determination of estrogenic activity in beer by biological and chemical means. J Agric Food Chem 2001; 49: 633-640
• 35 Guo D, Wang J, Wang X, Luo H, Zhang H, Cao D, Chen L, Huang N. Double directional adjusting estrogenic effect of naringin from Rhizoma drynariae (Gusuibu). J Ethnopharmacol 2011; 138: 451-457
• 36 Breinholt V, Larsen JC. Detection of weak estrogenic flavonoids using a recombinant yeast strain and a modified MCF7 cell proliferation assay. Chem Res Toxicol 1998; 11: 622-629
• 37 Han DH, Denison MS, Tachibana H, Yamada K. Relationship between estrogen receptor-binding and estrogenic activities of environmental estrogens and suppression by flavonoids. Biosci Biotechnol Biochem 2002; 66: 1479-1487
• 38 Reiter E, Beck V, Medjakovic S, Mueller M, Jungbauer A. Comparison of hormonal activity of isoflavone-containing supplements used to treat menopausal complaints. Menopause 2009; 16: 1049-1060
• 39 Tang JY, Li S, Li ZH, Zhang ZJ, Hu G, Cheang LC, Alex D, Hoi MP, Kwan YW, Chan SW, Leung GP, Lee SM. Calycosin promotes angiogenesis involving estrogen receptor and mitogen-activated protein kinase (MAPK) signaling pathway in zebrafish and HUVEC. PLoS One 2010; 5: e11822
• 40 Beck V, Unterrieder E, Krenn L, Kubelka W, Jungbauer A. Comparison of hormonal activity (estrogen, androgen and progestin) of standardized plant extracts for large scale use in hormone replacement therapy. J Steroid Biochem Mol Biol 2003; 84: 259-268
• 41 Mu H, Bai YH, Wang ST, Zhu ZM, Zhang YW. Research on antioxidant effects and estrogenic effect of formononetin from Trifolium pratense (red clover). Phytomedicine 2009; 16: 314-319
• 42 Chen J, Liu L, Hou R, Shao Z, Wu Y, Chen X, Zhou L. Calycosin promotes proliferation of estrogen receptor-positive cells via estrogen receptors and ERK1/2 activation in vitro and in vivo . Cancer Lett 2011; 308: 144-151
• 43 Zhu JT, Choi RC, Chu GK, Cheung AW, Gao QT, Li J, Jiang ZY, Dong TT, Tsim KW. Flavonoids possess neuroprotective effects on cultured pheochromocytoma PC12 cells: a comparison of different flavonoids in activating estrogenic effect and in preventing beta-amyloid-induced cell death. J Agric Food Chem 2007; 55: 2438-2445
• 44 Mfenyana C, De Beer D, Joubert E, Louw A. Selective extraction of Cyclopia for enhanced in vitro phytoestrogenicity and benchmarking against commercial phytoestrogen extracts. J Steroid Biochem Mol Biol 2008; 112: 74-86
• 45 Kitalong C, El-Halawany A, El-Dine R, Ma C, Hattori M. Phenolics from Phaleria nisidai with estrogenic activity. Records Nat Prod 2012; 6: 296-300
• 46 Collins-Burow BM, Burow ME, Duong BN, McLachlan JA. Estrogenic and antiestrogenic activities of flavonoid phytochemicals through estrogen receptor binding-dependent and -independent mechanisms. Nutr Cancer 2000; 38: 229-244
• 47 Wagner H, Ulrich-Merzenich G. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine 2009; 16: 97-110
• 48 Geller SE, Studee L. Botanical and dietary supplements for menopausal symptoms: what works, what does not. J Womens Health (Larchmt) 2005; 14: 634-649
• 49 Nilsson S, Mäkelä S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M, Gustafsson JÅ. Mechanisms of estrogen action. Physiol Rev 2001; 81: 1535-1565
• 50 Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med 2006; 354: 270-282
• 51 Humphries KH, Gill S. Risks and benefits of hormone replacement therapy: the evidence speaks. Can Med Assoc J 2003; 168: 1001-1010
• 52 Rymer J, Wilson R, Ballard K. Making decisions about hormone replacement therapy. Br Med J 2003; 326: 322-326
• 53 Glazier MG, Bowman MA. A review of the evidence for the use of phytoestrogens as a replacement for traditional estrogen replacement therapy. Arch Intern Med 2001; 161: 1161-1172
• 54 Rossouw J, Anderson G, Prentice R, LaCroix AZ, Kooperberg C, Stefanick M, Jackson RD, Beresford SA, Howard BV, Johnson KC. Writing Group for the Womenʼs Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Womenʼs Health Initiative randomized controlled trial. JAMA 2002; 288: 321-333
• 55 Farquhar D. Postmenopausal hormone replacement therapy for chronic disease prevention: results from the Womenʼs Health Initiative trial. CMAJ 2002; 167: 377-378
• 56 Van Leeuwen FE, Rookus MA. Breast cancer and hormone-replacement therapy: the Million Women Study. The Lancet 2003; 362: 1330
• 57 Warren MP, Halpert S. Hormone replacement therapy: controversies, pros and cons. Best Pract Res Clin Endocrinol Metab 2004; 18: 317-332
• 58 Santen RJ, Allred DC, Ardoin SP, Archer DF, Boyd N, Braunstein GD, Burger HG, Colditz GA, Davis SR, Gambacciani M. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab 2010; 95: s1-s66
• 59 Scheiber MD, Rebar RW. Isoflavones and postmenopausal bone health: a viable alternative to estrogen therapy?. Menopause 1999; 6: 233
• 60 Russell L, Hicks GS, Low AK, Shepherd JM, Brown CA. Phytoestrogens: a viable option?. Am J Med Sci 2002; 324: 185-188
• 61 Mackey R, Eden J. Phytoestrogens and the menopause. Climacteric 1998; 1: 302-308
• 62 Adlercreutz H, Mazur W. Phyto-oestrogens and Western diseases. Ann Med 1997; 29: 95-120
• 63 Magee PJ, Rowland IR. Phytoestrogens, their mechanism of action: current evidence for a role in breast and prostate cancer. Br J Nutr 2004; 91: 513-531
• 64 Amin A, Buratovich M. The anti-cancer charm of flavonoids: a cup-of-tea will do. Recent Pat Anticancer Drug Discov 2007; 2: 109-117
• 65 Setchell K. Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones. Am J Clin Nutr 1998; 68: 1333S-1346S
• 66 Palmieri C, Cheng G, Saji S, Zelada-Hedman M, Weihua Z, Van Noorden S, Wahlstrom T, Coombes R, Warner M, Gustafsson J. Estrogen receptor beta in breast cancer. Endocr Relat Cancer 2002; 9: 1-13
• 67 Hartman J, Ström A, Gustafsson JÅ. Estrogen receptor beta in breast cancer–diagnostic and therapeutic implications. Steroids 2009; 74: 635-641
• 68 Maximov PY, Lee TM, Jordan VC. The discovery and development of Selective Estrogen Receptor Modulators (SERMs) for clinical practice. Curr Clin Pharmacol 2013; 8: 135-155
• 69 Ververidis F, Trantas E, Douglas C, Vollmer G, Kretzschmar G, Panopoulos N. Biotechnology of flavonoids and other phenylpropanoid-derived natural products. Part I: Chemical diversity, impacts on plant biology and human health. Biotechnol J 2007; 2: 1214-1234
• 70 Cornwell T, Cohick W, Raskin I. Dietary phytoestrogens and health. Phytochemistry 2004; 65: 995-1016
• 71 Usui T. Pharmaceutical prospects of phytoestrogens. Endocr J 2006; 53: 7-20
• 72 Rice S, Whitehead SA. Phytoestrogens oestrogen synthesis and breast cancer. J Steroid Biochem Mol Biol 2008; 108: 186-195
• 73 Tempfer CB, Bentz EK, Leodolter S, Tscherne G, Reuss F, Cross HS, Huber JC. Phytoestrogens in clinical practice: a review of the literature. Fertil Steril 2007; 87: 1243-1249
• 74 Messina M, Hughes C. Efficacy of soyfoods and soybean isoflavone supplements for alleviating menopausal symptoms is positively related to initial hot flush frequency. J Med Food 2003; 6: 1-11
• 75 Boucher BA, Cotterchio M, Anderson LN, Kreiger N, Kirsh VA, Thompson LU. Use of isoflavone supplements is associated with reduced postmenopausal breast cancer risk. Int J Cancer 2013; 132: 1439-1450
• 76 Fink BN, Steck SE, Wolff MS, Britton JA, Kabat GC, Gaudet MM, Abrahamson PE, Bell P, Schroeder JC, Teitelbaum SL. Dietary flavonoid intake and breast cancer survival among women on Long Island. Cancer Epidemiol Biomarkers Prev 2007; 16: 2285-2292
• 77 Wu A, Yu M, Tseng C, Pike M. Epidemiology of soy exposures and breast cancer risk. Br J Cancer 2008; 98: 9-14
• 78 Shu XO, Zheng Y, Cai H, Gu K, Chen Z, Zheng W, Lu W. Soy food intake and breast cancer survival. JAMA 2009; 302: 2437-2443
• 79 Lee SA, Shu XO, Li H, Yang G, Cai H, Wen W, Ji BT, Gao J, Gao YT, Zheng W. Adolescent and adult soy food intake and breast cancer risk: results from the Shanghai Womenʼs Health Study. Am J Clin Nutr 2009; 89: 1920-1926
• 80 Travis RC, Allen NE, Appleby PN, Spencer EA, Roddam AW, Key TJ. A prospective study of vegetarianism and isoflavone intake in relation to breast cancer risk in British women. Int J Cancer 2008; 122: 705-710
• 81 Hooper L, Madhavan G, Tice JA, Leinster SJ, Cassidy A. Effects of isoflavones on breast density in pre- and post-menopausal women: a systematic review and meta-analysis of randomized controlled trials. Hum Reprod Update 2010; 16: 745-760
• 82 Mersereau JE, Levy N, Staub RE, Baggett S, Zogric T, Chow S, Ricke WA, Tagliaferri M, Cohen I, Bjeldanes LF. Liquiritigenin is a plant-derived highly selective estrogen receptor β agonist. Mol Cell Endocrinol 2008; 283: 49-57
• 83 Leitman DC, Christians U. MF101: a multi-component botanical selective estrogen receptor beta modulator for the treatment of menopausal vasomotor symptoms. Expert Opin Investig Drugs 2012; 21: 1031-1042
• 84 Rhomberg LR, Goodman JE, Foster WG, Borgert CJ, Van Der Kraak G. A critique of the European Commission Document, “State of the Art Assessment of Endocrine Disrupters”. Crit Rev Toxicol 2012; 42: 465-473
• 85 Bock C, Waldmann KH, Ternes W. Mangiferin and hesperidin metabolites are absorbed from the gastrointestinal tract of pigs after oral ingestion of a Cyclopia genistoides (honeybush tea) extract. Nutr Res 2008; 28: 879-891
• 86 Bock C, Ternes W. The phenolic acids from bacterial degradation of the mangiferin aglycone are quantified in the feces of pigs after oral ingestion of an extract of Cyclopia genistoides (honeybush tea). Nutr Res 2010; 30: 348-357
• 87 Efferth T, Koch E. Complex interactions between phytochemicals. The multi-target therapeutic concept of phytotherapy. Curr Drug Targets 2011; 12: 122-132
• 88 Kong DX, Li XJ, Zhang HY. Where is the hope for drug discovery? Let history tell the future. Drug Discov Today 2009; 14: 115-119
• 89 Patwardhan B, Mashelkar RA. Traditional medicine-inspired approaches to drug discovery: can Ayurveda show the way forward?. Drug Discov Today 2009; 14: 804-811
• 90 Katiyar C, Gupta A, Kanjilal S, Katiyar S. Drug discovery from plant sources: An integrated approach. AYU (An international quarterly journal of research in Ayurveda) 2012; 33: 10-19
• 91 Gertsch J. Botanical drugs, synergy, and network pharmacology: forth and back to intelligent mixtures. Planta Med 2011; 77: 1086-1089
• 92 Joubert E, Manley M, Maicu C, de Beer D. Effect of pre-drying treatments and storage on color and phenolic composition of green honeybush (Cyclopia subternata) herbal tea. J Agric Food Chem 2010; 58: 338-344
• 93 Zava DT, Blen M, Duwe G. Estrogenic activity of natural and synthetic estrogens in human breast cancer cells in culture. Environ Health Perspect 1997; 105 (Suppl. 03) 637-645
• 94 Zava DT, Duwe G. Estrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cells in vitro . Nutr Cancer 1997; 27: 31-40
• 95 Hwang SL, Yen GC. Effect of hesperetin against oxidative stress via ER- and TrkA-mediated actions in PC12 cells. J Agric Food Chem 2011; 59: 5779-5785
• 96 Lee S, Chung H, Maier CG, Wood AR, Dixon RA, Mabry TJ. Estrogenic Flavonoids from Artemisia vulgaris L. J Agric Food Chem 1998; 46: 3325-3329
• 97 Poon CH, Wong TY, Wang Y, Tsuchiya Y, Nakajima M, Yokoi T, Leung LK. The citrus flavanone naringenin suppresses CYP1B1 transactivation through antagonising xenobiotic-responsive element binding. Br J Nutr advance online publication 31 August 2012;
• 98 Zand RS, Jenkins DJ, Diamandis EP. Steroid hormone activity of flavonoids and related compounds. Breast Cancer Res Treat 2000; 62: 35-49
• 99 Overk CR, Yao P, Chadwick LR, Nikolic D, Sun Y, Cuendet MA, Deng Y, Hedayat AS, Pauli GF, Farnsworth NR, van Breemen RB, Bolton JL. Comparison of the in vitro estrogenic activities of compounds from hops (Humulus lupulus) and red clover (Trifolium pratense). J Agric Food Chem 2005; 53: 6246-6253
• 100 Shemesh M, Lindner HR, Ayalon N. Affinity of rabbit uterine oestradiol receptor for phyto-oestrogens and its use in a competitive protein-binding radioassay for plasma coumestrol. J Reprod Fertil 1972; 29: 1-9
• 101 Ji ZN, Zhao WY, Liao GR, Choi RC, Lo CK, Dong TT, Tsim KW. In vitro estrogenic activity of formononetin by two bioassay systems. Gynecol Endocrinol 2006; 22: 578-584
• 102 Matsumoto T, Kobayashi M, Moriwaki T, Kawai S, Watabe S. Survey of estrogenic activity in fish feed by yeast estrogen-screen assay. Comp Biochem Physiol C Toxicol Pharmacol 2004; 139: 147-152
• 103 Chemler JA, Lim CG, Daiss JL, Koffas MAG. A versatile microbial system for biosynthesis of novel polyphenols with altered estrogen receptor binding activity. Chem Biol 2010; 17: 392-401
• 104 Murata M, Midorikawa K, Koh M, Umezawa K, Kawanishi S. Genistein and daidzein induce cell proliferation and their metabolites cause oxidative DNA damage in relation to isoflavone-induced cancer of estrogen-sensitive organs. Biochemistry 2004; 43: 2569-2577
• 105 Sotoca AM, Bovee TFH, Brand W, Velikova N, Boeren S, Murk AJ, Vervoort J, Rietjens IM. Superinduction of estrogen receptor mediated gene expression in luciferase based reporter gene assays is mediated by a post-transcriptional mechanism. J Steroid Biochem Mol Biol 2010; 122: 204-211
• 106 Zych M, Folwarczna J, Trzeciak HI. Natural phenolic acids may increase serum estradiol level in ovariectomized rats. Acta Biochim Pol 2009; 56: 503-507