Skip to main content
PMC home page
Cellular & Molecular Biology Letters logoLink to Cellular & Molecular Biology Letters
. 2014 Oct 13;19(4):542–560. doi: 10.2478/s11658-014-0211-7

In vitro effects of prolonged exposure to quercetin and epigallocatechin gallate of the peripheral blood mononuclear cell membrane

Denisa Margina 1, Mihaela Ilie 1,✉, Gina Manda 2, Ionela Neagoe 2, Rucsandra Danciulescu-Miulescu 3, Carmen Nicoleta Purdel 1, Daniela Gradinaru 1
PMCID: PMC6275756  PMID: 25311813

Abstract

The study aimed to assess biophysical changes that take place in the peripheral blood mononuclear cell (PBMC) membranes when exposed in vitro to 10 μM quercetin or epigallocatechin gallate (EGCG) for 24 and 48 h. PBMCs isolated from hypercholesterolemia patients were compared to those from normocholesterolemia subjects. The membrane fluidity and transmembrane potential were evaluated and the results were correlated with biochemical parameters relevant to oxidative stress, assessed in the patients’ plasma. The baseline value of PBMC membrane anisotropy for the hypercholesterolemia patients was lower than that of the control group. These results correlated with the plasma levels of advanced glycation end products, which were significantly higher in the hypercholesterolemia group, and the total plasma antioxidant status, which was significantly higher in normocholesterolemia subjects. In the case of normocholesterolemia cells in vitro, polyphenols induced a decrease in membrane anisotropy (7.25–11.88% at 24 h, 1.82–2.26% at 48 h) and a hyperpolarizing effect (8.30–8.90% at 24 h and 4.58–13.00% at 48 h). The same effect was induced in hypercholesterolemia cells, but only after 48 h exposure to the polyphenols: the decrease in membrane anisotropy was 5.70% for quercetin and 2.33% for EGCG. After 48 h of in vitro incubation with the polyphenols, PBMCs isolated from hypercholesterolemia patients exhibited the effects that had been registered in cells from normocholesterolemia subjects after 24 h exposure. These results outlined the beneficial action of the studied polyphenols, quercetin and EGCG, as dietary supplements in normocholesterolemia and hypercholesterolemia patients.

Keywords: Membrane fluidity, Transmembrane potential, Total antioxidant status, Advanced glycation end products, Hypercholesterolemia, Quercetin, Epigallocatechin gallate

Full Text

The Full Text of this article is available as a PDF (1.8 MB).

Abbreviations used

AGEs

advanced glycation end products

DiBAC4(3)

bis-(1,3-dibutylbarbituric acid) trimethine oxonol

DPPP

diphenyl-1-pyrenylphosphine

EGCG

epigallocatechin gallate

FCS

fetal calf serum

HC

hypercholesterolemia

NC

normocholesterolemia

PBMCs

peripheral blood mononuclear cells

TAS

total antioxidant status

TMA-DPH

1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene p-toluensulfonate

References

  • 1.Dykesa L, Peterson GC, Rooney WL, Rooney LW. Flavonoid composition of lemon-yellow sorghum genotypes. Food Chemistry. 2011;128:173–179. doi: 10.1016/j.foodchem.2011.03.020. [DOI] [PubMed] [Google Scholar]
  • 2.Davies KM, Bloor SJ, Spiller GB, Deroles SC. Production of yellow colour in flowers: redirection of flavonoid biosynthesis in Petunia. The Plant Journal. 1998;13:259–266. [Google Scholar]
  • 3.Procházková D, Boušová I, Wilhelmová N. Antioxidant and prooxidant properties of flavonoids. Fitoterapia. 2011;82:513–523. doi: 10.1016/j.fitote.2011.01.018. [DOI] [PubMed] [Google Scholar]
  • 4.Weber JM, Ruzindana-Umunyana A, Imbeault L, Sircar S. Inhibition of adenovirus infection and adenain by green tea catechins. Antivir. Res. 2003;58:167–173. doi: 10.1016/s0166-3542(02)00212-7. [DOI] [PubMed] [Google Scholar]
  • 5.Alvesalo J, Vuorela H, Tammela P, Leinonen M, Saikku P, Vuorela P. Inhibitory effect of dietary phenolic compounds on Chlamydia pneumoniae in cell cultures. Biochem. Pharmacol. 2006;71:735–741. doi: 10.1016/j.bcp.2005.12.006. [DOI] [PubMed] [Google Scholar]
  • 6.Widlansky ME, Duffy SJ, Hamburg NM, Gokce N, Warden BA, Wiseman S, Keaney JF, Jr., Frei B, Vita JA. Effects of black tea consumption on plasma catechins and markers of oxidative stress and inflammation in patients with coronary artery disease. Free Radic. Biol. Med. 2005;38:499–506. doi: 10.1016/j.freeradbiomed.2004.11.013. [DOI] [PubMed] [Google Scholar]
  • 7.Hubbard GP, Wolffram S, Lovegrove JA, Gibbins JM. Ingestion of quercetin inhibits platelet aggregation and essential components of the collagen-stimulated platelet activation pathway in humans. J. Thromb. Haemost. 2004;2:2138–2145. doi: 10.1111/j.1538-7836.2004.01067.x. [DOI] [PubMed] [Google Scholar]
  • 8.Kaliora AC, Dedoussis GVZ, Schmidt H. Dietary antioxidants in preventing atherogenesis. Atherosclerosis. 2006;187:1–17. doi: 10.1016/j.atherosclerosis.2005.11.001. [DOI] [PubMed] [Google Scholar]
  • 9.Ajdžanović VZ, Milošević VLj, Spasojević IB. Glucocorticoid excess and disturbed hemodynamics in advanced age: the extent to which soy isoflavones may be beneficial. Gen. Physiol. Biophys. 2012;31:367–374. doi: 10.4149/gpb_2012_041. [DOI] [PubMed] [Google Scholar]
  • 10.Ajdžanović VZ, Medigović IM, Pantelić JB, Milošević VLj. Soy isoflavones and cellular mechanics. J. Bioenerg. Biomembr. 2014;46:99–107. doi: 10.1007/s10863-013-9536-6. [DOI] [PubMed] [Google Scholar]
  • 11.Chanet A, Milenkovic D, Manach C, Mazur A, Morand C. Citrus flavanones: what is their role in cardiovascular protection? J. Agric. Food Chem. 2012;60:8809–8822. doi: 10.1021/jf300669s. [DOI] [PubMed] [Google Scholar]
  • 12.Siasos G, Tousoulis D, Tsigkou V, Kokkou E, Oikonomou E, Vavuranakis M, Basdra EK, Papavassiliou AG, Stefanadis C. Flavonoids in atherosclerosis: an overview of their mechanisms of action. Curr. Med. Chem. 2013;20:2641–2660. doi: 10.2174/0929867311320210003. [DOI] [PubMed] [Google Scholar]
  • 13.Xiao, Q., Park, Y., Hollenbeck, A.R. and Kitahara, C.M. Dietary flavonoid intake and thyroid cancer risk in the NIH-AARP diet and health study. Cancer Epidemiol. Biomarkers Prev.23 (2014). [Epub ahead of print] DOI: 10.1158/1055-9965.EPI-13-1150. [DOI] [PMC free article] [PubMed]
  • 14.Bhatti SK, O’Keefe JH, Lavie CJ. Coffee and tea: perks for health and longevity? Curr. Opin. Clin. Nutr. Metab. Care. 2013;16:688–697. doi: 10.1097/MCO.0b013e328365b9a0. [DOI] [PubMed] [Google Scholar]
  • 15.Fraga CG, Galleano M, Verstraeten SV, Oteiza PI. Basic biochemical mechanisms behind the health benefits of polyphenols. Mol. Aspects Med. 2010;31:435–445. doi: 10.1016/j.mam.2010.09.006. [DOI] [PubMed] [Google Scholar]
  • 16.Weng CJ, Yen GC. Chemopreventive effects of dietary phytochemicals against cancer invasion and metastasis: phenolic acids, monophenol, polyphenol, and their derivatives. Cancer Treat. Rev. 2012;38:76–87. doi: 10.1016/j.ctrv.2011.03.001. [DOI] [PubMed] [Google Scholar]
  • 17.Karewicza A, Bielska D, Gzyl-Malcher B, Kepczynski M, Lach R, Nowakowska M. Interaction of curcumin with lipid monolayers and liposomal bilayers. Colloids Surf. B: Biointerfaces. 2011;88:231–239. doi: 10.1016/j.colsurfb.2011.06.037. [DOI] [PubMed] [Google Scholar]
  • 18.Androutsopoulos VP, Papakyriakou A, Vourloumis D, Tsatsakis AM, Spandidos DA. Dietary flavonoids in cancer therapy and prevention: substrates and inhibitors of cytochrome P450 CYP1 enzymes. Pharmacol. Ther. 2010;126:9–20. doi: 10.1016/j.pharmthera.2010.01.009. [DOI] [PubMed] [Google Scholar]
  • 19.Margina D, Ilie M, Manda G, Neagoe I, Mocanu M, Ionescu D, Gradinaru D, Ganea C. Quercetin and epigallocatechin gallate effects on the cell membranes biophysical properties correlate with their antioxidant potential. Gen. Physiol. Biophys. 2012;31:47–55. doi: 10.4149/gpb_2012_005. [DOI] [PubMed] [Google Scholar]
  • 20.Chen R, Wang JB, Zhang XQ, Ren J, Zeng CM. Green tea polyphenol epigallocatechin-3-gallate (EGCG) induced intermolecular cross-linking of membrane proteins. Arch. Biochem. Biophys. 2011;507:343–349. doi: 10.1016/j.abb.2010.12.033. [DOI] [PubMed] [Google Scholar]
  • 21.Ajdzanović V, Spasojević I, Filipović B, Sosić-Jurjević B, Sekulić M, Milosević V. Effects of genistein and daidzein on erythrocyte membrane fluidity: an electron paramagnetic resonance study. Can. J. Physiol. Pharmacol. 2010;88:497–500. doi: 10.1139/y10-020. [DOI] [PubMed] [Google Scholar]
  • 22.Kimura Y, Hyogo H, Yamagishi S, Takeuchi M, Ishitobi T, Nabeshima Y, Arihiro K, Chayama K. Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH. J. Gastroenterol. 2010;45:750–757. doi: 10.1007/s00535-010-0203-y. [DOI] [PubMed] [Google Scholar]
  • 23.Stirban A, Gawlowski T, Roden M. Vascular effects of advanced glycation endproducts: Clinical effects and molecular mechanisms. Mol. Metab. 2013;3:94–108. doi: 10.1016/j.molmet.2013.11.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Margina D, Ilie M, Gradinaru D. Quercetin and Epigallocatechin Gallate Induce in Vitro a Dose-Dependent Stiffening and Hyperpolarizing Effect on the Cell Membrane of Human Mononuclear Blood Cells. Int. J. Mol. Sci. 2012;13:4839–4859. doi: 10.3390/ijms13044839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Ionescu D, Margina D, Ilie M, Iftime A, Ganea C. Quercetin and epigallocatechin-3-gallate effect on the anisotropy of model membranes with cholesterol. Food Chem. Toxicol. 2013;61:94–100. doi: 10.1016/j.fct.2013.03.007. [DOI] [PubMed] [Google Scholar]
  • 26.Llorente-Cortés V, De Gonzalo-Calvo D, Orbe J, Páramo JA, Badimon L. Signature of subclinical femoral artery atherosclerosis in peripheral blood mononuclear cells. Eur. J. Clin. Invest. 2014;44:539–548. doi: 10.1111/eci.12267. [DOI] [PubMed] [Google Scholar]
  • 27.Rentoukas E, Tsarouhas K, Kaplanis I, Korou E, Nikolaou M, Marathonitis G, Kokkinou S, Haliassos A, Mamalaki A, Kouretas D, Tsitsimpikou C. Connection between telomerase activity in PBMC and markers of inflammation and endothelial dysfunction in patients with metabolic syndrome. PLoS One. 2012;7:e35739. doi: 10.1371/journal.pone.0035739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Miller NJ, Rice-Evans C, Davies MJ, Gopinathan V, Milner A. A novel method for measuring antioxidant capacity and its application to monitoring the antioxidant status in premature neonates. Clin. Sci. (Lond.) 1993;84:407–412. doi: 10.1042/cs0840407. [DOI] [PubMed] [Google Scholar]
  • 29.Randox Total Antioxidant Status (TAS) manual, http://www.veritastk.co.jp/attached/3556/NX2332manual.pdf, last accessed 14.06.2014.
  • 30.Pebay-Peyroula E, Dufourc EJ, Szabo AG. Location of diphenylhexatriene and trimethylammonium-diphenyl-hexatriene in dipalmitoylphosphatidylcholine bilayers by neutron diffraction. Biophys. Chem. 1994;53:45–56. doi: 10.1016/0301-4622(94)00075-1. [DOI] [PubMed] [Google Scholar]
  • 31.Ilie M, Margina D, Katona E, Ganea C, Pencea C, Gradinaru D, Mitrea N, Balalau D. Quercetin and epigallocatechin gallate effect on the lipid order parameter of peripheral blood mononuclear cells from diabetes patients. Rom. Biotechnol. Lett. 2009;14:4804–4811. [Google Scholar]
  • 32.Lakowicz JR. Principles of fluorescence spectroscopy. 2-nd Edition. New York: Kluwer Academic/Plenum Press; 1999. pp. 298–395. [Google Scholar]
  • 33.Epps DE, Wolfe ML, Groppi V. Characterization of the steady-state and dynamic fluorescence properties of the potential-sensitive dye bis-(1,3-dibutylbarbituric acid)trimethine oxonol (DiBAC4(3)) in model systems and cells. Chem. Phys. Lipids. 1994;69:137–150. doi: 10.1016/0009-3084(94)90035-3. [DOI] [PubMed] [Google Scholar]
  • 34.Okimoto Y, Watanabe A, Niki E, Yamashita T, Noguchi N. A novel fluorescent probe diphenyl-1-pyrenylphosphine to follow lipid peroxidation in cell membranes. FEBS Lett. 2000;474:137–140. doi: 10.1016/s0014-5793(00)01587-8. [DOI] [PubMed] [Google Scholar]
  • 35.Sebeková K, Podracká L, Blazícek P, Syrová D, Heidland A, Schinzel R. Plasma levels of advanced glycation end products in children with renal disease. Pediatr. Nephrol. 2001;16:1105–1112. doi: 10.1007/s004670100038. [DOI] [PubMed] [Google Scholar]
  • 36.Margina D, Gradinaru D, Panaite C, Cimponeriu D, Vladica M, Danciulescu R, Mitrea N. The association of adipose tissue markers for redox imbalance and the cardio-vascular risk in obese patients. HealthMED. 2011;5:194–199. [Google Scholar]
  • 37.Takahashi M, Shibata M, Niki E. Estimation of lipid peroxidation of live cells using a fluorescent probe, diphenyl-1-pyrenylphosphine. Free Radic. Biol. Med. 2001;31:164–174. doi: 10.1016/s0891-5849(01)00575-5. [DOI] [PubMed] [Google Scholar]
  • 38.Valencia JV, Weldon SC, Quinn D, Kiers GH, DeGroot J, TeKoppele JM, Huges TE. Advanced glycation end product ligands for the receptor for advanced glycation end products: biochemical characterization and formation kinetics. Anal. Biochem. 2004;324:68–78. doi: 10.1016/j.ab.2003.09.013. [DOI] [PubMed] [Google Scholar]
  • 39.Yan SF, Ramasamy R, Naka Y, Schmidt AM. Glycation, inflammation, and RAGE: A scaffold for the macrovascular complications of diabetes and beyond. Circ. Res. 2003;93:1159–1169. doi: 10.1161/01.RES.0000103862.26506.3D. [DOI] [PubMed] [Google Scholar]
  • 40.Sergent O, Ekroos K, Lefeuvre-Orfila L, Rissel M, Forsberg GB, Oscarsson J, Andersson TB, Lagadic-Gossmann D. Ximelagatran increases membrane fluidity and changes membrane lipid composition in primary human hepatocytes. Toxicol. in Vitro. 2009;23:1305–1310. doi: 10.1016/j.tiv.2009.07.019. [DOI] [PubMed] [Google Scholar]
  • 41.Wu L, Ma L, Nicholson LFB, Black PN. Advanced glycation end products and its receptor (RAGE) are increased in patients with COPD. Respir. Med. 2011;105:329–336. doi: 10.1016/j.rmed.2010.11.001. [DOI] [PubMed] [Google Scholar]
  • 42.Hirose J, Yamabe S, Takada K, Okamoto N, Nagai R, Mizuta H. Immunohistochemical distribution of advanced glycation end products (AGEs) in human osteoarthritic cartilage. Acta Histochem. 2011;113:613–618. doi: 10.1016/j.acthis.2010.06.007. [DOI] [PubMed] [Google Scholar]
  • 43.Pytel E, Olszewska-Banaszczyk M, Koter-Michalak M, Broncel M. Increased oxidative stress and decreased membrane fluidity in erythrocytes of CAD patients. Biochem. Cell Biol. 2013;91:315–318. doi: 10.1139/bcb-2013-0027. [DOI] [PubMed] [Google Scholar]
  • 44.Ziobro A, Duchnowicz P, Mulik A, Koter-Michalak M, Broncel M. Oxidative damages in erythrocytes of patients with metabolic syndrome. Mol. Cell Biochem. 2013;378:267–273. doi: 10.1007/s11010-013-1617-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Sonmez M, Ince HY, Yalcin O, Ajdžanović V, Spasojević I, Meiselman HZ, Baskurt OK. The effect of alcohols on red blood cell mechanical properties and membrane fluidity depends on their molecular size. PLoS One. 2013;8:e76579. doi: 10.1371/journal.pone.0076579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Olchowik E, Lotkowski K, Mavlyanov S, Abdullajanova N, Ionov M, Bryszewska M, Zamaraeva M. Stabilization of erythrocytes against oxidative and hypotonic stress by tannins isolated from sumac leaves (Rhus typhina L.) and grape seeds (Vitis vinifera L.) Cell. Mol. Biol. Lett. 2012;17:333–348. doi: 10.2478/s11658-012-0014-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Ajdžanović V, Spasojević I, Sošić-Jurjević B, Filipović B, Trifunović S, Sekulić M, Milošević V. The negative effect of soy extract on erythrocyte membrane fluidity: an electron paramagnetic resonance study. J. Membr. Biol. 2011;239:131–135. doi: 10.1007/s00232-010-9332-8. [DOI] [PubMed] [Google Scholar]
  • 48.Ajdžanović V, Mojić M, Maksimović-Ivanić D, Bulatović M, Mijatović S, Milošević V, Spasojević I. Membrane fluidity, invasiveness and dynamic phenotype of metastatic prostate cancer cells after treatment with soy isoflavones. J. Membr. Biol. 2013;246:307–314. doi: 10.1007/s00232-013-9531-1. [DOI] [PubMed] [Google Scholar]
  • 49.Maldonado-Celis ME, Bousserouel S, Gosse F, Lobstein A, Raul F. Apple procyanidins activate apoptotic signaling pathway in human colon adenocarcinoma cells by a lipid-raft independent mechanism. Biochem. Biophys. Res. Commun. 2009;388:372–376. doi: 10.1016/j.bbrc.2009.08.016. [DOI] [PubMed] [Google Scholar]
  • 50.Annaba F, Kumar P, Dudeja AK, Saksena S, Gill RK, Alrefai WA. Green tea catechin EGCG inhibits ileal apical sodium bile acid transporter ASBT. Am. J. Physiol. Gastrointest. Liver Physiol. 2010;298:G467–G473. doi: 10.1152/ajpgi.00360.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Mylonas C, Kouretas D. Lipid peroxidation and tissue damage. In Vivo. 1999;13:295–309. [PubMed] [Google Scholar]
  • 52.Veskoukis AS, Tsatsakis AM, Kouretas D. Dietary oxidative stress and antioxidant defense with an emphasis on plant extract administration. Cell Stress Chaperones. 2012;17:11–21. doi: 10.1007/s12192-011-0293-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Shimizu M, Shirakami Y, Sakai H, Yasuda Y, Kubota M, Adachi S, Tsurumi H, Hara Y, Moriwaki H. (−)-Epigallocatechin gallate inhibits growth and activation of the VEGF/VEGFR axis in human colorectal cancer cells. Chem. Biol. Interact. 2010;185:247–252. doi: 10.1016/j.cbi.2010.03.036. [DOI] [PubMed] [Google Scholar]
  • 54.Tarahovsky YS, Kim YA, Yagolnik EA, Muzafarov EN. Flavonoid-membrane interactions: Involvement of flavonoid-metal complexes in raft signaling. Biochim. Biophys. Acta (BBA) — Biomembranes. 2014;1838:1235–1246. doi: 10.1016/j.bbamem.2014.01.021. [DOI] [PubMed] [Google Scholar]
  • 55.Scheidt HA, Pampel A, Nissler L, Gebhardt R, Huster D. Investigation of the membrane localization and distribution of flavonoids by high-resolution magic angle spinning NMR spectroscopy. Biochim. Biophys. Acta (BBA) - Biomembranes. 2004;1663:97–107. doi: 10.1016/j.bbamem.2004.02.004. [DOI] [PubMed] [Google Scholar]
  • 56.Oh HY, Leem J, Yoon SJ, Yoon S, Hong SJ. Lipid raft cholesterol and genistein inhibit the cell viability of prostate cancer cells via the partial contribution of EGFR-Akt/p70S6k pathway and down-regulation of androgen receptor. Biochem. Biophys. Res. Commun. 2010;393:319–324. doi: 10.1016/j.bbrc.2010.01.133. [DOI] [PubMed] [Google Scholar]
  • 57.Pike L. J. Rafts defined: a report on the Keystone Symposium on Lipid Rafts and Cell Function. J. Lipid Res. 2006;47:1597–1598. doi: 10.1194/jlr.E600002-JLR200. [DOI] [PubMed] [Google Scholar]
  • 58.Simons K, Vaz WL. Model systems, lipid rafts, and cell membranes. Annu. Rev. Biophys. Biomol. Struct. 2004;33:269–295. doi: 10.1146/annurev.biophys.32.110601.141803. [DOI] [PubMed] [Google Scholar]
  • 59.Spector AA, Mathur SN, Kaduce TL, Hyman BT. Lipid nutrition and metabolism of cultured mammalian cells. Prog. Lipid Res. 1981;19:155–186. doi: 10.1016/0163-7827(80)90003-x. [DOI] [PubMed] [Google Scholar]
  • 60.Spector AA, Yorek MA. Membrane lipid composition and cellular function. J. Lipid Res. 1985;26:1015–1035. [PubMed] [Google Scholar]
  • 61.Elson EL, Fried E, Dolbow JE, Genin GM. Phase separation in biological membranes: integration of theory and experiment. Annu. Rev. Biophys. 2010;39:207–226. doi: 10.1146/annurev.biophys.093008.131238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Golfetto O, Hinde E, Grattone E. Laurdan fluorescence lifetime discriminates cholesterol content from changes in fluidity in living cell membranes. Biophys. J. 2013;104:1238–1247. doi: 10.1016/j.bpj.2012.12.057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Nowotarski K, Sapoń K, Kowalska M, Janas T, Janas T. Membrane potential-dependent binding of polysialic acid to lipid monolayers and bilayers. Cell. Mol. Biol. Lett. 2013;18:579–594. doi: 10.2478/s11658-013-0108-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Naudí A, Jové M, Ayala V, Portero-Otín M, Barja G, Pamplona G. Membrane lipid unsaturation as physiological adaptation to animal longevity. Front. Physiol. 2013;4:1–13. doi: 10.3389/fphys.2013.00372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Van der Heide D, Kastelijn J, Schröder-van der Elst JP. Flavonoids and thyroid disease. Biofactors. 2003;19:113–119. doi: 10.1002/biof.5520190303. [DOI] [PubMed] [Google Scholar]
  • 66.Leclercq G, Jacquot Y. Interactions of isoflavones and other plant derived estrogens with estrogen receptors for prevention and treatment of breast cancer-considerations concerning related efficacy and safety. J. Steroid Biochem. Mol. Biol. 2014;139:237–244. doi: 10.1016/j.jsbmb.2012.12.010. [DOI] [PubMed] [Google Scholar]
  • 67.Cederroth CR, Zimmermann C, Nef S. Soy, phytoestrogens and their impact on reproductive health. Mol. Cell. Endocrinol. 2012;355:192–200. doi: 10.1016/j.mce.2011.05.049. [DOI] [PubMed] [Google Scholar]
  • 68.Ohlsson A, Ullerås E, Cedergreen N, Oskarsson A. Mixture effects of dietary flavonoids on steroid hormone synthesis in the human adrenocortical H295R cell line. Food Chem. Toxicol. 2010;48:3194–3200. doi: 10.1016/j.fct.2010.08.021. [DOI] [PubMed] [Google Scholar]

Articles from Cellular & Molecular Biology Letters are provided here courtesy of BMC

RESOURCES