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Hormone Molecular Biology and Clinical Investigation

Editor-in-Chief: Chetrite, Gérard S.

Editorial Board: Alexis, Michael N. / Baniahmad, Aria / Beato, Miguel / Bouillon, Roger / Brodie, Angela / Carruba, Giuseppe / Chen, Shiuan / Cidlowski, John A. / Clarke, Robert / Coelingh Bennink, Herjan J.T. / Darbre, Philippa D. / Drouin, Jacques / Dufau, Maria L. / Edwards, Dean P. / Falany, Charles N. / Fernandez-Perez, Leandro / Ferroud, Clotilde / Feve, Bruno / Flores-Morales, Amilcar / Foster, Michelle T. / Garcia-Segura, Luis M. / Gastaldelli, Amalia / Gee, Julia M.W. / Genazzani, Andrea R. / Greene, Geoffrey L. / Groner, Bernd / Hampl, Richard / Hilakivi-Clarke, Leena / Hubalek, Michael / Iwase, Hirotaka / Jordan, V. Craig / Klocker, Helmut / Kloet, Ronald / Labrie, Fernand / Mendelson, Carole R. / Mück, Alfred O. / Nicola, Alejandro F. / O'Malley, Bert W. / Raynaud, Jean-Pierre / Ruan, Xiangyan / Russo, Jose / Saad, Farid / Sanchez, Edwin R. / Schally, Andrew V. / Schillaci, Roxana / Schindler, Adolf E. / Söderqvist, Gunnar / Speirs, Valerie / Stanczyk, Frank Z. / Starka, Luboslav / Sutter, Thomas R. / Tresguerres, Jesús A. / Wahli, Walter / Wildt, Ludwig / Yang, Kaiping / Yu, Qi

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Volume 16, Issue 3


Ovariectomy lowers urine levels of unconjugated (+)-catechin, (–)-epicatechin, and their methylated metabolites in rats fed grape seed extract

John K. Cutts
  • Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA
  • Other articles by this author:
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/ Thomas R. Peavy
  • Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA
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/ Doyle R. Moore
  • Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA
  • Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham, Birmingham, AL, USA
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/ Jeevan Prasain
  • Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA
  • Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham, Birmingham, AL, USA
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/ Stephen Barnes
  • Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA
  • Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham, Birmingham, AL, USA
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/ Helen Kim
  • Corresponding author
  • Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA
  • Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham, Birmingham, AL, USA
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  • Other articles by this author:
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Published Online: 2013-11-26 | DOI: https://doi.org/10.1515/hmbci-2013-0044


Steroid hormones modulate expression of enzymes that metabolize xenobiotics, including dietary supplements. Half of the human population undergoes menopause, yet the effect of this age-related loss of ovarian steroid hormones on the metabolism of dietary supplements has yet to be determined. Grape seed extract (GSE) is a dietary supplement comprised of monomeric and oligomeric catechins and has health benefits in models of age-related diseases. We hypothesized that surgically-induced loss of ovarian hormones would increase methylation, glucuronidation, and/or sulfation of the grape seed polyphenols (+)-catechin and (–)-epicatechin. Fourteen-week-old spontaneously hypertensive rats (SHRs) were ovariectomized (OVX) or sham-OVX. At 17 weeks of age, SHRs were gavaged with vehicle (water) or GSE (300 mg/kg body weight) once daily for 6 days. Urinary excretion of (+)-catechin, (–)-epicatechin, and their metabolites was analyzed by liquid chromatography-mass spectrometry. Although total urinary output of (+)-catechin, (–)-epicatechin, and their methylated metabolites was unaffected by OVX, the amounts of (+)-catechin, (–)-epicatechin and their methylated metabolites that were not conjugated with glucuronic acid or sulfate were lowered by OVX. Specifically, urine from OVX SHRs administered GSE contained 30% higher proportions (91.8% vs. 62.3%) of glucuronidated (+)-catechin and (–)-epicatechin and glucuronidated methyl (+)-catechin and methyl (–)-epicatechin than urine from sham-OVX SHRs. However, there were no differences in urinary levels of total methylated or sulfated catechins in OVX SHRs. This is the first quantitative characterization of metabolites of grape seed polyphenols in a model of menopause; it indicates that ovariectomy causes either an increase in expression and/or activity of select uridine 5′-diphospho-glucuronosyltransferase(s).

Keywords: catechin; glucuronides; grape seed extract; menopause; metabolism


  • 1.

    Tsuchiya Y, Nakajima M, Kyo S, Kanaya T, Inoue M, Yokoi T. Human CYP1B1 is regulated by estradiol via estrogen receptor. Cancer Res 2004;64:3119–25.PubMedCrossrefGoogle Scholar

  • 2.

    Ishii T, Nishimura K, Nishimura M. Administration of xenobiotics with anti-estrogenic effects results in mRNA induction of adult male-specific cytochrome P450 isozymes in the livers of adult female rats. J Pharmacol Sci 2006;101:220–55.Google Scholar

  • 3.

    Scott LM, Durant P, Leone-Kabler S, Wood CE, Register TC, Townsend A, Cline JM. Effects of prior oral contraceptive use and soy isoflavonoids on estrogen-metabolizing cytochrome P450 enzymes. J Steroid Biochem Mol Biol 2008;112:179–85.Web of ScienceGoogle Scholar

  • 4.

    Mwinyi J, Cavaco I, Pedersen RS, Persson A, Burkhardt S, Mkrtchian S, Ingelman-Sundberg M. Regulation of CYP2C19 expression by estrogen receptor α: implications for estrogen-dependent inhibition of drug metabolism. Mol Pharm 2010;78:886–94.Google Scholar

  • 5.

    Inoue K, Creveling CR. Induction of catechol-O-methyltransferase in the luminal epithelium of rat uterus by progesterone. J Histochem Cytochem 1991;39:823–28.CrossrefPubMedGoogle Scholar

  • 6.

    Jeong H, Choi S, Song JW, Chen H, Fischer JH. Regulation of UDP-glucuronosyltransferase (UGT) 1A1 by progesterone and its impact on labetalol elimination. Xenobiotica 2008;38:62–75.Web of ScienceCrossrefPubMedGoogle Scholar

  • 7.

    Jiang H, Xie T, Ramsden DB, Ho SL. Human catechol-O-methyltransferase down-regulation by estradiol. Neuropharm 2003;45:1011–8.CrossrefGoogle Scholar

  • 8.

    Schendzielorz N, Rysa A, Reenila I, Raasmaja A, Mannisto PT. Complex estrogenic regulation of catechol-O-methyltransferase (COMT) in rats. J Physiol Pharmacol 2011;62:483–90.PubMedGoogle Scholar

  • 9.

    Strasser SI, Smid SA, Mashford ML, Desmond PV. Sex hormones differentially regulate isoforms of UDP-glucuronosyltransferase. Pharm Res 1997;14:1115–21.CrossrefPubMedGoogle Scholar

  • 10.

    Guillemette C, Hum DW, Belanger A. Regulation of steroid glucuronosyltransferase activities and transcripts by androgen in the human prostatic cancer LNCaP cell line. Endocrinology 1996;137:2872–9.PubMedGoogle Scholar

  • 11.

    Akhtar S, Meeran SM, Katiyar N, Katiyar SK. Grape seed proanthocyanidins inhibit the growth of human non-small cell lung cancer xenografts by targeting insulin-like growth factor binding protein-3, tumor cell proliferation, and angiogenic factors. Clin Cancer Res 2009;15:821–31.Web of SciencePubMedGoogle Scholar

  • 12.

    Meeran SM, Vaid M, Punathil T, Katiyar SK. Dietary grape seed proanthocyanidins 12-O-tetradecanoyl phorbol-13-acetate-caused skin tumor promotion in 7,12-dimethylbenz[a]anthracene-initiated mouse skin, which is associated with the inhibition of inflammatory responses. Carcinogenesis 2009;30:520–8.Web of ScienceGoogle Scholar

  • 13.

    Velmurugan B, Singh RP, Agarwal R, Agarwal C. Dietary-feeding of grape seed extract prevents azoxymethane-induced colonic aberrant crypt foci formation in fischer 344 rats. Mol Carcinogen 2010;49:641–52.Web of ScienceGoogle Scholar

  • 14.

    Velmurugan B, Singh RP, Daul N, Agarwal R, Agarwal C. Dietary feeding of grape seed extract prevents intestinal tumorigenesis in APCmin/+ mice. Neoplasia 2010;12:95–102.Web of ScienceGoogle Scholar

  • 15.

    Gao N, Budhraja A, Cheng S, Yao H, Zhang Z, Shi X. Induction of apoptosis in human leukemia cells by grape seed extract occurs via activation of c-Jun NH2-terminal kinase. Clin Cancer Res 2009;15:140–9.CrossrefPubMedGoogle Scholar

  • 16.

    Pataki T, Bak I, Kovacs P, Bagchi D, Das DK, Tosaki A. Grape seed proanthocyanidins improved cardiac recovery during reperfusion after ischemia in isolated rat hearts. Am J Clin Nutr 2002;75:894–9.PubMedGoogle Scholar

  • 17.

    Peng N, Clark JT, Prasain J, Kim H, White CR, Wyss JM. Antihypertensive and cognitive effects of grape polyphenols in estrogen-depleted, female, spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 2005;289:R771–5.Google Scholar

  • 18.

    Wang J, Ho L, Zhao W, Ono K, Rosensweig C, Chen L, Humala N, Teplow DB, Pasinetti GM. Grape-derived polyphenolics prevent Aβ oligomerization and attenuate cognitive deterioration in a mouse model of Alzheimer’s disease. J Neurosci 2008;28:6388–92.CrossrefWeb of ScienceGoogle Scholar

  • 19.

    Wang Y-J, Thomas P, Zhong J-H, Bi F-F, Kosaraju S, Pollard A, Fenech M, Zhou X-F. Consumption of grape seed extract prevents amyloid-β deposition and attenuates inflammation in brain of an Alzheimer’s disease mouse. Neurotox Res 2009;15:3–14.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 20.

    Yamakoshi J, Saito M, Kataoka S, Kikuchi M. Safety evaluation of proanthocyanidin-rich extract from grape seeds. Food Chem Toxicol 2002;40:599–607.CrossrefPubMedGoogle Scholar

  • 21.

    Wang J, Ferruzzi MG, Ho L, Blount J, Janle EM, Gong B, Pan Y, Gowda GA, Raftery D, Arrieta-Cruz I, Sharma V, Cooper B, Lobo J, Simon JE, Zhang C, Cheng A, Qian X, Ono K, Teplow DB, Pavlides C, Dixon RA, Pasinetti GM. Brain-targeted proanthocyanidin metabolites for Alzheimer’s disease treatment. J Neuroscience 2012;32:5144–50.CrossrefGoogle Scholar

  • 22.

    Schroeter H, Heiss C, Balzer J, Kleinbongard P, Keen CL, Hollenberg NK, Sies H, Kwik-Uribe C, Schmitz HH, Kelm M. (-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. PNAS 2006;103:1024–9.CrossrefGoogle Scholar

  • 23.

    Donovan JL, Crespy V, Manach C, Morand C, Besson C, Scalbert A, Remesy C. Catechin is metabolized by both the small intestine and liver of rats. J Nutr 2001;131:1753–7.PubMedGoogle Scholar

  • 24.

    Tsang C, Auger C, Mullen W, Bornet A, Rouanet J-M, Crozier A, Teissedre P-L. The absorption, metabolism and excretion of flavan-3-ols and procyanidins following the ingestion of a grape seed extract by rats. Br J Nutr 2005;94:170–81.PubMedGoogle Scholar

  • 25.

    Ottaviani JI, Momma TY, Kuhnle GK, Keen CL, Schroeter H. Structurally related (-)-epicatechin metabolites in humans: assessment using de novo chemically synthesized authentic standards. Free Radical Biol Med 2012;52:1403–12.Web of ScienceGoogle Scholar

  • 26.

    Prasain JK, Peng N, Dai Y, Moore R, Arabshahi A, Wilson L, Barnes S, Wyss JM, Kim H, Watts RL. Liquid chromatography tandem mass spectrometry identification of proanthocyanidins in rat plasma after oral administration of grape seed extract. Phytomedicine 2009;16:233–43.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 27.

    Deshane J, Chaves L, Sarikonda KV, Isbell S, Wilson L, Kirk M, Grubbs C, Barnes S, Meleth S, Kim H. Proteomics analysis of rat brain protein modulations by grape seed extract. J Agric Food Chem 2004;52:7872–83.PubMedCrossrefGoogle Scholar

  • 28.

    Takahashi N, Boysen G, Li F, Li Y, Swenberg JA. Tandem mass spectrometry measurements of creatinine in mouse plasma and urine for determining glomerular filtration rate. Kidney Int 2007;71:266–71.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 29.

    Li H-J, Deinzer ML. Tandem mass spectrometry for sequencing proanthocyanidins. Anal Chem 2007;79:1739–48.CrossrefWeb of SciencePubMedGoogle Scholar

  • 30.

    Cren-Olive C, Deprez S, Lebrun S, Coddeville B, Rolando C. Characterization of methylation site of monomethylflavan-3-ols by liquid chromatography/electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spec 2000;14: 2312–9.Google Scholar

  • 31.

    Marcondes FK, Miguel KJ, Melo LL, Spadari-Bratfisch RC. Estrous cycle influences the response of female rats in the elevated plus-maze test. Physiol Behav 2001;74:435–40.CrossrefPubMedGoogle Scholar

  • 32.

    Lapointe J, Roy M, St-Pierre I, Kimmins S, Gauvreau D, MacLaren LA, Bilodeau J-F. Hormonal and spatial regulation of nitric oxide synthases (NOS) (neuronal NOS, inducible NOS, and endothelial NOS) in the oviducts. Endocrinology 2006;147:5600–10.PubMedCrossrefGoogle Scholar

  • 33.

    Znamensky V, Akama KT, McEwen BS, Milner TA. Estrogen levels regulate the subcellular distribution of phosphorylated Akt in hippocampal CA1 dendrites. J Neurosci 2003;23:2340–7.Google Scholar

  • 34.

    Kulkarni KH, Yang Z, Niu T, Hu M. Effects of estrogen and estrus cycle on pharmacokinetics, absorption, and disposition of genistein in female Sprague-Dawley rats. J Agric Food Chem 2012;60:7949–56.CrossrefWeb of SciencePubMedGoogle Scholar

  • 35.

    Saha S, Hollands W, Needs PW, Ostertag LM, de Roos B, Duthie GG, Kroon PA. Human O-sulfated metabolites of (-)-epicatechin and methyl-(-)-epicatechin are poor substrates for commercial aryl-sulfatases: implications for studies concerned with quantifying epicatechin bioavailability. Pharmacol Res 2012;65:592–602.CrossrefWeb of ScienceGoogle Scholar

  • 36.

    Fortepiani LA, Zhang H, Racusen L, Roberts II LJ, Reckelhoff JF. Characterization of an animal model of postmenopausal hypertension in spontaneously hypertensive rats. Hypertension 2003;41:640–5.CrossrefGoogle Scholar

  • 37.

    Lopez-Sepulveda R, Jimenez R, Romero M, Zarzuelo MJ, Sanchez M, Gomez-Guzman M, Vargas F, O’Valle F, Zarzuelo A, Perez-Vizcaino F, Duarte J. Wine polyphenols improve endothelial function in large vessels of female spontaneously hypertensive rats. Hypertension 2008;51:1088–95.CrossrefGoogle Scholar

  • 38.

    Oropeza-Hernandez LF, Sierra-Santoyo A, Cebrian ME, Manno M, Albores A. Ovariectomy modulates the response of some cytochrome P450 isozymes to lindane in the rat. Toxicol Lett 2001;124:91–9.Google Scholar

  • 39.

    Liao D-Z, Porsch-Hallstrom I, Gustafsson J-A, Blanck A. Persistent sex differences in growth control of early rat liver lesions are programmed during promotion in the resistant hepatocyte model. Hepatology 1996;23:835–9.PubMedCrossrefGoogle Scholar

  • 40.

    Blount JW, Ferruzzi M, Raftery D, Pasinetti GM, Dixon RA. Enzymatic synthesis of substituted epicatechins for bioactivity studies in neurological disorders. Biochem Biophys Res Comm 2012;417:457–61.Web of ScienceGoogle Scholar

About the article

Corresponding author: Helen Kim, University of Alabama at Birmingham, Department of Pharmacology and Toxicology, McCallum Building, Room 460, 1918 University Blvd., Birmingham, AL 35294, USA, Phone: (205) 934-3880, Fax: (205) 934-6944, E-mail: ; and Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham, Birmingham, AL, USA

Received: 2013-08-16

Accepted: 2013-10-29

Published Online: 2013-11-26

Published in Print: 2013-12-01

Citation Information: Hormone Molecular Biology and Clinical Investigation, Volume 16, Issue 3, Pages 129–138, ISSN (Online) 1868-1891, ISSN (Print) 1868-1883, DOI: https://doi.org/10.1515/hmbci-2013-0044.

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