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Comparison of enzymically glucuronidated flavonoids with flavonoid aglycones in an in vitro cellular model of oxidative stress protection

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An Erratum to this article was published on 02 July 2008

Abstract

This study modeled, in vitro, the potential effect of conjugative (phase II) metabolism on the cytoprotective capacity of fruit flavonoids against oxidative stress. Flavonoid aglycones were compared with their corresponding isomeric mixtures of glucuronides for their ability to enhance the survival of cultured human Jurkat T and neuroblastoma cells stressed with hydrogen peroxide. Various polyphenolic compounds were tested as substrates in vitro for an ovine liver glucuronyl transferase preparation. Flavonoids and their glycoside derivatives were found to be good substrates, whereas phenolic acids were either poor or nonsubstrates. Five common flavonoids were glucuronidated to prepare mixtures for bioassay testing. Glucuronidation generally weakened the cytoprotective capacities of flavonoids (in the presence of H2O2), but some compounds were weakened much more than others. The concentration that halved cell death was well below 0.5 μM for most flavonoids tested, but glucuronidation increased median effective concentration values to a range of 1–16 μM. This compares with the generally accepted physiological range (0.1–10 μM) for circulating dietary polyphenolics detected in the body. Therefore, some flavonoids may retain a reduced cytoprotective capacity in vitro, after glucuronidation, whereas others may be effectively inactivated.

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References

  • Antunes, F. and Cadenas, E. Cellular Titration Of Apoptosis With Steady State Concentrations Of H2O2: Submicromolar Levels Of H2O2 Induce Apoptosis Through Fenton Chemistry Independent Of The Cellular Thiol State. Free Radic Biol Med 30(9):1008–1018; 2001.

    Article  PubMed  CAS  Google Scholar 

  • Barbouti, A.; Doulias, P.-T.; Nousis, L.; Tenopoulou, M.; Galaris, D. DNA Damage And Apoptosis In Hydrogen Peroxide-Exposed Jurkat Cells: Bolus Addition Versus Continuous Generation Of H2O2. Free Radic Biol Med 33(5):691–702; 2002.

    Article  PubMed  CAS  Google Scholar 

  • Boersma, M. G.; van der Woude, H.; Bogaards, J.; Boeren, S.; Vervoort, J.; Cnubben, N. H. P.; van Iersel, M. L. P. S.; van Bladeren, P. J.; Rietjens, I. M. C. M. Regioselectivity of Phase II Metabolism of Luteolin and Quercetin by UDP-Glucuronosyl Transferases. Chem Res Toxicol 15(5):662–670; 2002.

    Article  PubMed  CAS  Google Scholar 

  • Charlotte, M.; Myhrstad, W.; Carlsen, H.; Dahl, I.; Ebihara, K.; Glemmestad, L.; Haffner, K.; Moskaug, J. O.; Blomhoff, R. Bilberry extracts induce gene expression through the electrophile response element. Nutr Cancer 54(1):94–101; 2006.

    Article  Google Scholar 

  • Chen, D.; Daniel, K. G.; Chen, M. S.; Kuhn, D. J.; Landis-Piwowar, K. R.; Dou, Q. P. Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells. Biochem Pharmacol 69:1421–1432; 2005.

    Article  PubMed  CAS  Google Scholar 

  • Chen, K. H.; Weng, M. S.; Lin, J. K. Tangeretin suppresses IL-1 beta-induced cyclooxygenase (COX)-2 expression through inhibition of p38 MAPK, JNK, and AKT activation in human lung carcinoma cells. Biochem Pharmacol 73(2):215–227; 2007.

    Article  PubMed  CAS  Google Scholar 

  • Clifford, M. N. Diet-derived Phenols in plasma and tissues and their implications for health. Planta Med 70(12):1103–1114; 2004.

    Article  PubMed  CAS  Google Scholar 

  • Comalada, M.; Camuesco, D.; Sierra, S.; Ballester, I.; Xaus, J.; Galvez, J.; Zarzuelo, A. In vivo quercitrin anti-inflammatory effect involves release of quercetin, which inhibits inflammation through down-regulation of the NF-kappa B pathway. Eur J Immunol 35(2):584–592; 2005.

    Article  PubMed  CAS  Google Scholar 

  • Day, A. J.; Mellon, F.; Barron, D.; Sarrazin, G.; Morgan, M. R. A.; Williamson, G. Human metabolism of dietary flavonoids: Identification of plasma metabolites of quercetin. Free Radical Res 35(6):941–952; 2001.

    Article  CAS  Google Scholar 

  • Goldberg, D. A.; Yan, J.; Soleas, G. J. Absorption of three wine-related polyphenols in three different matrices by healthy subjects. Clin Biochem 36(1):79–87; 2003.

    Article  PubMed  CAS  Google Scholar 

  • Heiss, C.; Finis, D.; Kleinbongard, P.; Hoffmann, A.; Rassaf, T.; Kelm, M.; Sies, H. Sustained Increase in Flow-Mediated Dilation After Daily Intake of High-Flavanol Cocoa Drink Over 1 Week. J Cardiovas Pharmacol Ther 49(2):74–80; 2007.

    Article  CAS  Google Scholar 

  • Hubl, U. and Stevenson, D. E. In vitro enzymic synthesis of mammalian liver xenobiotic metabolites catalysed by ovine liver microsomal cytochrome P-450. Enzyme Microb Technol 29(4–5):306; 2001.

    Article  CAS  Google Scholar 

  • Janisch, K. M.; Williamson, G.; Needs, P.; Plumb, G. W. Properties of quercetin conjugates: Modulation of LDL oxidation and binding to human serum albumin. Free Radical Res 38(8):877–884; 2004.

    Article  CAS  Google Scholar 

  • Kim, D. K.; Eun Sook Cho, E. S.; Um, H.-D. Caspase-Dependent and -Independent Events in Apoptosis Induced by Hydrogen Peroxide. Exp Cell Res 257:82–88; 2000.

    Article  PubMed  CAS  Google Scholar 

  • Kroon, P. A.; Clifford, M. N.; Crozier, A.; Day, A. J.; Donovan, J. L.; Manach, C.; Williamson, G. How should we assess the effects of exposure to dietary polyphenols in vitro? Am J Clin Nutr 80(1):15–21; 2004.

    PubMed  CAS  Google Scholar 

  • Kuhnle, G.; Spencer, J. P. E.; Schroeter, H.; Shenoy, B.; Debnam, E. S.; Srai, S. K. S.; Rice-Evans, C.; Hahn, U. Epicatechin and catechin are O-methylated and glucuronidated in the small intestine. Biochem Biophys Res Commun 277(2):507–512; 2000.

    Article  PubMed  CAS  Google Scholar 

  • Lee-Hilz, Y. Y.; Boerboom, A. M. J. F.; Westphal, A. H.; van Berkel, W. J. H.; Aarts, J. M. M. J. G.; Rietjens, I. M. C. M. Pro-oxidant activity of flavonoids induces EpRE-mediated gene expression. Chem Res Toxicol 19(11):1499–1505; 2006.

    Article  PubMed  CAS  Google Scholar 

  • Lewinsky, R. H.; Smith, P. A.; Mackenzie, P. I. Glucuronidation of bioflavonoids by human UGT1A10: structure–function relationships. Xenobiotica 35(2):117; 2005.

    Article  PubMed  CAS  Google Scholar 

  • Lu, H.; Meng, X.; Li, C.; Hong, J.; Yang, C. S.; Sang, S.; Bai, N.; Ho, C.-T.; Sheng, S.; Patten, C.; Winnik, B. Glucuronides of tea catechins: Enzymology of biosynthesis and biological activities. Drug Metab Dispos 31(4):452–461; 2003.

    Article  PubMed  CAS  Google Scholar 

  • Manach, C. and Donovan, J. L. Pharmacokinetics and metabolism of dietary flavonoids in humans. Free Radical Res 38(8):771–785; 2004.

    Article  CAS  Google Scholar 

  • Mink, P. J.; Scrafford, C. G.; Barraj, L. M.; Harnack, L.; Hong, C.-P.; Nettleton, J. A.; Jacobs, D. R., Jr. Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. Am J Clin Nutr 85(3):895–909; 2007.

    PubMed  CAS  Google Scholar 

  • Naissides, M.; Pal, S.; Mamo, J. C. L.; James, A. P.; Dhaliwal, S. The effect of chronic consumption of red wine polyphenols on vascular function in postmenopausal women. Eur J Clin Nutr 60(6):740–745; 2006.

    Article  PubMed  CAS  Google Scholar 

  • Nemeth, K.; Plumb, G. W.; Berrin, J.-G.; Juge, N.; Jacob, R.; Naim, H. Y.; Williamson, G.; Swallow, D. M.; Kroon, P. A. Deglycosylation by small intestinal epithelial cell beta-glucosidases is a critical step in the absorption and metabolism of dietary flavonoid glycosides in humans. Eur J Nutr 42(1):29–42; 2003.

    Article  PubMed  CAS  Google Scholar 

  • Niering, P.; Michels, G.; Watjen, W.; Ohler, S.; Steffan, B.; Chovolou, Y.; Kampkotter, A.; Proksch, P.; Kahl, R. Protective and detrimental effects of kaempferol in rat H4IIE cells: implication of oxidative stress and apoptosis. Toxicol Appl Pharmacol 209(2):114–22; 2005.

    Article  PubMed  CAS  Google Scholar 

  • Ou, H. C.; Chou, F. P.; Sheen, H. M.; Lin, T. M.; Yang, C. H.; Huey-Herng Sheu, W. Resveratrol, a polyphenolic compound in red wine, protects against oxidized LDL-induced cytotoxicity in endothelial cells. Clin Chim Acta 364(1–2):196–204; 2006.

    Article  PubMed  CAS  Google Scholar 

  • Plochmann, K.; Korte, G.; Koutsilieri, E.; Richling, E.; Riederer, P.; Rethwilm, A.; Schreier, P.; Scheller, C. Structure–activity relationships of flavonoid-induced cytotoxicity on human leukemia cells. Arch Biochem Biophys 460(1):1–9; 2007.

    Article  PubMed  CAS  Google Scholar 

  • Shirai, M.; Yamanishi, R.; Moon, J. H.; Murota, K.; Terao, J. Effect of quercetin and its conjugated metabolite on the hydrogen peroxide-induced intracellular production of reactive oxygen species in mouse fibroblasts. Biosci Biotechnol Biochem 66(5):1015–1021; 2002.

    Article  PubMed  CAS  Google Scholar 

  • Spencer, J. P. E.; Abd El Mohsen, M. M.; Rice-Evans, C. Cellular uptake and metabolism of flavonoids and their metabolites: implications for their bioactivity. Archives of Biochemistry and Biophysics 423(1):148–161; 2004.

    Article  PubMed  CAS  Google Scholar 

  • Spencer, J. P. E.; Schroeter, H.; Crossthwaithe, A. J.; Kuhnle, G.; Williams, R. J.; Rice-Evans, C. Contrasting influences of glucuronidation and O-methylation of epicatechin on hydrogen peroxide-induced cell death in neurons and fibroblasts. Free Radic Biol Med 31(9):1139–1146; 2001.

    Article  PubMed  CAS  Google Scholar 

  • Stevenson, D. E. Optimisation of UDP-glucuronyl transferase-catalysed synthesis of testosterone-beta-D-glucuronide by inhibition of contaminating beta-glucuronidase. Biotechnol. Tech. 13(1):17–21; 1999.

    Article  CAS  Google Scholar 

  • Stevenson, D. E. and Hubl, U. Optimization of beta-D-glucuronide synthesis using UDP-glucuronyl transferase. Enzyme Microb Technol 24(7):388–396; 1999.

    Article  CAS  Google Scholar 

  • Stevenson, D. E.; Wibisono, R.; Jensen, D. J.; Stanley, R. A.; Cooney, J. M. Direct acylation of flavonoid glycosides with phenolic acids catalysed by Candida antarctica lipase B (Novozym 435(R)). Enzyme Microb Technol 39(6):1236–1241; 2006.

    Article  CAS  Google Scholar 

  • Tavani, A.; Spertini, L.; Bosetti, C.; Parpinel, M.; Gnagnarella, P.; Bravi, F.; Peterson, J.; Dwyer, J.; Lagiou, P.; Negri, E.; La Vecchia, C. Intake of specific flavonoids and risk of acute myocardial infarction in Italy. Public Health Nutr 9(3):369–374; 2006.

    Article  PubMed  Google Scholar 

  • Walle, T. Absorption and metabolism of flavonoids. Free Radic Biol Med 36(7):829–837; 2004.

    Article  PubMed  CAS  Google Scholar 

  • Williams, R. J.; Spencer, J. P. E.; Rice-Evans, C. Flavonoids: Antioxidants or signalling molecules? Free Radical Biology and Medicine 36(7):838–849; 2004.

    Article  PubMed  CAS  Google Scholar 

  • Williamson, G.; Barron, D.; Shimoi, K.; Terao, J. In vitro biological properties of flavonoid conjugates found in vivo. Free Radical Res 39(5):457–469; 2005.

    Article  CAS  Google Scholar 

  • Wittig, J.; Herderich, M.; Graefe, E. U.; Veit, M. Identification of quercetin glucuronides in human plasma by high-performance liquid chromatography–tandem mass spectrometry. J Chromatogr B 753(2):237–243; 2001.

    Article  CAS  Google Scholar 

  • Yoshizumi, M.; Tsuchiya, K.; Suzaki, Y.; Kirima, K.; Kyaw, M.; Moon, J.-H.; Terao, J.; Tamaki, T. Quercetin glucuronide prevents VSMC hypertrophy by angiotensin II via the inhibition of JNK and AP-1 signaling pathway. Biochem Biophys Res Commun 293(5):1458–1465; 2002.

    Article  PubMed  CAS  Google Scholar 

  • Zhang, J.; Stanley, R. A.; Adaim, A.; Melton, D. L.; Skinner, A. M. Free radical scavenging and cytoprotective activities of phenolic antioxidants. Mol Nutr Food Res 50(11):996–1005; 2006.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by the New Zealand Foundation for Research, Science and Technology, under project NSOF-2004-50. We thank Drs. William Laing Harry Martin and Roger Hurst for helpful discussions and careful review of the manuscript.

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Authors and Affiliations

  1. The Horticulture and Food Research Institute of New Zealand, Private Bag 3123, Waikato Mail Centre, Hamilton, 3240, New Zealand

    David E. Stevenson, Janine M. Cooney & Dwayne J. Jensen

  2. The Horticulture and Food Research Institute of New Zealand, Private Bag 92-169, Mt Albert, Auckland, New Zealand

    Reginald Wibisono, Aselle Adaim, Margot A. Skinner & Jingli Zhang

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  1. David E. Stevenson
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  2. Janine M. Cooney
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Correspondence to David E. Stevenson.

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Editor: J. Denry Sato

An erratum to this article can be found at http://dx.doi.org/10.1007/s11626-008-9119-8

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Stevenson, D.E., Cooney, J.M., Jensen, D.J. et al. Comparison of enzymically glucuronidated flavonoids with flavonoid aglycones in an in vitro cellular model of oxidative stress protection. In Vitro Cell.Dev.Biol.-Animal 44, 73–80 (2008). https://doi.org/10.1007/s11626-007-9072-y

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