Skip to main content
SpringerLink
Log in

Flavonoids inhibit the formation of the cross-linking AGE pentosidine in collagen incubated with glucose, according to their structure

  • ORIGINAL CONTRIBUTION
  • Published:
European Journal of Nutrition Aims and scope Submit manuscript

Summary

Background

Glycoxidation of collagens contributes to development of vascular complications in diabetes.

Aim of the study

Since flavonoids are potent antioxidants present in vegetal foods, it was interesting to examine their effect on the formation of a cross-linking advanced glycation endproduct, pentosidine, in collagens.

Methods

Collagen was incubated with glucose (250 mM), in the presence of different flavonoids. Pentosidine was measured by HPLC, hydroxyproline colorimetrically.

Results

Monomeric flavonoids (25 and 250 µM) markedly reduced pentosidine/hydroxyproline values in a concentration- and structure-dependent manner. In decreasing order of their specific inhibitory activity, they rank as follows: myricetin ≥ quercetin > rutin > (+)catechin > kaempferol. Thus 3′-OH or 4-oxo + Delta2–3 increase the inhibitory activity; conjugation by Rha-Glc on 3-OH decreases it. Procyanidin oligomers from grape seed were more active than pine bark procyanidin oligomers: this may be related to the galloyl residues present in grape seed oligomers only. Procyanidin oligomers are known to be cleaved into monomers in the gastric milieu and monomeric flavonoids to be absorbed and recovered at micromolar concentrations (with a long plasmatic half-life) in extracellular fluids, in contact with collagens.

Conclusion

Flavonoids are very potent inhibitors of pentosidine formation in collagens. They are active at micromolar concentrations; these might be achieved in plasma of diabetic patients after oral intake of natural flavonoids.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Aherne SA, O’Brien NM (2002) Dietary flavonols: chemistry, food content, and metabolism. Nutrition 18:75–81

    Article  CAS  Google Scholar 

  2. Balant L, Burki B, Wermeille M, Golden G (1979) Comparison of some pharmacokinetic parameters of (+)-cyanidanol-3 obtained with specific and non-specific analytical methods. Arzneimitteforschung 29:1758–1762

    CAS  Google Scholar 

  3. Carando S, Teissedre P-L, Pascual-Martinez L, Cabanis J-C (1999) Levels of flavan-3-ols in french wines. J Agric Food Chem 47:4161–4166

    Article  CAS  Google Scholar 

  4. Cervantes-Laurean D, Schramm DD, Jacobson EL, Halaweish I, Bruckner GG, Boissonneault GA (2006) Inhibition of advanced glycation end product formation on collagen by rutin and its metabolites. J Nutr Biochem 17:531–540

    Article  CAS  Google Scholar 

  5. De Groot H, Rauen U (1998) Tissue injury by reactive oxygen species and the protective effects of flavonoids. Fundam Clin Pharmacol 12:249–255

    Article  Google Scholar 

  6. De Pascual-Teresa S, Santos-Buelga C, Rivas-Gonzalo JC (2000) Quantitative analysis of flavan-3-ols in spanish foodstuffs and beverages. J Agric Food Chem 48:5331–5337

    Article  CAS  Google Scholar 

  7. De Vries JH, Hollman PC, van Amersfoort I, Olthof MR, Katan MB (2001) Red wine is a poor source of bioavailable flavonols in men. J Nutr 131:745–748

    Google Scholar 

  8. Elgawish A, Glomb M, Friedlander MA, Monnier VM (1996) Involvement of hydrogen peroxide in collagen crosslinking by high glucose in vitro and in vivo. J Biol Chem 271:12964–12971

    Article  CAS  Google Scholar 

  9. Fuleki T, Ricardo-Da-Silva JM (2003) Effects of cultivar and processing method on the contents of catechins and procyanidins in grape juice. J Agric Food Chem 51:640–646

    Article  CAS  Google Scholar 

  10. Graefe EU, Wittig J, Mueller S, Tiethling AK, Uehleke B, Drewelow B, Pforte B, Jacobasch G, Derendorf H, Veit M (2001) Pharmacokinetics and bioavailability of quercetin glycosides in humans. J Clin Pharmacol 41:492–499

    Article  CAS  Google Scholar 

  11. Gu L, Kelm M, Hammerstone JF, Beecher G, Holden J, Haytowitz D, Prior RL (2003) Screening of foods containing proanthocyanidins and their structural characterization using LC-MS/MS and thiolytic degradation. J Agric Food Chem 51:7513–7521

    Article  CAS  Google Scholar 

  12. Hakkinen SH, Karenlampi SO, Heinonen M, Mykkanen HM, Torronen AR (1999) Content of the flavanols quercetin, myricetin, and kaempferol in 25 edibles berries. J Agric Food Chem 47:2274–2279

    Article  CAS  Google Scholar 

  13. Hammerstone JF, Lazarus SA, Schmitz HH (2000) Procyanidin content and variation in some commonly consumed foods. J Nutr 130(Suppl):2086S–2092S

    CAS  Google Scholar 

  14. Hertog MGL, Hollman PCH, Katan MB (1992) Content of potentially anticarcinogenic flavonoids of 28 vegetables and 9 fruits commonly consumed in The Netherlands. J Agric Food Chem 40:2379–2383

    Article  CAS  Google Scholar 

  15. Hertog MGL, Hollman PCH, van de Putte B (1993) Content of potentially anti-carcinogenic flavonoids of tea infusions, wines, and fruit juices. J Agric Food Chem 41:1242–1246

    Article  CAS  Google Scholar 

  16. Holt RR, Lazarus SA, Cameron Sullards M, Yan Zhu Q, Schramm DD, Hammerstone JF, Fraga CG, Schmitz HH, Keen CL (2002) Procyanidin dimer B2 [epicatechin-(4b–8)-epicatechin] in human plasma after the consuption of a flavanol-rich cocoa. Am J Clin Nutr 76:798–804

    CAS  Google Scholar 

  17. Kiho T, Usui S, Hirano K, Aizawa K, Inakuma T (2004) Tomato paste fraction inhibiting the formation of advanced glycation end-products. Biosci Biotechnol Biochem 68: 200–205

    Article  CAS  Google Scholar 

  18. Kris-Etherton PM, Lefevre M, Beecher GR, Gross MD, Keen CL, Etherton TD (2004) Bioactive compounds in nutrition and health-research methodologies for establishing biological function: the antioxidant and anti-inflammatory effects of flavonoids on atheroscerosis. Annu Rev Nutr 24:511–538

    Article  CAS  Google Scholar 

  19. Lamuela-Raventos RM, Andres-Lacueva C, Permanyer J, Izquierdo-Pulido M (2001) More antioxidants in cocoa. J Nutr 131:834

    CAS  Google Scholar 

  20. Lee M-J, Wang Z-Y, Li H, Chen L, Sun Y, Gobbo S, Balentine DA, Yang CS (1995) Analysis of plasma and urinary tea polyphenols in human subjects. Cancer Epidemiol Biomark Prev 4:393–399

    CAS  Google Scholar 

  21. Leenen R, Roodenburg AJ, Tijburg LB, Wiseman SA (2000) A single dose of tea with or without milk increases plasma antioxidant activity in humans. Eur J Clin Nutr 54:87–92

    Article  CAS  Google Scholar 

  22. Manach C, Scalbert A, Morand C, Remesy C, Jimenez L (2004) Polyphenols: food sources and bioaviability. Am J Clin Nutr 79:727–747

    CAS  Google Scholar 

  23. Manach C, Williamson G, Morand C, Scalbert A, Remesy C (2005) Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Nutr 81(Suppl):230S–242S

    CAS  Google Scholar 

  24. Matsuda H, Wang T, Managi H, Yoshikawa M (2003) Structural requirements of flavonoids for inhibition of protein glycation and radical scavenging activities. Bioorg Med Chem 11:5317–5323

    Article  CAS  Google Scholar 

  25. Monnier VM, Bautista O, Kenny D, Sell DR, Fogarty J, Dahms W, Cleary PA, Lachin J, Genuth S, the DCCT Skin Collagen Ancillary Study Group (1999) Skin collagen glycation, glycoxidation, and cross-linking are lower in subjects with long-term intensive versus conventional therapy of type−1 diabetes: relevance of glycated collagen products versus HbA1c as markers of diabetic complications. Diabetes 48:870–880

    Article  CAS  Google Scholar 

  26. Monnier V, Fogarty JF, Monnier CS, Sell DR (1999) Glycation, glycoxidation and other Maillard recation products. In: Byung Pal Yu (ed) Methods in aging research. CRC Press, New York, pp 657-681

  27. Monnier VM, Glomb M, Elgawish A, Sell DR (1996) The mechanism of collagen cross-linking in diabetes: a puzzle nearing resolution. Diabetes 45(Suppl 3):S67–S72

    CAS  Google Scholar 

  28. Morimitsu Y, Yoshida K, Esaki S, Hirota H (1995) Protein glycation inhibitors from thyme (Thymus vulgaris). Biosci Biotech Biochem 59:2018–2021

    CAS  Google Scholar 

  29. Nakagawa K, Okuda S, Miyazawa T (1997) Dose-dependent incorporation of tea catechins, (-)-epigallocatechin-3-gallate and (-)-epigallocatechin, into human plasma. Biosci Biotechnol Biochem 61:1981–1985

    Article  CAS  Google Scholar 

  30. Odetti PR, Borgoglio A, De Pascale A, Rolandi R, Adezati L (1990) Prevention of diabetes-increased aging effect on rat collagen-linked fluorescence by aminoguanidine and rutin. Diabetes 39:796–801

    Article  CAS  Google Scholar 

  31. Olthof MR, Hollman PC, Vree TB, Katan MB (2000) Bioavailabilities of quercetin−3-glucoside and quercetin−4′-glucoside do not differ in humans. J Nutr 130:1200–1203

    CAS  Google Scholar 

  32. Pannala AS, Chan TS, O’Brien PJ, Rice-Evans CA (2001) Flavonoid B-ring chemistry and antioxidant activity: fast reaction kinetics. Biochem Biophys Res Commun 282:1161–1168

    Article  CAS  Google Scholar 

  33. Plumb GW, De Pascual-Teresa S, Santos-Buelga C, Cheynier V, Williamson G (1998) Antioxidant properties of catechins and proanthocyanidins: effect of polymerisation, galloylation and glycosylation. Free Radic Res 29:351–358

    Article  CAS  Google Scholar 

  34. Price DL, Rhett PM, Thorpe SR, Baynes JW (2001) Chelating activity of advanced glycation end-product inhibitors. J Biol Chem 276:48967–48972

    Article  CAS  Google Scholar 

  35. Sano A, Yamakoshi J, Tokutake S, Tobe K, Kubota Y, Kikuchi M (2003) Procyanidin B1 is detected in human serum after intake of proanthocyanidin-rich grape seed extract. Biosci Biotechnol Biochem 67:1140–1143

    Article  CAS  Google Scholar 

  36. Scalbert A, Williamson G (2000) Dietary intake and bioavailability of polyphenols. J Nutr 130:2073S–2085S

    CAS  Google Scholar 

  37. Sell DR, Lapolla A, Odetti P, Fogarty J, Monnier VM (1992) Pentosidine formation in skin correlates with severity of complications in individuals with long-standing IDDM. Diabetes 41:1286–1292

    Article  CAS  Google Scholar 

  38. Spencer JP, Chaudry F, Pannala AS, Srai SK, Debnam E, Rice-Evans C (2000) Decomposition of cocoa procyanidins in the gastric milieu. Biochem Biophys Res Comm 272:236–241

    Article  CAS  Google Scholar 

  39. Sternberg M, Borsos AM, Roux A, Adam C, Urios P (2002) Compared inhibition of pentosidine formation in type-I collagen incubated with glucose by catechin, myricetin, kaempferol and quercetin: role of flavonoid structure. Diabetologia 45(Suppl 2):393

    Google Scholar 

  40. Sternberg MC, M’Bemba J, Urios P, Borsos AM, Roux A, Adam C, Berne C, Selam JL, Slama G (2003) Skin-collagen pentosidine and fluorescence at 370/440 nm as markers of diabetes duration and complications in a french population. Diabetologia 46(Suppl 2):A406

    Google Scholar 

  41. Stitt A, Gardiner TA, Anderson NL, Canning P, Frizzell N, Duffy N, Boyle C, Januszewski AS, Chachich M, Baynes JW, Thorpe SR (2002) The AGE inhibitor pyridoxamine inhibits development of retinopathy in experimental diabetes. Diabetes 51:2826–2832

    Article  CAS  Google Scholar 

  42. Tourino S, Selga A, Jimenez A, Julia L, Lozano C, Lizarraga D, Cascante M, Torres JL (2005) Procyanidin fractions from pine (Pinus pinaster) bark: radical scavenging power in solution, antioxidant activity in emulsion, and antiproliferative effect in melanoma cells. J Agric Food Chem 53:4728–4735

    Article  CAS  Google Scholar 

  43. Urios P, Grigorova-Borsos AM, Feing-Kwong-Chan S, Sternberg M (2000a) Quercetin and rutin inhibit pentosidine formation on type-I collagen incubated with glucose. Exp Clin Endocrinol Diabetes 18/5:A11

  44. Urios P, Kassab I, Borsos AM, Guillot R, Peyroux J, Sternberg M (2000b) Long-term treatment with a purified micronized flavonoid fraction reduces urinary albumin clearance and restores albuminemia in normotensive and hypertensive diabetic rats. Diabetes Res Clin Pract 50, Suppl 1: S362

    Google Scholar 

  45. Vertommen J, Van den Enden M, Simoens L, De Leew I (1994) Flavonoid treatment reduces glycation and lipid peroxidation in experimental diabetic rats. Phytother Res 8:430–432

    Article  CAS  Google Scholar 

  46. Waterhouse AL (2002) Wine phenolics. Ann NY Acad Sci 957:21–36

    Article  CAS  Google Scholar 

  47. Woessner JF (1961) The determination of hydroxyproline and protein samples containing small proportions of this imino acid. Arch Biochem Biophys 93:440–447

    Article  CAS  Google Scholar 

  48. Wu C-H, Yen G-C (2005) Inhibitory effect of naturally occuring flavonoids on the formation of advanced glycation endproducts. J Agric Food Chem 53:3167–3173

    CAS  Google Scholar 

  49. Yang Y, Chien M (2000) Characterization of grape procyanidins using high-performance liquid chromatography/mass spectrometry and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. J Agric Food Chem 48:3990–3996

    Article  CAS  Google Scholar 

  50. Yokozawa T, Nakagawa T (2004) Inhibitory effects of Luobuma tea and its components against glucose-mediated protein damage. Food Chem Toxicol 42:975–981

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the “Fondation pour la Recherche Médicale” and “Naturalia et Biologia”. We thank J. Peyroux for his help and critical reviewing, S. Feing, J. Garaud, A. Roux and C. Adam for their technical assistance.

Author information

Authors and Affiliations

  1. Equipe de recherche “Protéines modifiées, protéases et physiopathologie de l’endothélium vasculaire”, Dépt. de Biochimie, Faculté de Médecine & Laboratoire de Pharmacologie, Faculté de Pharmacie, Université René Descartes, Paris, France

    Paul Urios, Anne-Marie Grigorova-Borsos &  Michel Sternberg

  2. Laboratoire de Biochimie, Hormonologie et Génétique, Hôpital Bichat, Paris, France

    Paul Urios

  3. Laboratoire de Biochimie, Hôpital St Vincent-de-Paul, 82, av. Denfert-Rochereau, 75014, Paris, France

    Michel Sternberg

Authors
  1. Paul Urios
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anne-Marie Grigorova-Borsos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michel Sternberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michel Sternberg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Urios, P., Grigorova-Borsos, AM. & Sternberg, M. Flavonoids inhibit the formation of the cross-linking AGE pentosidine in collagen incubated with glucose, according to their structure. Eur J Nutr 46, 139–146 (2007). https://doi.org/10.1007/s00394-007-0644-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00394-007-0644-0

Keywords

Search

Navigation