Advertisement

Structure activity relationship of antioxidative property of flavonoids and inhibitory effect on matrix metalloproteinase activity in UVA-irradiated human dermal fibroblast

  • Gwan-Sub Sim
  • Bum-Chun Lee
  • Ho Seung Cho
  • Jae Woong Lee
  • Jin-Hwa Kim
  • Dong-Hwan Lee
  • Jin-Hui Kim
  • Hyeong-Bae Pyo
  • Dong Cheul Moon
  • Ki-Wan Oh
  • Yeo Pyo Yun
  • Jin Tae Hong
Drug Design

Abstract

Collagenase, a matrix metalloproteinases (MMPs), is a key regulator in the photoaging process of skin due to the reactive oxygen species generated after exposure to ultraviolet A (UVA). Flavonoid compounds have been demonstrated to possess antioxidant properties, and could be useful in the prevention of photoaging. In this study, to investigate the structure-activity relationship of flavonoid compounds on their antioxidant property and inhibitory effects against the MMP activity, the effects of several flavonoids; myricetin, quercetin, kaempferol, luteolin, apigenin and chrysin, on the reactive oxygen species scavengering activity and inhibitory effect against the MMP activity were examinedin vitro and in human dermal fibroblasts induced by UVA. The relative order of antioxidative efficacy, as determined using the 1, 1 -diphenyl-2-picrylhydrazyl (DPPH) method and the xanthine/xanthine oxidase system, was as follows; flavones: luteolin > apigenin > chrysin, flavonols: myricetin > quercetin > kaempferol, and correlated with the respective number of OH group on their B-ring. In good correlation with the antioxidant properties, the flavonoids inhibited the collagenase activities, in a dose-dependent manner, and the MMP expression. These results suggested the UVA induced antioxidative activity and inhibitory effects of flavonoids on the collagenase in human dermal fibroblasts depends on the number of OH group in the flavonoid structure, and those with a higher number of OH group may be more useful in the prevention of UV stressed skin aging.

Key words

Flavonoids Antioxidant MMP Structure activity relationship Human skin fibro-blast 

References

  1. Arora, A., Nair, M.G, and Strasburg, G. M., Structure-activity relationships for antioxidant activities of a series of flavonoids in a liposomal system.Free Radic. Biol. Med., 24, 1355–1363 (1998).PubMedCrossRefGoogle Scholar
  2. Blois, M. S., Antioxidant determinations by the use of a stable free radical.Nature, 181, 1199–1200 (1958).CrossRefGoogle Scholar
  3. Bors, W., Heller, W., Michel, C., and Saran, M.,. Flavonoids as antioxidants: determination of radical scavenging efficiencies.Methods Enzymol., 186, 343–355 (1990).PubMedCrossRefGoogle Scholar
  4. Brenneisen, P., Sies, H., and Scharffetter-Kochanek, K., UV-B irradiation and matrix metalloproteinases: from induction via signaling to initial events.Ann. N. Y. Acad. Sci., 973, 31–43 (2002).PubMedCrossRefGoogle Scholar
  5. Cao, G., Sofic, E., and Prior, R. L., Antioxidant and prooxidant behavior of flavonoids: structure-activity relationships.Free Radi. Biol. Med., 22, 749–760 (1997).CrossRefGoogle Scholar
  6. Chambers, A. F. and Matrisian, L. M., Changing views of the role of matrix metalloproteinases in metastasis.J. Natl. Cancer Inst, 89, 1260–1270 (1997).PubMedCrossRefGoogle Scholar
  7. Chen, Z. Y, Chan, P. T., Ho, K. Y, Fung, K.,P, and Wang, J., Antioxidant activity of natural flavonoids is governed by number and location of their aromatic hydroxyl groups.Chem. Phys. Lipids, 79, 157–163 (1996).PubMedCrossRefGoogle Scholar
  8. Cos, P., Ying, L Y, Calomme, N., Hu, J. K, Cimanga, K., Van Poel, B., Pieters, L, Vlietinck, A. J., and Berghe, D. V, Structure activity relationships and classification of flavonoids as inhibitors of xanthine oxidase and Superoxide scavengers.J.Nat. Prod., 61, 71–76 (1998).PubMedCrossRefGoogle Scholar
  9. Cotelle, N., Bemier, J. L, Catteau, J. P., Pommery, J., Wallet, J. C., and Caydou, E. M., Antioxidant properties of hydroxyl- flavones.Free Radi. Biol. Med., 20, 35–43 (1996).CrossRefGoogle Scholar
  10. Cunningham, M. L., Krinsky, N. I., Giovanazzi, S. M., and Peak, M. J., Superoxide anion is generated from cellular metabolites by solar radiation and its components.Free Radi. Biol. Med, 1, 381–385 (1985).Google Scholar
  11. Demeule, M., Brassard, M., Page, M., Gingras, D., and Beliveau, R., Matrix metalloproteinase inhibition by green tea catechins.Biochim. Biophys. Acta 1478, 51–60 (2000).PubMedGoogle Scholar
  12. Ende, C. and Gebhardt, R., Inhibition of matrix metallproteinase- 2 and -9 activity by selected flavonoids.Planta Med., 70, 1006–1008 (2004).PubMedCrossRefGoogle Scholar
  13. Fisher, G. J., Datta, S. C., Talwar, H. S., Wang, Z. Q., Varani, J., Kang, S., and Vorhees, J. J., Molecular basis of sun-induced premature skin aging and retinoid antagonism.Nature, 379, 335–339 (1996).PubMedCrossRefGoogle Scholar
  14. Fisher, G J. and Voorhees, J. J., Molecular mechanism of photoaging and its prevention by retinoic acid: ultraviolet irradiation induces MAP kinase signaling transduction cascade that induce AP-1 regulated matrix metalloproteinases that degrade human skinin vivo.J. Invest. Dermatol. Symposium Proceedings, 3, 61–68 (1998).Google Scholar
  15. Fisher, G. J., Wang, Z. Q., Datta, S. C, Varani, J., Kang, S., and Voorhees, J. J., Pathophysiology of premature skin aging induced by ultraviolet light.N. Engl. J. Med, 337, 1419–1428 (1997).PubMedCrossRefGoogle Scholar
  16. Furuno, K., Akasako, T., and Sugihara, N., The contribution of the pyrogallol moiety to the Superoxide radical scavenging activity of flavonoids.Bid. Pharm. Bull., 25, 19–23 (2002).CrossRefGoogle Scholar
  17. Gamet-Payrastre, L, Manenti, S., Gratacap, M. P., Tulliez, J., Chap, H., and Payrastre, B., Flavonoids and the inhibition of PCK and Pl 3-kinase.Gen. Pharmacol., 32, 279–286 (1999).PubMedCrossRefGoogle Scholar
  18. Gilchrest, B.A., Skin aging and photoaging: an overview.J. Am. Acad. Dermatol., 21, 610–613 (1989).PubMedCrossRefGoogle Scholar
  19. Hanson, K. M., and Clegg, R. M., Observation and quantification of ultraviolet-induced reactive oxygen species in ex vivo human skin.Photochem. Photobiol., 76, 57–63 (2002).PubMedCrossRefGoogle Scholar
  20. Heijnen, C. G. M., Haenen, G. R. M. M., Van Acker, F. A. A., Van der Vijgh, W. J. F, and Bast, A., Flavonoids as peroxynitrite scavengers: the role of the hydroxyl groups.Toxicol. In Vitro 5, 3–6 (2001).CrossRefGoogle Scholar
  21. Huang, C., Schmid, P. C., Ma, W. Y, Schmid, H. H., and Dong, Z., Phophatidylinositol-3 kinase is necessary for 12-O- tetradecanoylphorbol-13-acetate-induced cell transformation and activated protein 1 activation.J. Biol. Chem., 272, 4187–4194 (1997).PubMedCrossRefGoogle Scholar
  22. Jenkins, G., Molecular mechanisms of skin aging.Mech. Aging Dev, 123, 801–810 (2002).PubMedCrossRefGoogle Scholar
  23. Kligman, A. M., Early destructive effects of sunlight on human skin.J. Am. Med. Assoc., 210, 2377–2380 (1969).CrossRefGoogle Scholar
  24. Lien, E. J., Ren, S., Bui, H. H., and Wang, R., Quantitative structure-activity relationship analysis of phenolic antioxidants.Free Radi. Biol. Med, 26, 285–294 (1999).CrossRefGoogle Scholar
  25. Makimura, M., Hirasawa, M., Kobayashi, K., Indo, J., Sakanaka, S., Taguchi, T., and Otake, S., Inhibitory effect of tea catechins on collagenase activity.J. Periodontol., 64, 630–636 (1993).PubMedGoogle Scholar
  26. Melzig, M. F., Loser, B., and Ciesielski, S., Inhibition of neutrophil elastase activity by phenolic compounds from plants.Pharmazie, 56, 967–970 (2001).PubMedGoogle Scholar
  27. Middleton, Jr, E., Kandaswami, C, and Theoharides, T. C., The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer.Pharmacol. Rev., 52, 673–751 (2000).PubMedGoogle Scholar
  28. Nagase, H., Sasaki, K., Kito, H., Haga, A., and Sato, T., Inhibitory effect of delphinidin from Solanum melonena on human fibrosarcoma HT-1080 invasivenessin vitro.Planta Med, 64, 216–219 (1998).PubMedCrossRefGoogle Scholar
  29. Ozcelik, B., Lee, J. H., and Min, D. B., Effects of light, oxygen and pH on the 2,2-diphenyl-l-picrylhydrazyl (DPPH) method to evaluate antioxidants.J. Food Sci., 68, 487–490 (2003).CrossRefGoogle Scholar
  30. Parejo, I., Viladomat, F., Bastida, J., Rosas-Romero, A., Flerlage, N., Burillo, J., and Codina, C, Comparison between the radical scavenging activity and antioxidant activity of six distilled and nondistilled Mediterranean herbs and aromatic plants.J. Agric. Food Chem., 50, 6882–6890 (2002).PubMedCrossRefGoogle Scholar
  31. Pietta, P. G., Flavonoids as antioxidants.J. Nat. Prod., 63,1035- 1042 (2000).PubMedCrossRefGoogle Scholar
  32. Rice-Evans, C. A., Miller, N. J., and Paganga, G, Structure- antioxidant activity relationship of flavonoids and phenolic acids.Free Radi. Biol. Med., 20, 933–956 (1996).CrossRefGoogle Scholar
  33. Robinson, M. J. and Cobb, M. H., Mitogen-activated protein kinase pathways.Curr.t Opin. Cell Biol., 9, 180–186 (1997).CrossRefGoogle Scholar
  34. Sartor, L, Pexxato, E., Dell’Aica, I., Caniato, R., Biggin, S., and Garbisa, S., Inhibition of matrix-proteases by polyphenols: chemical insights for anti-inflammatroy and anti-invasion drug design.Biochem. Pharmacol., 64, 229–237 (2002).PubMedCrossRefGoogle Scholar
  35. Sato, T, Koike, L., Miyata, Y, Hirata, M., Mimaki, Y, Sashida, Y., Yano, M., and Ito, A., Inhibition of activator protein-1 binding activity and phosphatidylinositol 3-kinase pathway by nobiletin, a polymethoxy flavonoid, results in augmentation of tissue inhibitor of metalloproteinases-1 production and suppression of production of matrix metalloproteinases-1 and -9 in human fibrosarcoma HT-1080 cells.Cancer Res., 62, 1025–1029 (2002).PubMedGoogle Scholar
  36. Scharffetter-Kochanek, K., Brenneisen, P., and Wenk, J., Photoaging of the skin from phenotype to mechanisms.Exp. Gerontol. 35, 307–316 (2000).PubMedCrossRefGoogle Scholar
  37. Scharffetter, K., Wiaschek, M., Hogg, A., Bolsen, K., Schothorst, A., Goerz, G, Krieg, T., and Plewig, G., UVA irradiation induces collagenase in human dermal fibroblasts in vitro andin vivo.Arch. Dermatol. Res., 283, 506–511 (1991).PubMedCrossRefGoogle Scholar
  38. Shang, J., Schwarz, C., Sanchez Ruderisch, H., Hertting, T., Orfanos, C. E., and Tebbe, B., Effects of UVA and L-ascorbic acid on nuclear factor-kappa B in melanocytes and in HaCaT keratinocytes.Skin Pharmacol. Appl. Skin Physiol., 15, 353- 359 (2002).PubMedCrossRefGoogle Scholar
  39. Van Acker, S. A. B. E., Van den, Berg, D. J., Tromp, M. N. J. L., Griffioen, D. H., Van Bennekom, W. P., Van derVijgh, W. J. F, and Bast, A., Structural aspects of antioxidant activity of flavonoids.Free Radi. Biol. Med, 20, 331–342 (1996).CrossRefGoogle Scholar
  40. Van Acker, S. A. B. E., De Groot, M. J., Van denBerg, D. J., Tromp, M. N. J. L, Den Kelder, G. D. O., Van derVijgh, W. J. F., Bast, A., A Quantum chemical explanation of the antioxidant activity of flavonoids.Chem. Res. Toxicol., 9, 1305–1312 (1996B).CrossRefGoogle Scholar
  41. Varani, J., Warner, R. L., Gharaee-Kermani, M., Phan, S. H., Kang, S., Chung, J. H., Wang, Z. Q., Datta, S. C, Fisher, G J., and Voorhees, J. J., Vitamin A antagonizes decreased cell growth and elevated collagen-degrading matrix metallpro- teinases and stimulates collagen accumulation in naturally aged human skin.J. Invest. Dermatol., 114, 480–486 (2000).PubMedCrossRefGoogle Scholar
  42. Vile, G. F. and Tyrrell, R. M., UVA radiation-induced oxidative damage to lipids and proteinsin vitro and in human skin fibroblasts is dependent on iron and singlet oxygen.J. Invest. Dermatol., 18,721–730 (1995).Google Scholar
  43. Wenk, J., Brenneisen, P., Wlaschek, M., Poswig, A., Briviba, K., Oberley, T. D., and Scharffetter-Kochanek, K., Stable overex- pression of manganese Superoxide dismutase in mitochondria identifies hydrogen peroxide as a major oxidant in the AP-1 - mediated induction of matrix-degrading metalloproteinase-1.J. Biol. Chem., 274, 25869–25876 (1999).PubMedCrossRefGoogle Scholar
  44. Went, J., Brenneisen, P., and Meewes, C, UV-induced oxidative stress and photoaging.Curr. Probl. Dermatol., 29, 74–82 (2001).Google Scholar
  45. Whisler, R. L, Goyette, M. A., Grants, I. S., and Newhouse, Y G, Sublethal levels of oxidant stress stimulate multiple serine/threonine kinases and suppress protein phosphatases in Jurkat T cells.Arch. Biochem. Biophys., 319, 23–35 (1995).PubMedCrossRefGoogle Scholar
  46. Yokozawa, T., Chen, C. P., Dong, E., Tanaka, T., Nonaka, G. I., and Nishioka, I., Study on the Inhibitory Effect of Tannins and Flavonoids against the 1,1-Diphenyl-2-picrylhydrazyl Radical.Biochem. Pharmacol., 56, 213–222 (1998).PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2007

Authors and Affiliations

  • Gwan-Sub Sim
    • 2
  • Bum-Chun Lee
    • 2
  • Ho Seung Cho
    • 1
  • Jae Woong Lee
    • 1
  • Jin-Hwa Kim
    • 2
  • Dong-Hwan Lee
    • 2
  • Jin-Hui Kim
    • 2
  • Hyeong-Bae Pyo
    • 2
  • Dong Cheul Moon
    • 1
  • Ki-Wan Oh
    • 1
  • Yeo Pyo Yun
    • 1
  • Jin Tae Hong
    • 1
  1. 1.College of PharmacyChungbuk National UniversityCheungjuKorea
  2. 2.R & D CenterHanbul Cosmetics Co.ChungbukKorea

Personalised recommendations