Skip to main content
Log in

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

  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

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.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Blois, M. S., Antioxidant determinations by the use of a stable free radical.Nature, 181, 1199–1200 (1958).

    Article  CAS  Google Scholar 

  • Bors, W., Heller, W., Michel, C., and Saran, M.,. Flavonoids as antioxidants: determination of radical scavenging efficiencies.Methods Enzymol., 186, 343–355 (1990).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  CAS  Google Scholar 

  • 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).

    CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • Ende, C. and Gebhardt, R., Inhibition of matrix metallproteinase- 2 and -9 activity by selected flavonoids.Planta Med., 70, 1006–1008 (2004).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Gilchrest, B.A., Skin aging and photoaging: an overview.J. Am. Acad. Dermatol., 21, 610–613 (1989).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Jenkins, G., Molecular mechanisms of skin aging.Mech. Aging Dev, 123, 801–810 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Kligman, A. M., Early destructive effects of sunlight on human skin.J. Am. Med. Assoc., 210, 2377–2380 (1969).

    Article  CAS  Google Scholar 

  • 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).

    Article  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • Melzig, M. F., Loser, B., and Ciesielski, S., Inhibition of neutrophil elastase activity by phenolic compounds from plants.Pharmazie, 56, 967–970 (2001).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Pietta, P. G., Flavonoids as antioxidants.J. Nat. Prod., 63,1035- 1042 (2000).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  CAS  Google Scholar 

  • Robinson, M. J. and Cobb, M. H., Mitogen-activated protein kinase pathways.Curr.t Opin. Cell Biol., 9, 180–186 (1997).

    Article  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • Scharffetter-Kochanek, K., Brenneisen, P., and Wenk, J., Photoaging of the skin from phenotype to mechanisms.Exp. Gerontol. 35, 307–316 (2000).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  Google Scholar 

  • 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).

    Article  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Went, J., Brenneisen, P., and Meewes, C, UV-induced oxidative stress and photoaging.Curr. Probl. Dermatol., 29, 74–82 (2001).

    Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jin Tae Hong.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sim, GS., Lee, BC., Cho, H.S. et al. Structure activity relationship of antioxidative property of flavonoids and inhibitory effect on matrix metalloproteinase activity in UVA-irradiated human dermal fibroblast. Arch Pharm Res 30, 290–298 (2007). https://doi.org/10.1007/BF02977608

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02977608

Key words

Navigation