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.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
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).
Blois, M. S., Antioxidant determinations by the use of a stable free radical.Nature, 181, 1199–1200 (1958).
Bors, W., Heller, W., Michel, C., and Saran, M.,. Flavonoids as antioxidants: determination of radical scavenging efficiencies.Methods Enzymol., 186, 343–355 (1990).
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).
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).
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).
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).
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).
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).
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).
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).
Ende, C. and Gebhardt, R., Inhibition of matrix metallproteinase- 2 and -9 activity by selected flavonoids.Planta Med., 70, 1006–1008 (2004).
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).
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).
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).
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).
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).
Gilchrest, B.A., Skin aging and photoaging: an overview.J. Am. Acad. Dermatol., 21, 610–613 (1989).
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).
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).
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).
Jenkins, G., Molecular mechanisms of skin aging.Mech. Aging Dev, 123, 801–810 (2002).
Kligman, A. M., Early destructive effects of sunlight on human skin.J. Am. Med. Assoc., 210, 2377–2380 (1969).
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).
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).
Melzig, M. F., Loser, B., and Ciesielski, S., Inhibition of neutrophil elastase activity by phenolic compounds from plants.Pharmazie, 56, 967–970 (2001).
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).
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).
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).
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).
Pietta, P. G., Flavonoids as antioxidants.J. Nat. Prod., 63,1035- 1042 (2000).
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).
Robinson, M. J. and Cobb, M. H., Mitogen-activated protein kinase pathways.Curr.t Opin. Cell Biol., 9, 180–186 (1997).
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).
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).
Scharffetter-Kochanek, K., Brenneisen, P., and Wenk, J., Photoaging of the skin from phenotype to mechanisms.Exp. Gerontol. 35, 307–316 (2000).
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).
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).
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).
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).
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).
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).
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).
Went, J., Brenneisen, P., and Meewes, C, UV-induced oxidative stress and photoaging.Curr. Probl. Dermatol., 29, 74–82 (2001).
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).
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).
Author information
Authors and Affiliations
Corresponding author
Rights 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
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF02977608