Skip to main content
SpringerLink
Log in

Topical applications of iron chelators in photosensitization

  • Paper
  • Published:
Photochemical & Photobiological Sciences Aims and scope Submit manuscript

Abstract

Generation of the reactive oxygen species (ROS) in skin by exposure to ultraviolet (UV) radiation induces a number of cutaneous pathologies such as skin cancer, photosensitization, and photoaging among others. Skin iron catalyzes UV generation of ROS. Topical application of iron chelators reduces erythema, epidermal and dermal hypertrophy, wrinkle formation, tumour appearance. It has been proposed that iron chelators can be useful agents against damaging effects of both short- and long-term UV exposure. A better understanding of the action mechanisms of iron chelators, might be useful to developing effective anticancer and antiphotoaging cosmetic products. Iron chelators may lead to accumulation of protoporphyrin IX (PpIX), a strong photosensitizer. The action of iron chelators in skin, related to PpIX increase has not yet been thoroughly studied. Therefore, we have investigated the formation of PpIX in normal mouse skin after topical application of creams containing metal chelators. The amount and distribution of porphyrins formed was determined by means of non-invasive fluorescence spectroscopy. Deferoxamine (DF), ethylenediaminetetraacetic acid (EDTA), 1,2-diethyl-3-hydroxypyridin-4-one (CP94), but not meso-2,3-dimercaptosuccinic acid (DMSA), caused increased accumulation of endogenous porphyrins in the skin. Fluorescence excitation and emission spectroscopy confirmed that PpIX was the main fluorescent species. The amount of PpIX accumulated in skin under the present conditions was not large enough to produce any significant erythema after light exposure. Further studies are needed to evaluate the role of PpIX induced by iron chelators used, against photoaging and cancer prevention.

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

Similar content being viewed by others

References

  1. H. S. Black, Potential involvement of free radical reactions in ultraviolet light-mediated cutaneous damage, Photochem. Photobiol., 1987, 46, 213–221.

    Article  CAS  PubMed  Google Scholar 

  2. A. Svobodova, D. Walterova, J. Vostalova, Ultraviolet light induced alteration to the skin, Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub., 2006, 150, 25–38.

    Article  CAS  PubMed  Google Scholar 

  3. C. Pourzand, R. D. Watkin, J. E. Brown, R. M. Tyrrell, Ultraviolet A radiation induces immediate release of iron in human primary skin fibroblasts: the role of ferritin, Proc. Natl. Acad. Sci. U. S. A., 1999, 96, 6751–6756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. M. Kruszewski, Labile iron pool: the main determinant of cellular response to oxidative stress, Mutat. Res., 2003, 531, 81–92.

    Article  CAS  PubMed  Google Scholar 

  5. P. Brenneisen, J. Wenk, L. O. Klotz, M. Wlaschek, K. Briviba, T. Krieg, H. Sies, K. Scharffetter-Kochanek, Central role of ferrous/ferric iron in the ultraviolet B irradiation-mediated signaling pathway leading to increased interstitial collagenase (matrix-degrading metalloprotease (MMP)-1) and stromelysin-1 (MMP-3) mRNA levels in cultured human dermal fibroblasts, J. Biol. Chem., 1998, 273, 5279–5287.

    Article  CAS  PubMed  Google Scholar 

  6. M. Kitazawa, K. Iwasaki, Reduction of ultraviolet light-induced oxidative stress by amino acid–based iron chelators, Biochim. Biophys. Acta, 1999, 1473, 400–408.

    Article  CAS  PubMed  Google Scholar 

  7. B. A. Jurkiewicz, G. R. Buettner, Ultraviolet light-induced free radical formation in skin: an electron paramagnetic resonance study, Photochem. Photobiol., 1994, 59, 1–4.

    Article  CAS  PubMed  Google Scholar 

  8. B. A. Jurkiewicz, G. R. Buettner, EPR detection of free radicals in UV-irradiated skin: mouse versus human, Photochem. Photobiol., 1996, 64, 918–922.

    Article  CAS  PubMed  Google Scholar 

  9. D. L. Bissett, D. M. Oelrich, D. P. Hannon, Evaluation of a topical iron chelator in animals and in human beings: short-term photoprotection by 2-furildioxime, J. Am. Acad. Dermatol., 1994, 31, 572–578.

    Article  CAS  PubMed  Google Scholar 

  10. D. L. Bissett, R. Chatterjee, D. P. Hannon, Chronic ultraviolet radiation-induced increase in skin iron and the photoprotective effect of topically applied iron chelators, Photochem. Photobiol., 1991, 54, 215–223.

    Article  CAS  PubMed  Google Scholar 

  11. H. Mitani, I. Koshiishi, T. Sumita, T. Imanari, Prevention of the photodamage in the hairless mouse dorsal skin by kojic acid as an iron chelator, Eur. J. Pharmacol., 2001, 411, 169–174.

    Article  CAS  PubMed  Google Scholar 

  12. D. L. Bissett, J. F. McBride, Synergistic topical photoprotection by a combination of the iron chelator 2-furildioxime and sunscreen, J. Am. Acad. Dermatol., 1996, 35, 546–549.

    Article  CAS  PubMed  Google Scholar 

  13. M. Kitazawa, Y. Ishitsuka, M. Kobayashi, T. Nakano, K. Iwasaki, K. Sakamoto, K. Arakane, T. Suzuki, L. H. Kligman, Protective effects of an antioxidant derived from serine and vitamin B6 on skin photoaging in hairless mice, Photochem. Photobiol., 2005, 81, 970–974.

    Article  CAS  PubMed  Google Scholar 

  14. M. Kitazawa, K. Iwasaki, K. Sakamoto, Iron chelators may help prevent photoaging, J. Cosmet. Dermatol., 2006, 5, 210–217.

    Article  CAS  PubMed  Google Scholar 

  15. I. N. H. White, J. A. White, H. H. Liem, U. Muller-Eberhard, Decreased cytochrome p450 and increased porphyrin concentrations in the livers of rats on a low iron diet given a single dose of desferrioxamine, Biochem. Pharmacol., 1978, 27, 865–870.

    Article  CAS  PubMed  Google Scholar 

  16. P. R. Sinclair, S. Granick, Heme control on the synthesis of delta-aminolevulinic acid synthetase in cultured chick embryo liver cells, Ann. N. Y. Acad. Sci., 1975, 244, 509–520.

    Article  CAS  PubMed  Google Scholar 

  17. A. G. Smith, B. Clothier, J. E. Francis, A. H. Gibbs, M. F. De, R. C. Hider, Protoporphyria induced by the orally active iron chelator 1,2-diethyl-3-hydroxypyridin-4-one in C57BL/10ScSn mice, Blood, 1997, 89, 1045–1051.

    Article  CAS  PubMed  Google Scholar 

  18. M. G. Strakhovskaya, A. O. Shumarina, G. Y. Fraikin, A. B. Rubin, Endogenous porphyrin accumulation and photosensitization in the yeast Saccharomyces cerevisiae in the presence of 2,2’-dipyridyl, J. Photochem. Photobiol., B, 1999, 49, 18–22.

    Article  CAS  Google Scholar 

  19. M. G. Strakhovskaya, E. V. Ivanova, O. A. Kolesnikova, G. Y. Fraikin, Effect of 2,2’-dipyridyl on accumulation of protoporphyrin IX and its derivatives in yeast mitochondria and plasma membranes, Biochemistry (Moscow), 1999, 64, 213–216.

    CAS  Google Scholar 

  20. P. Juzenas, A. Juzeniene, J. Moan, Deferoxamine photosensitizes cancer cells in vitro, Biochem. Biophys. Res. Commun., 2005, 332, 388–391.

    Article  CAS  PubMed  Google Scholar 

  21. Z. Malik, G. Kostenich, L. Roitman, B. Ehrenberg, A. Orenstein, Topical application of 5-aminolevulinic acid, DMSO and EDTA: protoporphyrin IX accumulation in skin and tumours of mice, J. Photochem. Photobiol., B, 1995, 28, 213–218.

    Article  CAS  Google Scholar 

  22. B. Ortel, A. Tanew, H. Honigsmann, Lethal photosensitization by endogenous porphyrins of PAM cells-modification by desferrioxamine, J. Photochem. Photobiol., B, 1993, 17, 273–278.

    Article  CAS  Google Scholar 

  23. S. Fijan, H. Honigsmann, B. Ortel, Photodynamic therapy of epithelial skin tumours using delta-aminolaevulinic acid and desferrioxamine, Br. J. Dermatol., 1995, 133, 282–288.

    Article  CAS  PubMed  Google Scholar 

  24. Y. Ninomiya, Y. Itoh, T. Henta, A. Ishibashi, Photodynamic diagnosis of basal cell carcinoma on the lower eyelid using topical 5-aminolaevulinic acid and desferrioxamine, Br. J. Dermatol., 1999, 141, 580–581.

    Article  CAS  PubMed  Google Scholar 

  25. K. Choudry, R. C. Brooke, W. Farrar, L. E. Rhodes, The effect of an iron chelating agent on protoporphyrin IX levels and phototoxicity in topical 5-aminolaevulinic acid photodynamic therapy, Br. J. Dermatol., 2003, 149, 124–130.

    Article  CAS  PubMed  Google Scholar 

  26. A. Curnow, A. J. MacRobert, S. G. Bown, Comparing and combining light dose fractionation and iron chelation to enhance experimental photodynamic therapy with aminolevulinic acid, Lasers Surg. Med., 2006, 38, 325–331.

    Article  PubMed  Google Scholar 

  27. P. Uehlinger, J. P. Ballini, B. H. van den, G. Wagnieres, On the role of iron and one of its chelating agents in the production of protoporphyrin IX generated by 5-aminolevulinic acid and its hexyl ester derivative tested on an epidermal equivalent of human skin, Photochem. Photobiol., 2006, 82, 1069–1076.

    Article  CAS  PubMed  Google Scholar 

  28. M. Tronchin, G. Jori, M. Neumann, M. Schuetz, A. Saiyadpour, H.-D. Brauer, Sunlight-promoted Photosensitizing and Photophysical Properties of Porphyrins, Internet J. Sci., 1997, 3, C37.

    Google Scholar 

  29. J. L. Domingo, Prevention by chelating agents of metal-induced developmental toxicity, Reprod. Toxicol., 1995, 9, 105–113.

    Article  CAS  PubMed  Google Scholar 

  30. A. L. Miller, Dimercaptosuccinic acid (DMSA), a non-toxic, water-soluble treatment for heavy metal toxicity, Altern. Med. Rev., 1998, 3, 199–207.

    CAS  PubMed  Google Scholar 

  31. Y. Liu, G. Viau, R. Bissonnette, Multiple large-surface photodynamic therapy sessions with topical or systemic aminolevulinic acid and blue light in UV-exposed hairless mice, J. Cutan. Med Surg., 2004, 8, 131–139.

    Article  PubMed  Google Scholar 

  32. S. Sharfaei, G. Viau, H. Lui, D. Bouffard, R. Bissonnette, Systemic photodynamic therapy with aminolaevulinic acid delays the appearance of ultraviolet-induced skin tumours in mice, Br. J. Dermatol., 2001, 144, 1207–1214.

    Article  CAS  PubMed  Google Scholar 

  33. S. Sharfaei, P. Juzenas, J. Moan, R. Bissonnette, Weekly topical application of methyl aminolevulinate followed by light exposure delays the appearance of UV-induced skin tumours in mice, Arch. Dermatol. Res., 2002, 294, 237–242.

    Article  CAS  PubMed  Google Scholar 

  34. I. M. Stender, N. Bech-Thomsen, T. Poulsen, H. C. Wulf, Photodynamic therapy with topical delta-aminolevulinic acid delays UV photocarcinogenesis in hairless mice, Photochem. Photobiol., 1997, 66, 493–496.

    Article  CAS  PubMed  Google Scholar 

  35. A. Donfrancesco, G. Deb, S. L. De, R. Cozza, A. Castellano, Role of deferoxamine in tumor therapy, Acta Haematol., 1996, 95, 66–69.

    Article  CAS  PubMed  Google Scholar 

  36. M. Alam, J. S. Dover, Treatment of photoaging with topical aminolevulinic acid and light, Skin Ther. Lett., 2004, 9, 7–9.

    CAS  Google Scholar 

  37. J. S. Dover, A. C. Bhatia, B. Stewart, K. A. Arndt, Topical 5-aminolevulinic acid combined with intense pulsed light in the treatment of photoaging, Arch. Dermatol., 2005, 141, 1247–1252.

    Article  PubMed  Google Scholar 

  38. M. H. Gold, The evolving role of aminolevulinic acid hydrochloride with photodynamic therapy in photoaging, Cutis, 2002, 69, 8–13.

    PubMed  Google Scholar 

  39. M. P. Goldman, R. A. Weiss, M. A. Weiss, Intense pulsed light as a nonablative approach to photoaging, Dermatol. Surg., 2005, 31, 1179–1187.

    Article  CAS  PubMed  Google Scholar 

  40. T. M. Busch, Local physiological changes during photodynamic therapy, Lasers Surg. Med., 2006, 38, 494–499.

    Article  PubMed  Google Scholar 

  41. B. W. Henderson, T. M. Busch, J. W. Snyder, Fluence rate as a modulator of PDT mechanisms, Lasers Surg. Med., 2006, 38, 489–493.

    Article  PubMed  Google Scholar 

  42. G. Zonios, J. Bykowski, N. Kollias, Skin melanin, hemoglobin, and light scattering properties can be quantitatively assessed in vivo using diffuse reflectance spectroscopy, J. Invest. Dermatol., 2001, 117, 1452–1457.

    Article  CAS  PubMed  Google Scholar 

  43. J. A. Bouwstra, P. L. Honeywell-Nguyen, G. S. Gooris, M. Ponec, Structure of the skin barrier and its modulation by vesicular formulations, Prog. Lipid Res., 2003, 42, 1–36.

    Article  CAS  PubMed  Google Scholar 

  44. J. T. van den Akker, V. Iani, W. M. Star, H. J. Sterenborg, J. Moan, Topical application of 5-aminolevulinic acid hexyl ester and 5-aminolevulinic acid to normal nude mouse skin: differences in protoporphyrin IX fluorescence kinetics and the role of the stratum corneum, Photochem. Photobiol., 2000, 72, 681–689.

    Article  PubMed  Google Scholar 

  45. T. Yano, N. Higo, K. Fukuda, M. Tsuji, K. Noda, M. Otagiri, Further evaluation of a new penetration enhancer, HPE-101, J. Pharm. Pharmacol., 1993, 45, 775–778.

    Article  CAS  PubMed  Google Scholar 

  46. M. Nakashima, M. F. Zhao, H. Ohya, M. Sakurai, H. Sasaki, K. Matsuyama, M. Ichikawa, Evaluation of in vivotransdermal absorption of cyclosporin with absorption enhancer using intradermal microdialysis in rats, J. Pharm. Pharmacol., 1996, 48, 1143–1146.

    Article  CAS  PubMed  Google Scholar 

  47. J. L. Buss, F. M. Torti, S. V. Torti, The role of iron chelation in cancer therapy, Curr. Med. Chem., 2003, 10, 1021–1034.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiation Biology, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, The Norwegian Radium Hospital, Montebello, 0310, Oslo, Norway

    Asta Juzeniene, Petras Juzenas, Vladimir Iani & Johan Moan

  2. Institute of Physics, University of Oslo, Blindern, 0316, Oslo, Norway

    Johan Moan

Authors
  1. Asta Juzeniene
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Petras Juzenas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vladimir Iani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Johan Moan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Asta Juzeniene.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Juzeniene, A., Juzenas, P., Iani, V. et al. Topical applications of iron chelators in photosensitization. Photochem Photobiol Sci 6, 1268–1274 (2007). https://doi.org/10.1039/b703861e

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1039/b703861e

Search

Navigation