Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

Phototoxicity: Its Mechanism and Animal Alternative Test Methods

  • Received : 2015.05.27
  • Accepted : 2015.06.18
  • Published : 2015.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

The skin exposure to solar irradiation and photoreactive xenobiotics may produce abnormal skin reaction, phototoxicity. Phototoxicity is an acute light-induced response, which occurs when photoreacive chemicals are activated by solar lights and transformed into products cytotoxic against the skin cells. Multifarious symptoms of phototoxicity are identified, skin irritation, erythema, pruritis, and edema that are similar to those of the exaggerated sunburn. Diverse organic chemicals, especially drugs, are known to induce phototoxicity, which is probably from the common possession of UV-absorbing benzene or heterocyclic rings in their molecular structures. Both UVB (290~320 nm) and UVA (320~400 nm) are responsible for the manifestation of phototoxicity. Absorption of photons and absorbed energy (hv) by photoactive chemicals results in molecular changes or generates reactive oxygen species and depending on the way how endogenous molecules are affected by phototoxicants, mechanisms of phototoxcity is categorized into two modes of action: Direct when unstable species from excited state directly react with the endogenous molecules, and indirect when endogeneous molecules react with secondary photoproducts. In order to identify phototoxic potential of a chemical, various test methods have been introduced. Focus is given to animal alternative test methods, i.e., in vitro, and in chemico assays as well as in vivo. 3T3 neutral red uptake assay, erythrocyte photohemolysis test, and phototoxicity test using human 3-dimensional (3D) epidermis model are examples of in vitro assays. In chemico methods evaluate the generation of reactive oxygen species or DNA strand break activity employing plasmid for chemicals, or drugs with phototoxic potential.

Keywords

References

  1. Freeman, A.K. and Gordon, M. (2006) Dermatologic diseases and problems. Geriatric Medicine (4th edition), Springer, New York, pp. 869-881.
  2. Boudon, S.M., Morandi, G., Prideaux, B., Staab, D., Junker, U., Odermatt, A., Stoeckli, M. and Bauer, D. (2014) Evaluation of Sparfloxacin Distribution by Mass Spectrometry Imaging in a Phototoxicity Model. J. Am. Soc. Mass Spectrom., 25, 1803-1809. https://doi.org/10.1007/s13361-014-0947-3
  3. OECD. (2004) Test No. 432: In vitro 3T3 NRU Phototoxicity Test. OECD, Paris: OECD Publishing. No. 432.
  4. Lugovic, L., Situm, M., Ozanic-Bulic, S. and Sjerobabski-Masnec, I. (2007) Phototoxic and photoallergic skin reactions. Coll. Antropol., 31 Suppl 1, 63-67.
  5. FDA U. (2003) Guidance for industry - Photosafety Testing. FDA, US: FDA Publishing, pp. 1-22.
  6. Tonnesen, H.H. (2001) Formulation and stability testing of photolabile drugs. Int. J. Pharm., 225, 1-14. https://doi.org/10.1016/S0378-5173(01)00746-3
  7. Goncalo, M. (2011) Phototoxic and photoallergic reactions. Contact Dermatitis, Springer, pp. 361-376.
  8. Ferguson, J. (2002) Photosensitivity due to drugs. Photodermatol. Photoimmunol. photomed., 18, 262-269. https://doi.org/10.1034/j.1600-0781.2002.02778.x
  9. Adachi, T., Satou, Y., Satou, H., Shibata, H., Miwa, S., Iwase, Y., Yamamoto, T., Nishida, A. and Masutomi, N. (2015) Assessment of 8-methosypsoralen, lomefloxacin, sparfloxacin, and Pirfenidone phototoxicity in Long-Evans rats. Int. J. Toxicol., 34, 16-23. https://doi.org/10.1177/1091581814559397
  10. Boudon, S.M., Plappert-Helbig, U., Odermatt, A. and Bauer, D. (2014) Characterization of vemurafenib phototoxicity in a mouse model. Toxicol. Sci., 137, 259-267. https://doi.org/10.1093/toxsci/kft237
  11. Yazici, A.C., Baz, K., Ikizoglu, G., Kokturk, A., Uzumlu, H. and Tataroglu, C. (2004) Celecoxib?induced photoallergic drug eruption. Int. J. Dermatol., 43, 459-461. https://doi.org/10.1111/j.1365-4632.2004.02149.x
  12. Onoue, S., Seto, Y., Kato, M., Aoki, Y., Kojo, Y. and Yamada, S. (2013) Inhalable powder formulation of pirfenidone with reduced phototoxic risk for treatment of pulmonary fibrosis. Pharm. Res., 30, 1586-1596. https://doi.org/10.1007/s11095-013-0997-4
  13. Seto, Y., Inoue, R., Kato, M., Yamada, S. and Onoue, S. (2013) Photosafety assessments on pirfenidone: photochemical, photobiological, and pharmacokinetic characterization. J. Photochem. Photobiol. B, 120, 44-51. https://doi.org/10.1016/j.jphotobiol.2013.01.010
  14. Chignell, C.F., Motten, A.G. and Buettner, G.R. (1985) Photoinduced free radicals from chiorpromazine and related phenothiazines: relationship to phenothiazine-induced photosensitization. Environ. Health Perspect., 64, 103-110. https://doi.org/10.1289/ehp.8564103
  15. Kochevar, K.E. (1981) Phototoxicity mechanisms: chlorpromazine photosensitized damage to DNA and cell membranes. J. Invest. Dermatol., 77, 59-64. https://doi.org/10.1111/1523-1747.ep12479244
  16. ICH. (2014) ICH guideline S10 on photosafety evaluation of pharmaceuticals. ICH, US: FDA.
  17. OECD. (1981) TG101: UV-VIS Absorption Spectra. OECD, Paris: OECD, pp. 1-6.
  18. Garg, S., Rose, A.L. and Waite, T.D. (2011) Photochemical production of superoxide and hydrogen peroxide from natural organic matter. Geochim. Cosmochim. Acta, 75, 4310-4320. https://doi.org/10.1016/j.gca.2011.05.014
  19. Sayre, R.M., Dowdy, J.C., Gerwig, A.J., Shlelds, W.J. and Lioyd, R.V. (2005) Unexpected photolysis of the sunscreen octinoxate in the presence of the sunscreen avobenzone. Photochem. Photobiol., 81, 452-456. https://doi.org/10.1562/2004-02-12-RA-083.1
  20. ICH. (2013) Photosafety Evaluation of Pharmaceuticals S10. ICH, US: FDA, pp. 1-15.
  21. Vinardell, M.P. (2015) The use of non-animal alternatives in the safety evaluations of cosmetics ingredients by the Scientific Committee on Consumer Safety (SCCS). Regul. Toxicol. Pharmacol., 71, 198-204. https://doi.org/10.1016/j.yrtph.2014.12.018
  22. Haranosono, Y., Kurata, M. and Sakaki, H. (2014) Establishment of an in silico phototoxicity prediction method by combining descriptors related to photo-absorption and photoreaction. J. Toxicol. Sci., 39, 655-664. https://doi.org/10.2131/jts.39.655
  23. Onoue, S. and Tsuda, Y. (2006) Analytical studies on the prediction of photosensitive/phototoxic potential of pharmaceutical substances. Pharm. Res., 23, 156-164. https://doi.org/10.1007/s11095-005-8497-9
  24. Onoue, S., Kawamura, K., Igarashi, N., Zhou, Y., Fujikawa, M., Yamada, H., Tsuda, Y., Seto, Y. and Yamada, S. (2008) Reactive oxygen species assay-based risk assessment of druginduced phototoxicity: classification criteria and application to drug candidates. J. Pharm. Biomed. Anal., 47, 967-972. https://doi.org/10.1016/j.jpba.2008.03.026
  25. Guideline IHT. (2009) ICH guideline M3 (R2) on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. ICH, European Medicines Agency, pp. 1-26.
  26. Bauer, D., Averett, L.A., De Smedt, A., Kleinman, M.H., Muster, W., Pettersen, B.A. and Robles, C. (2014) Standardized UV-vis spectra as the foundation for a threshold-based, integrated photosafety evaluation. Regul. Toxicol. Pharmacol., 68, 70-75. https://doi.org/10.1016/j.yrtph.2013.11.007
  27. Diffey, B.L. (2002) Sources and measurement of ultraviolet radiation. Methods, 28, 4-13. https://doi.org/10.1016/S1046-2023(02)00204-9
  28. Wang, C.C., Xia, Q., Li, M., Wang, S., Zhao, Y., Tolleson, W.H., Yin, J.J. and Fu, P.P. (2014) Metabolic activation of pyrrolizidine alkaloids leading to phototoxicity and photogenotoxicity in human HaCaT keratinocytes. J. Environ. Sci. Health Part C Environ. Carcinog. Ecotoxicol. Rev., 32, 362-384. https://doi.org/10.1080/10590501.2014.969980
  29. Schumann, J., Boudon, S., Ulrich, P., Loll, N., Garcia, D., Schaffner, R., Streich, J., Kittel, B. and Bauer, D. (2014) Integrated preclinical photosafety testing strategy for systemically applied pharmaceuticals. Toxicol. Sci., 139, 245-256. https://doi.org/10.1093/toxsci/kfu026
  30. Spielmann, H., Balls, M., Brand, M., Doring, B., Holzhutter, H.G., Kalweit, S., Klecak, G., Eplattenier, H.L., Liebsch, M., Lovell, W.W., Maurer, T., Moldenhauer, F., Moore, L., Pape, W.J., Pfanenbecker, U., Potthast, J., De Silva, O., Steiling, W. and Willshaw, A. (1994) EEC/COLIPA project on in vitro phototoxicity testing: First results obtained with a Balb/c 3T3 cell phototoxicity assay. Toxicol. In Vitro, 8, 793-796. https://doi.org/10.1016/0887-2333(94)90069-8
  31. Peters, B. and Holzhutter, H.G. (2002) In vitro phototoxicity testing: development and validation of a new concentration response analysis software and biostatistical analyses related to the use of various prediction models. Altern. Lab. Anim., 30, 415-432.
  32. Pape, W.J., Maurer, T., Pfannenbecker, U. and Steiling, W. (2001) The red blood cell phototoxicity test (photohaemolysis and haemoglobin oxidation): EU/COLIPA validation programme on phototoxicity (phase II). Altern. Lab. Anim., 29, 145-162.
  33. Yamamoto, T., Tsurumaki, Y., Takei, M., Hosaka, M. and Oomori, Y. (2001) In vitro method for prediction of the phototoxic potentials of fluoroquinolones. Toxicol. In Vitro, 15, 721-727. https://doi.org/10.1016/S0887-2333(01)00089-3
  34. Sugiyama, M., Itagaki, H., Hariya, T., Murakami, N. and Kato, S. (1994) In vitro assays to predict phototoxicity of chemicals:(I) Red blood cell hemolysis assay. AATEX, 2, 183-191.
  35. Netzaff, F., Lehr, C.M., Wertz, P.W. and Schaefer, U.F. (2005) The human epidermis models EpiSkin (R), SkinEthic (R) and EpiDerm (R): An evaluation of morphology and their suitability for testing phototoxicity, irritancy, corrosivity, and substance transport. Eur. J. Pharm. Biopharm., 60, 167-178. https://doi.org/10.1016/j.ejpb.2005.03.004
  36. Portes, P., Pygmalion, M.J., Popovic, E., Cottin, M. and Mariani, M. (2002) Use of human reconstituted epidermis Episkin(R) for assessment of weak phototoxic potential of chemical compounds. Photodermatol. Photoimmunol. Photomed., 18, 96-102. https://doi.org/10.1034/j.1600-0781.2002.180207.x
  37. Bernard, F.X., Barrault, C., Deguercy, A., De Wever, B. and Rosdy, M. (2000) Development of a highly sensitive in vitro phototoxicity assay using the SkinEthicTM reconstructed human epidermis. Cell Biol. Toxicol., 16, 391-400. https://doi.org/10.1023/A:1007604612003
  38. Aardema, M.J., Barnett, B.B., Mun, G.C., Dahl, E.L., Curren, R.D., Hewitt, N.J. and Pfuhler, S. (2013) Evaluation of chemicals requiring metabolic activation in the EpiDerm 3D human reconstructed skin micronucleus (RSMN) assay. Mutat. Res., 750, 40-49. https://doi.org/10.1016/j.mrgentox.2012.08.009
  39. Lelievre, D., Justine, P., Christiaens, F., Bonaventure, N., Coutet, J., Marrot, L. and Cotovio, J. (2007) The EpiSkin phototoxicity assay (EPA): development of an in vitro tiered strategy using 17 reference chemicals to predict phototoxic potency. Toxicol. In Vitro, 21, 977-995. https://doi.org/10.1016/j.tiv.2007.04.012
  40. Reus, A.A., Reisinger, K., Downs, T.R., Carr, G.J., Zeller, A., Corvi, R., Krul, C.A. and Pfuhler, S. (2013) Comet assay in reconstructed 3D human epidermal skin models--investigation of intra- and inter-laboratory reproducibility with coded chemicals. Mutagenesis, 28, 709-720. https://doi.org/10.1093/mutage/get051
  41. Matsumoto, N., Akimoto, A., Kawashima, H. and Kim, S. (2010) Comparative study of skin phototoxicity with three drugs by an in vivo mouse model. J. Toxicol. Sci., 35, 97-100. https://doi.org/10.2131/jts.35.97
  42. Wagai, N. and Tawara, K. (1992) Possible reasons for differences in phototoxic potential of a 5 quinolone antibacterial agents: generation of toxic oxygen. Free Radical Res. Commun., 17, 387-398. https://doi.org/10.3109/10715769209083143
  43. Clewell, H.J. 3rd. (1993) Coupling of computer modeling with in vitro methodologies to reduce animal usage in toxicity testing. Toxicol. Lett., 68, 101-117. https://doi.org/10.1016/0378-4274(93)90123-F
  44. Henry, B., Foti, C. and Alsante, K. (2009) Can light absorption and photostability data be used to assess the photosafety risks in patients for a new drug molecule? J. Photochem. Photobiol. B, 96, 57-62. https://doi.org/10.1016/j.jphotobiol.2009.04.005

Cited by

  1. Phototoxicity Evaluation of Pharmaceutical Substances with a Reactive Oxygen Species Assay Using Ultraviolet A vol.33, pp.1, 2017, https://doi.org/10.5487/TR.2017.33.1.043
  2. ) polyphenol extract against UVB-induced skin damage by modulating the p53 mitochondrial pathway in vitro and in vivo pp.01458884, 2018, https://doi.org/10.1111/jfbc.12708
  3. Phototoxicity of traditional chinese medicine (TCM) pp.2045-4538, 2018, https://doi.org/10.1039/C8TX00141C
  4. Development of a Phototoxicity Testing Strategy for Accurate Photosafety Evaluation of Pharmaceuticals Based on the Assessment of Possible Melanin-Binding Effects vol.37, pp.4, 2018, https://doi.org/10.1177/1091581818777998
  5. The potent pro-oxidant activity of rhododendrol-eumelanin is enhanced by ultraviolet A radiation vol.31, pp.4, 2018, https://doi.org/10.1111/pcmr.12696