Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Mechanisms of Resorcinol Antagonism of Benzo[a]pyrene-Induced Damage to Human Keratinocytes

  • Lee, Seung Eun (Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University) ;
  • Kwon, Kitae (Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University) ;
  • Oh, Sae Woong (Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University) ;
  • Park, Se Jung (Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University) ;
  • Yu, Eunbi (Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University) ;
  • Kim, Hyeyoun (Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University) ;
  • Yang, Seyoung (Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University) ;
  • Park, Jung Yoen (Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University) ;
  • Chung, Woo-Jae (Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University) ;
  • Cho, Jae Youl (Molecular Immunology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University) ;
  • Lee, Jongsung (Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University)
  • Received : 2020.05.12
  • Accepted : 2020.07.13
  • Published : 2021.03.01
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Abstract

Benzo[a]pyrene (B[a]P) is a polycyclic aromatic hydrocarbon and ubiquitous environmental toxin with known harmful effects to human health. Abnormal phenotypes of keratinocytes are closely associated with their exposure to B[a]P. Resorcinol is a component of argan oil with reported anticancer activities, but its mechanism of action and potential effect on B[a]P damage to the skin is unknown. In this study, we investigated the effects of resorcinol on B[a]P-induced abnormal keratinocyte biology and its mechanisms of action in human epidermal keratinocyte cell line HaCaT. Resorcinol suppressed aryl hydrocarbon receptor (AhR) activity as evidenced by the inhibition of B[a]P-induced xenobiotic response element (XRE)-reporter activation and cytochrome P450 1A1 (CYP1A1) expression. In addition, resorcinol attenuated B[a]P-induced nuclear translocation of AhR, and production of ROS and pro-inflammatory cytokines. We also found that resorcinol increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activity. Antioxidant response element (ARE)-reporter activity and expression of ARE-dependent genes NAD(P)H dehydrogenase [quinone] 1 (NQO1), heme oxygenase-1 (HO-1) were increased by resorcinol. Consistently, resorcinol treatment induced nuclear localization of Nrf2 as seen by Western analysis. Knockdown of Nrf2 attenuated the resorcinol effects on ARE signaling, but knockdown of AhR did not affect resorcinol activation of Nrf2. This suggests that activation of antioxidant activity by resorcinol is not mediated by AhR. These results indicate that resorcinol is protective against effects of B[a]P exposure. The mechanism of action of resorcinol is inhibition of AhR and activation of Nrf2-mediated antioxidant signaling. Our findings suggest that resorcinol may have potential as a protective agent against B[a]P-containing pollutants.

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References

  1. Beamish, L. A., Osornio-Vargas, A. R. and Wine, E. (2011) Air pollution: an environmental factor contributing to intestinal disease. J. Crohns Colitis 5, 279-286. https://doi.org/10.1016/j.crohns.2011.02.017
  2. Beischlag, T. V., Luis Morales, J., Hollingshead, B. D. and Perdew, G. H. (2008) The aryl hydrocarbon receptor complex and the control of gene expression. Crit. Rev. Eukaryot. Gene Expr. 18, 207-250. https://doi.org/10.1615/CritRevEukarGeneExpr.v18.i3.20
  3. Bellezza, I., Giambanco, I., Minelli, A. and Donato, R. (2018) Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim. Biophys. Acta Mol. Cell Res. 1865, 721-733. https://doi.org/10.1016/j.bbamcr.2018.02.010
  4. Charrouf, Z. and Guillaume, D. (2008) Argan oil: occurrence, composition and impact on human health. Eur. J. Lipid Sci. Technol. 110, 632-636. https://doi.org/10.1002/ejlt.200700220
  5. Choi, C. Y., Kim, J. Y., Wee, S. Y., Lee, J. H., Nam, D. H., Kim, C. H., Cho, M. K., Lee, Y. J., Nam, H. S., Lee, S. H. and Cho, S. W. (2014) Expression of nuclear factor erythroid 2 protein in malignant cutaneous tumors. Arch. Plast. Surg. 41, 654-660. https://doi.org/10.5999/aps.2014.41.6.654
  6. Dietrich, C. (2016) Antioxidant functions of the aryl hydrocarbon receptor. Stem Cells Int. 2016, 7943495. https://doi.org/10.1155/2016/7943495
  7. Fujii-Kuriyama, Y. and Mimura, J. (2005) Molecular mechanisms of AhR functions in the regulation of cytochrome P450 genes. Biochem. Biophys. Res. Commun. 338, 311-317. https://doi.org/10.1016/j.bbrc.2005.08.162
  8. Furue, M., Fuyuno, Y., Mitoma, C., Uchi, H. and Tsuji, G. (2018) Therapeutic agents with ahr inhibiting and NRF2 activating activity for managing chloracne. Antioxidants (Basel) 7, 90. https://doi.org/10.3390/antiox7070090
  9. Furue, M., Takahara, M., Nakahara, T. and Uchi, H. (2014) Role of AhR/ARNT system in skin homeostasis. Arch. Dermatol. Res. 306, 769-779. https://doi.org/10.1007/s00403-014-1481-7
  10. Furue, M., Uchi, H., Mitoma, C., Hashimoto-Hachiya, A., Chiba, T., Ito, T., Nakahara, T. and Tsuji, G. (2017) Antioxidants for healthy skin: the emerging role of aryl hydrocarbon receptors and nuclear factorerythroid 2-related factor-2. Nutrients 9, 223. https://doi.org/10.3390/nu9030223
  11. Hassan, A. M., Alam, S. S., Abdel-Aziem, S. H. and Ahmed, K. A. (2011) Benzo-a-pyrene induced genotoxicity and cytotoxicity in germ cells of mice: Intervention of radish and cress. J. Genet. Eng. Biotechnol. 9, 65-72. https://doi.org/10.1016/j.jgeb.2011.05.006
  12. Himejima, M. and Kubo, I. (1991) Antibacterial agents from the cashew Anacardium occidentale (Anacardiaceae) nut shell oil. J. Agric. Food Chem. 39, 418-421. https://doi.org/10.1021/jf00002a039
  13. Hwang, Y. S., Park, S. H., Kang, M., Oh, S. W., Jung, K., Park, Y. S. and Lee, J. (2017) Stemness and differentiation potential-recovery effects of sinapic acid against ultraviolet-A-induced damage through the regulation of p38 MAPK and NF-kappaB. Sci. Rep. 7, 909. https://doi.org/10.1038/s41598-017-01089-5
  14. Kang, M., Park, S. H., Oh, S. W., Lee, S. E., Yoo, J. A., Nho, Y. H., Lee, S., Han, B. S., Cho, J. Y. and Lee, J. (2018) Anti-melanogenic effects of resorcinol are mediated by suppression of cAMP signaling and activation of p38 MAPK signaling. Biosci. Biotechnol. Biochem. 82, 1188-1196. https://doi.org/10.1080/09168451.2018.1459176
  15. Kang, M., Park, S. H., Park, S. J., Oh, S. W., Yoo, J. A., Kwon, K., Kim, J., Yu, E., Cho, J. Y. and Lee, J. (2019) p44/42 MAPK signaling is a prime target activated by phenylethyl resorcinol in its anti-melanogenic action. Phytomedicine 58, 152877. https://doi.org/10.1016/j.phymed.2019.152877
  16. Kawachi, Y., Xu, X., Taguchi, S., Sakurai, H., Nakamura, Y., Ishii, Y., Fujisawa, Y., Furuta, J., Takahashi, T., Itoh, K., Yamamoto, M., Yamazaki, F. and Otsuka, F. (2008) Attenuation of UVB-induced sunburn reaction and oxidative DNA damage with no alterations in UVB-induced skin carcinogenesis in Nrf2 gene-deficient mice. J. Invest. Dermatol. 128, 1773-1779. https://doi.org/10.1038/sj.jid.5701245
  17. Kerins, M. J. and Ooi, A. (2018) A catalogue of somatic NRF2 gain-of-function mutations in cancer. Sci. Rep. 8, 12846. https://doi.org/10.1038/s41598-018-31281-0
  18. Kim, J., Cha, Y. N. and Surh, Y. J. (2010) A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutat. Res. 690, 12-23. https://doi.org/10.1016/j.mrfmmm.2009.09.007
  19. Lee, K. K., Miller, M. R. and Shah, A. S. V. (2018) Air pollution and stroke. J. Stroke 20, 2-11. https://doi.org/10.5853/jos.2017.02894
  20. Li, L., Dong, H., Song, E., Xu, X., Liu, L. and Song, Y. (2014) Nrf2/ARE pathway activation, HO-1 and NQO1 induction by polychlorinated biphenyl quinone is associated with reactive oxygen species and PI3K/AKT signaling. Chem. Biol. Interact. 209, 56-67. https://doi.org/10.1016/j.cbi.2013.12.005
  21. Mancebo, S. E. and Wang, S. Q. (2015) Recognizing the impact of ambient air pollution on skin health. J. Eur. Acad. Dermatol. Venereol. 29, 2326-2332. https://doi.org/10.1111/jdv.13250
  22. Manfredi, S., Federici, C., Picano, E., Botto, N., Rizza, A. and Andreassi, M. G. (2007) GSTM1, GSTT1 and CYP1A1 detoxification gene polymorphisms and susceptibility to smoking-related coronary artery disease: a case-only study. Mutat. Res. 621, 106-112. https://doi.org/10.1016/j.mrfmmm.2007.02.014
  23. Manke, A., Wang, L. and Rojanasakul, Y. (2013) Mechanisms of nanoparticle-induced oxidative stress and toxicity. Biomed. Res. Int. 2013, 942916.
  24. Matysiak, J., Karpinska, M. M., Skrzypek, A., Wietrzyk, J., Klopotowska, D., Niewiadomy, A., Paw, B., Juszczak, M. and Rzeski, W. (2015) Design, synthesis and antiproliferative activity against human cancer cell lines of novel benzo-, benzofuro-, azolo- and thieno-1,3-thiazinone resorcinol hybrids. Arab. J. Chem. doi: 10.1016/j.arabjc.2015.05.006.
  25. Murai, M., Tsuji, G., Hashimoto-Hachiya, A., Kawakami, Y., Furue, M. and Mitoma, C. (2018) An endogenous tryptophan photo-product, FICZ, is potentially involved in photo-aging by reducing TGF-beta-regulated collagen homeostasis. J. Dermatol. Sci. 89, 19-26. https://doi.org/10.1016/j.jdermsci.2017.10.002
  26. Nguyen, T., Nioi, P. and Pickett, C. B. (2009) The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J. Biol. Chem. 284, 13291-13295. https://doi.org/10.1074/jbc.R900010200
  27. Shin, S., Wakabayashi, N., Misra, V., Biswal, S., Lee, G. H., Agoston, E. S., Yamamoto, M. and Kensler, T. W. (2007) NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis. Mol. Cell. Biol. 27, 7188-7197. https://doi.org/10.1128/MCB.00915-07
  28. Stejskalova, L., Dvorak, Z. and Pavek, P. (2011) Endogenous and exogenous ligands of aryl hydrocarbon receptor: current state of art. Curr. Drug Metab. 12, 198-212. https://doi.org/10.2174/138920011795016818
  29. Tsuji, G., Takahara, M., Uchi, H., Takeuchi, S., Mitoma, C., Moroi, Y., and Furue, M. (2011) An environmental contaminant, benzo(a)pyrene, induces oxidative stress-mediated interleukin-8 production in human keratinocytes via the aryl hydrocarbon receptor signaling pathway. J. Dermatol. Sci. 62, 42-49. https://doi.org/10.1016/j.jdermsci.2010.10.017
  30. Velichkova, M. and Hasson, T. (2005) Keap1 regulates the oxidation-sensitive shuttling of Nrf2 into and out of the nucleus via a Crm1-dependent nuclear export mechanism. Mol. Cell. Biol. 25, 4501-4513. https://doi.org/10.1128/MCB.25.11.4501-4513.2005