The objective of this research project is to elucidate the photochemical and photobiological mechanisms whereby light (UVA and visible radiation) alone or in the presence of endogenous or exogenous photosensitizers exerts either toxic or therapeutic effects. UVA-induced apoptosis in keratinocytes is associated with a decrease in intracellular GSH and a concomitant increase in extracellular GSH produced by GSH efflux. We have used microarray technology to determine changes in gene expression in HaCaT human keratinocytes after UVA treatment. We have found in human HaCaT keratinocytes that exposure to UVA induces the EGF receptor internalization and down-regulation without receptor phosphorylation and ubiquitination. Berberine, the active constituent of the herbal medicine Goldenseal, commonly used in lotions and eyewashes, kills keratinocytes and damages DNA upon UV radiation. Juglone (5-hydroxy-1,4-naphthoquinone), found in herbal skin and hair products derived from Black Walnut, is metabolized by keratinocytes to a semiquinone free radical which reacts with oxygen to generate superoxide and the hydroxyl radical. 7-Dehydrocholesterol sensitizes keratinocytes to UVA and is probably responsible for the photosensitivity of Smith-Lemli-Opitz syndrome (SLOS) patients. A2E, a lipid degradation product found in lipofuscin granules deposited in the retina, is photoprotective in the young eye but may be phototoxic in older eyes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES050046-25
Application #
6838355
Study Section
(LPC)
Project Start
Project End
Budget Start
Budget End
Support Year
25
Fiscal Year
2003
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Wiechmann, Allan F; Chignell, Colin F; Roberts, Joan E (2008) Influence of dietary melatonin on photoreceptor survival in the rat retina: an ocular toxicity study. Exp Eye Res 86:241-50
Roberts, Joan E; Wielgus, Albert R; Boyes, William K et al. (2008) Phototoxicity and cytotoxicity of fullerol in human lens epithelial cells. Toxicol Appl Pharmacol 228:49-58
He, Yu-Ying; Council, Sarah E; Feng, Li et al. (2008) UVA-induced cell cycle progression is mediated by a disintegrin and metalloprotease/epidermal growth factor receptor/AKT/Cyclin D1 pathways in keratinocytes. Cancer Res 68:3752-8
Chignell, C F; Han, S-K; Mouithys-Mickalad, A et al. (2008) EPR studies of in vivo radical production by 3,3',5,5'-tetrabromobisphenol A (TBBPA) in the Sprague-Dawley rat. Toxicol Appl Pharmacol 230:17-22
He, Yu-Ying; Council, Sarah E; Feng, Li et al. (2008) Spatial distribution of protein damage by singlet oxygen in keratinocytes. Photochem Photobiol 84:69-74
Han, S K; Bilski, P; Karriker, B et al. (2008) Oxidation of flame retardant tetrabromobisphenol A by singlet oxygen. Environ Sci Technol 42:166-72
Chignell, Colin F; Sik, Robert H; Watson, Mary A et al. (2007) Photochemistry and photocytotoxicity of alkaloids from Goldenseal (Hydrastis canadensis L.) 3: effect on human lens and retinal pigment epithelial cells. Photochem Photobiol 83:938-43
Wielgus, Albert R; Chignell, Colin F; Miller, David S et al. (2007) Phototoxicity in human retinal pigment epithelial cells promoted by hypericin, a component of St. John's wort. Photochem Photobiol 83:706-13
He, Y-Y; Pi, J; Huang, J-L et al. (2006) Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance. Oncogene 25:3680-8
Matsumoto, Ken-ichiro; Kawai, Sayo; Chignell, Colin F et al. (2006) Location of anthralin radical generation in mouse skin by UV-A irradiation: an estimation using microscopic EPR spectral-spatial imaging. Magn Reson Med 55:738-42

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