The Tryptophan-Derived Endogenous Aryl Hydrocarbon Receptor Ligand 6-Formylindolo[3,2-b]Carbazole Is a Nanomolar UVA Photosensitizer in Epidermal Keratinocytes

Endogenous UVA chromophores may act as sensitizers of oxidative stress underlying cutaneous photoaging and photocarcinogenesis, but the molecular identity of non-DNA key chromophores displaying UVA-driven photodyamic activity in human skin remains largely undefined. Here we report that 6-formylindol...

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Bibliographic Details
Published in:Journal of investigative dermatology 2015-06, Vol.135 (6), p.1649-1658
Main Authors: Park, Sophia L., Justiniano, Rebecca, Williams, Joshua D., Cabello, Christopher M., Qiao, Shuxi, Wondrak, Georg T.
Format: Article
Language:English
Subjects:
Animals
Antioxidants - chemistry
Carbazoles - chemistry
Cell Line
DNA - chemistry
DNA Glycosylases - metabolism
Epidermis - drug effects
Epidermis - metabolism
Epidermis - radiation effects
Female
Gene Expression Regulation
Humans
Immunohistochemistry
Keratinocytes - drug effects
Keratinocytes - radiation effects
Ligands
Mice
Oxidative Stress
Photochemotherapy - methods
Photosensitizing Agents - chemistry
Polymerase Chain Reaction
Receptors, Aryl Hydrocarbon - chemistry
Skin - drug effects
Skin - radiation effects
Tryptophan - chemistry
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Summary:Endogenous UVA chromophores may act as sensitizers of oxidative stress underlying cutaneous photoaging and photocarcinogenesis, but the molecular identity of non-DNA key chromophores displaying UVA-driven photodyamic activity in human skin remains largely undefined. Here we report that 6-formylindolo[3,2-b]carbazole (FICZ), a tryptophan photoproduct and endogenous high-affinity aryl hydrocarbon receptor (AhR) agonist, acts as a nanomolar photosensitizer potentiating UVA-induced oxidative stress irrespective of AhR ligand activity. In human HaCaT and primary epidermal keratinocytes, photodynamic induction of apoptosis was elicited by the combined action of solar-simulated UVA and FICZ, whereas exposure to the isolated action of UVA or FICZ did not impair viability. In a human epidermal tissue reconstruct, FICZ/UVA cotreatment caused pronounced phototoxicity inducing keratinocyte cell death, and FICZ photodynamic activity was also substantiated in a murine skin exposure model. Array analysis revealed pronounced potentiation of cellular heat shock, endoplasmic reticulum stress, and oxidative stress response gene expression observed only upon FICZ/UVA cotreatment. FICZ photosensitization caused intracellular oxidative stress, and comet analysis revealed introduction of formamidopyrimidine-DNA glycosylase (Fpg)-sensitive oxidative DNA lesions suppressible by antioxidant cotreatment. Taken together, our data demonstrate that the endogenous AhR ligand FICZ displays nanomolar photodynamic activity representing a molecular mechanism of UVA-induced photooxidative stress potentially operative in human skin.
ISSN:0022-202X
1523-1747
DOI:10.1038/jid.2014.503