The tryptophan-derived endogenous aryl hydrocarbon receptor ligand 6-formylindolo[3,2-b]carbazole is a nanomolar UVA photosensitizer in epidermal keratinocytes

Sophia L. Park, Rebecca Justiniano, Joshua D. Williams, Christopher M. Cabello, Shuxi Qiao, Georg T Wondrak

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1649-1658
Number of pages10
JournalJournal of Investigative Dermatology
Volume135
Issue number6
DOIs
StatePublished - Jan 1 2015

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Aryl Hydrocarbon Receptors
Oxidative stress
Photosensitizing Agents
Keratinocytes
Tryptophan
Oxidative Stress
Ligands
Skin
Chromophores
DNA-Formamidopyrimidine Glycosylase
Phototoxic Dermatitis
Photosensitivity Disorders
Endoplasmic Reticulum Stress
Cell death
Gene expression
Shock
Cell Death
Antioxidants
Hot Temperature
Tissue

ASJC Scopus subject areas

  • Dermatology
  • Biochemistry
  • Cell Biology
  • Molecular Biology

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The tryptophan-derived endogenous aryl hydrocarbon receptor ligand 6-formylindolo[3,2-b]carbazole is a nanomolar UVA photosensitizer in epidermal keratinocytes. / Park, Sophia L.; Justiniano, Rebecca; Williams, Joshua D.; Cabello, Christopher M.; Qiao, Shuxi; Wondrak, Georg T.

In: Journal of Investigative Dermatology, Vol. 135, No. 6, 01.01.2015, p. 1649-1658.

Research output: Contribution to journalArticle

Park, Sophia L. ; Justiniano, Rebecca ; Williams, Joshua D. ; Cabello, Christopher M. ; Qiao, Shuxi ; Wondrak, Georg T. / The tryptophan-derived endogenous aryl hydrocarbon receptor ligand 6-formylindolo[3,2-b]carbazole is a nanomolar UVA photosensitizer in epidermal keratinocytes. In: Journal of Investigative Dermatology. 2015 ; Vol. 135, No. 6. pp. 1649-1658.
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