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

J Invest Dermatol. 2015 Jun;135(6):1649-1658. doi: 10.1038/jid.2014.503. Epub 2014 Nov 28.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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*

Substances

  • 6-formylindolo(3,2-b)carbazole
  • Antioxidants
  • Carbazoles
  • Ligands
  • Photosensitizing Agents
  • Receptors, Aryl Hydrocarbon
  • Tryptophan
  • DNA
  • DNA Glycosylases