title: The Tryptophan-Derived Endogenous Aryl Hydrocarbon Receptor Ligand 6-Formylindolo[3,2-b]Carbazole Is a Nanomolar UVA Photosensitizer in Epidermal Keratinocytes.
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.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy & Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Sophia L
authors.initials: SL
authors.lastname: Park
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy & Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Justiniano
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy & Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Williams
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy & Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Cabello
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy & Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Shuxi
authors.initials: S
authors.lastname: Qiao
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy & Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Georg T
authors.initials: GT
authors.lastname: Wondrak
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D002227:Carbazoles / Q000737:chemistry*; D002460:Cell Line; D004247:DNA / Q000737:chemistry; D045647:DNA Glycosylases / Q000378:metabolism; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000187:drug effects* / Q000528:radiation effects*; D008024:Ligands; D051379:Mice; D018384:Oxidative Stress; D010778:Photochemotherapy / Q000379:methods; D017319:Photosensitizing Agents / Q000737:chemistry*; D016133:Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000737:chemistry; D012867:Skin / Q000187:drug effects* / Q000528:radiation effects*; D014364:Tryptophan / Q000737:chemistry*
chemical_list: C111855:6-formylindolo(3,2-b)carbazole; D000975:Antioxidants; D002227:Carbazoles; D008024:Ligands; D017319:Photosensitizing Agents; D018336:Receptors, Aryl Hydrocarbon; D014364:Tryptophan; D004247:DNA; D045647:DNA Glycosylases