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, ER 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.

The B6‐vitamer Pyridoxal is a Sensitizer of UVA‐induced Genotoxic Stress in Human Primary Keratinocytes and Reconstructed Epidermis

“…b). As documented before in HaCaT keratinocytes and other target cells exposed to B 6 ‐vitamers and UVA , an almost four‐fold increase in DCF fluorescence intensity was observed in HEKa cells, indicative of the generation of reactive species of sufficient longevity, such as protein peroxides , capable of oxidizing the indicator dye DCFH during cell loading after irradiation . Likewise, a significant depletion of the cellular reduced glutathione (GSH) pool by almost 20% was detectable 6 h after exposure, an effect consistent with treatment‐induced redox dysregulation confined to cells exposed to combined PL/UVA treatment (Fig.…”

Systemic administration of the apocarotenoid bixin protects skin against solar UV-induced damage through activation of NRF2

“…Irradiation with solar UV occurred as described before [38-40]. A KW large area light source solar simulator, model 91293, from Oriel Corporation (Stratford, CT) was used, equipped with a 1000 W Xenon arc lamp power supply, model 68920, and a VIS-IR bandpass blocking filter combined with an atmospheric attenuation filter (output 290-400 nm plus residual 650-800 nm).…”

“…Bixin cytotoxicity was assessed by flow cytometric analysis of annexinV/PI-stained cells using a commercial kit from Sigma (APO-AF, St. Louis, MO) as published before [40,42]. Bixin toxicity was also assessed examining functional impairment of mitochondria using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) standard assay [43].…”

Antifungal activity of selected Malassezia indolic compounds detected in culture

“…Among potential biological effects of these substances, preliminary data indicate that indirubin possesses some antifungal and antiparasitic activity, whilst it could also potentiate the antibacterial effect of ciprofloxacin against resistant S. aureus strains in vitro . Moreover, pityriacitrin has a small, yet measurable, sunlight protective factor (SPF: 1.7) at 5% concentration and FICZ is considered a candidate endogenous aryl‐hydrocarbon receptor (AhR) ligand and an ultraviolet damage mediator on human skin . Regarding indirubin, it mediates functions as inflammation and tumorigenesis and is currently suggested as a potent topical treatment for psoriasis .…”

“…13 Moreover, pityriacitrin has a small, yet measurable, sunlight protective factor (SPF: 1.7) at 5% concentration 14 and FICZ is considered a candidate endogenous aryl-hydrocarbon receptor (AhR) ligand and an ultraviolet damage mediator on human skin. 15 Regarding indirubin, it mediates functions as inflammation and tumorigenesis 16 and is currently suggested as a potent topical treatment for psoriasis. 17 The production of these ligands from L-tryptophan is not restricted to yeasts of the Malassezia genus but has also been described in the ascomycetous gastrointestinal truck commensal C. glabrata underscoring the wider biological significance of this pathway.…”