Influence of light on aryl hydrocarbon receptor signaling and consequences in drug metabolism, physiology and disease

Abstract

Introduction: A key to understanding the biological function(s) of the aryl hydrocarbon receptor (AHR) – a xenobiotic-activated receptor – is to identify its endogenous ligand(s). The discovery of a tryptophan photoproduct 6-formylindolo[3,2-b]carbazole (FICZ) as an endogenous, high affinity agonist of AHR filled this knowledge gap in the context of skin physiology and pathology in response to light and opened several new directions for research on AHR.Area covered: This paper reviews major developments in the study of light-elicited AHR signaling and its impact on drug metabolism, skin physiology and disease with a focus on the identification of AHR ligands from Trp photoproducts and the AHR-mediated UV response. This review consists of material obtained from Medline and PubMed literature searches up to May 2011.Expert opinion: The recognition of FICZ as a potent, endogenous ligand of AHR provided a molecular link between light exposure and AHR signaling and function. The uncovering of the bifurcated signaling pathway of AHR in the mammalian UV response – that is, activation of the cytoplasmic AHR by light via FICZ leads to: i) AHR/AH response element-dependent transcription to induce CYP1A1 and ii) activation of the AHR-pp60src-EGFR pathway to induce Cox-2 – put forward a working model for the multiple roles of AHR in skin function and disease that include drug metabolism, circadian oscillation, melanogenesis, inflammation, immunosuppression and cancer. Such findings suggest AHR as a therapeutic target for cancer, autoimmune dysfunction, inflammatory disease and stem cell therapy.