131 Enzymatically-derived hydroxy-lumisterols regulate epidermal keratinocytes and act as agonists on the aryl hydrocarbon receptor (AhR)

We recently discovered pathways of lumisterol (L3) activation by CYP11A1 and CYP27A1, with resulting CYP11A1-derived hydroxymetabolites being detectable in the human serum epidermis. hydroxylumisterols induced keratinocyte differentiation photoprotective actions against UVB. In follow-up studies we detected hydroxyproducts CYP27A1 action on L3, 25(OH)L3, 25R27(OH)L3 25S27(OH)L3, epidermal keratinocytes serum. They inhibited cell proliferation stimulated differentiation. Previously made unexpected discovery that vitamin D3 hydroxyderivatives act as ligands for AhR. Therefore, investigated possible interactions both Molecular docking using crystal structures ligand binding domains (LBDs) AhR revealed high scores L3 were even better than their natural ligands, predicting tight L3-derivatives to receptor. Functional a reporter assay system marked series L3-hydroxyderivatives. Finally, L3-hydroxyderivatives expression CYP1A1 CYP1B1 genes, which are downstream targets signaling pathway. These results consistent translocation from cytoplasm nucleus. dynamics simulations predicted derivatives conformational changes could mediate AhR-dependent signaling. Thus, these not only challenges existing dogmas is biologically inactive, but together our identification AhR, they open new possibilities regulation barrier functions nuclear receptor general.