Novel non-calcemic secosteroids that are produced by human epidermal keratinocytes protect against solar radiation

Abstract

CYP11A1 hydroxylates the side chain of vitamin D3 (D3) in a sequential fashion [D3→20S(OH)D3→20,23(OH)2D3→ 17,20,23(OH)3D3], in an alternative to the classical pathway of activation [D3→25(OH)D3→1,25(OH)2D3]. The products/intermediates of the pathway can be further modified by the action of CYP27B1. The CYP11A1-derived products are biologically active with functions determined by the lineage of the target cells. This pathway can operate in epidermal keratinocytes. To further define the role of these novel secosteroids we tested them for protective effects against UVB-induced damage in human epidermal keratinocytes, melanocytes and HaCaT keratinocytes, cultured in vitro. The secosteroids attenuated ROS, H2O2 and NO production by UVB-irradiated keratinocytes and melanocytes, with an efficacy similar to 1,25(OH)2D3, while 25(OH)D3 had lower efficacy. These attenuations were also seen to some extent for the 20(OH)D3 precursor, 20S-hydroxy-7-dehydrocholesterol. These effects were accompanied by upregulation of genes encoding enzymes responsible for defence against oxidative stress. Using immunofluorescent staining we observed that the secosteroids reduced the generation cyclobutane pyrimidine dimers in response to UVB and enhanced expression of p53 phosphorylated at Ser-15, but not at Ser-46. Additional evidence for protection against DNA damage in cells exposed to UVB and treated with secosteroids was provided by the Comet assay where DNA fragmentation was markedly reduced by 20(OH)D3 and 20,23(OH)2D3. In conclusion, novel secosteroids that can be produced by the action of CYP11A1 in epidermal keratinocytes have protective effects against UVB radiation.

The α7 nicotinic acetylcholine receptor agonist tropisetron counteracts ultraviolet A‐mediated oxidative stress in human dermal fibroblasts

“…[8,9] It is thus fascinating to speculate on a protective role of the α7nAchR within the skin and of natural α7nAchR ligands that may act against the harmful effects of UVA. So far, acetylcholine has been identified as the only endogenous natural α7nAchR ligand which however binds to many other AchR subtypes besides α7nAchR.…”

CYP11A1 in skin: An alternative route to photoprotection by vitamin D compounds

“…20-Hydroxyvitamin D 3 (major product) and other novel hydroxyderivatives of vitamin D 3 have been detected in extracts of human skin by LC-MS, at relative levels similar to those of 25-hydroxyvitamin D and 1,25D. The actual concentration of 20OHD in human skin remains to be determined, as does any change to its concentration in response to UV radiation [39]. Endogenous production of 20OHD is supported by the detection of a peak by LC-MS in an extract of human serum with a mass and retention time the same as 20(OH)D, at a concentration of approximately 5% of that of 25OHD [40].…”

Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORα and RORγ

“…20(OH)D3 shows antifibrotic properties both in vitro [87–89] and in an in vivo mouse model of bleomycin induced scleroderma [89]. Most recently it was shown that both 20(OH)D3 and 20,23(OH) 2 D3 enhance defense mechanisms against UVB-induced oxidative stress and DNA damage in cultured human keratinocytes [23] and murine skin in vivo [22]. 20(OH)D3 and its hydroxymetabolites also show anti-cancer properties that are cell-lineage dependent [53, 54, 64, 68, 69, 88, 90, 92–97].…”

“…Most recently, it was reported that it can inhibit skin cell death and DNA damage induced by exposure to UVR [20–23]. Because of the toxic effect secondary to calcemia, the pharmacological use of 1,25(OH) 2 D3 is limited.…”