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

Tongkao-on, Wannit; Carter, Sally; Reeve, Vivienne E.; Dixon, Katie M.; Gordon-Thomson, Clare; Halliday, Gary M.; Tuckey, Robert C.; Mason, Rebecca S.

doi:10.1016/j.jsbmb.2014.11.015

Cited by 59 publications

(57 citation statements)

References 65 publications

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“…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].…”

Section: Biological Activity Of Cyp11a1-derived Vitamin D Hydroxydmentioning

confidence: 99%

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

Slominski

Kim²,

Hobrath

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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126

143

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The classical pathway of vitamin D activation follows the sequence D3→25(OH)D3→1,25(OH)2D3 with the final product acting on the receptor for vitamin D (VDR). An alternative pathway can be started by the action of CYP11A1 on the side chain of D3, primarily producing 20(OH)D3, 22(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3 and 17,20,23(OH)3D3. Some of these metabolites are hydroxylated by CYP27B1 at C1α, by CYP24A1 at C24 and C25, and by CYP27A1 at C25 and C26. The products of these pathways are biologically active. In the epidermis and/or serum or adrenals we detected 20(OH)D3, 22(OH)D3, 20,22(OH)2D3, 20,23(OH)2D3, 17,20,23(OH)3D3, 1,20(OH)2D3, 1,20,23(OH)3D3, 1,20,22(OH)3D3, 20,24(OH)2D3, 1,20,24(OH)3D3, 20,25(OH)2D3, 1,20,25(OH)3D3, 20,26(OH)2D3 and 1,20,26(OH)3D3. 20(OH)D3 and 20,23(OH)2D3 are non-calcemic, while the addition of an OH at C1α confers some calcemic activity. Molecular modeling and functional assays show that the major products of the pathway can act as “biased” agonists for the VDR with high docking scores to the ligand binding domain (LBD), but lower than that of 1,25(OH)2D3. Importantly, cell based functional receptor studies and molecular modeling have identified the novel secosteroids as inverse agonists of both RORα and RORγ receptors. Specifically, they have high docking scores using crystal structures of RORα and RORγ LBDs. Furthermore, 20(OH)D3 and 20,23(OH)2D3 have been tested in cell model that expresses a Tet-on RORα or RORγ vector and a RORE-LUC reporter (ROR-responsive element), and in a mammalian 2-hybrid model that test interactions between an LBD-interacting LXXLL-peptide and the LBD of RORα/γ. These assays demonstrated that the novel secosteroids have ROR-antagonist activities that were further confirmed by the inhibition of IL17 promoter activity in cells overexpressing RORα/γ. In conclusion, endogenously produced novel D3 hydroxy-derivatives can act both as “biased” agonists of the VDR and/or inverse agonists of RORα/γ. We suggest that the identification of large number of endogenously produced alternative hydroxy-metabolites of D3 that are biologically active, and of possible alternative receptors, may offer an explanation for the pleiotropic and diverse activities of vitamin D, previously assigned solely to 1,25(OH)2D3 and VDR.

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Section: Biological Activity Of Cyp11a1-derived Vitamin D Hydroxydmentioning

confidence: 99%

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

Slominski

Kim²,

Hobrath

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

Self Cite

126

143

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“…In addition, both 20(OH)D3 and 20,23(OH) 2 D3 possess anti-fibrotic properties on human dermal fibroblasts isolated from scleroderma and normal subjects [26]. In rodent models, administration of 20(OH)D3 has been found to be effective in reducing the symptoms of scleroderma [26] and rheumatoid arthritis [16] as well as protecting DNA in skin from damage caused by UV irradiation [30]. Importantly, unlike 1,25(OH) 2 D3, both 20(OH)D3 and 20,23(OH) 2 D3 are noncalcemic in rodents at high concentrations [25, 26, 31].…”

Section: Introductionmentioning

confidence: 99%

Metabolism of 20-hydroxyvitamin D3 and 20,23-dihydroxyvitamin D3 by rat and human CYP24A1

Tieu

Chen

et al. 2015

The Journal of Steroid Biochemistry and Molecular Biology

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CYP11A1 hydroxylates vitamin D3 producing 20S-hydroxyvitamin D3 [20(OH)D3] and 20S,23-dihydroxyvitamin D3 [20,23(OH)2D3] as the major and most characterized metabolites. Both display immuno-regulatory and anti-cancer properties while being non-calcemic. A previous study indicated 20(OH)D3 can be metabolized by rat CYP24A1 to products including 20S,24-dihydroxyvitamin D3 [20,24(OH)2D3] and 20S,25-dihydroxyvitamin D3, with both producing greater inhibition of melanoma colony formation than 20(OH)D3. The aim of this study was to characterize the ability of rat and human CYP24A1 to metabolize 20(OH)D3 and 20,23(OH)2D3. Both isoforms metabolized 20(OH)D3 to the same dihydroxyvitamin D species with no secondary metabolites being observed. Hydroxylation at C24 produced both enantiomers of 20,24(OH)2D3. For rat CYP24A1 the preferred initial site of hydroxylation was at C24 whereas the human enzyme preferred C25. 20,23(OH)2D3 was initially metabolized to 20S,23,24-trihydroxyvitamin D3 and 20S,23,25-trihydroxyvitamin D3 by rat and human CYP24A1 as determined by NMR, with both isoforms showing a preference for initial hydroxylation at C25. CYP24A1 was able to further oxidize these metabolites in a series of reactions which included the cleavage of C23-C24 bond, as indicated by high resolution mass spectrometry of the products, analogous to the catabolism of 1,25(OH)2D3 via the C24-oxidation pathway. Similar catalytic efficiencies were observed for the metabolism of 20(OH)D3 and 20,23(OH)2D3 by human CYP24A1 and were lower than for the metabolism of 1,25(OH)2D3. We conclude that rat and human CYP24A1 metabolizes 20(OH)D3 producing only dihydroxyvitamin D3 species as products which retain biological activity, whereas 20,23(OH)2D3 undergoes multiple oxidations which include cleavage of the side chain.

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“…Recent data indicate that biologically active forms of vitamin D 3 play an important role in protection against DNA damage [21, 58, 59] and UVB-induced carcinogenesis in the epidermis [60–63]. These protective effects are also seen for the novel, CYP11A1-derived hydroxy-derivatives of vitamin D as demonstrated in human epidermal cells [21], and mouse skin in vivo [64]. Since the predominant effect of UVA irradiation, which has no effect on cutaneous vitamin D production, is to generate reactive oxygen species (ROS), active forms of vitamin D may accelerate elimination of cells with neoplastic potential induced by ROS, which would be consistent with their role as protectors of epidermal integrity [65].…”

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confidence: 99%

Vitamin D derivatives enhance cytotoxic effects of H2O2 or cisplatin on human keratinocytes

et al. 2016

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Although the skin production of vitamin D is initiated by ultraviolet radiation type B (UVB), the role vitamin D plays in antioxidative or pro-oxidative responses remains to be elucidated.. We have used immortalized human HaCaT keratinocytes as a model of proliferating epidermal cells to test the influence of vitamin D on cellular response to H2O2 or the anti-cancer drug, cisplatin. Incubation of keratinocytes with 1,25(OH)2D3 or its low calcemic analogues, 20(OH)D3, 21(OH)pD or calcipotriol, sensitized cells to ROS resulting in more potent inhibition of keratinocyte proliferation by H2O2 in the presence of vitamin D compounds. These results were supported by cell cycle and apoptosis analyses, and measurement of the mitochondrial transmembrane potentials (MMP), however some unique properties of individual secosteroids were observed. Furthermore, in HaCaT keratinocytes treated with H2O2, 1,25(OH)2D3, 21(OH)pD and calcipotriol stimulated the expression of SOD1 and CAT genes, but not SOD2, indicating a possible role of mitochondria in ROS-modulated cell death. 1,25(OH)2D3 also showed a short-term, protective effect on HaCaT keratinocytes, as exemplified by the inhibition of apoptosis and the maintenance of MMP. However, with prolonged incubation with H2O2 or cisplatin, 1,25(OH)2D3 caused an acceleration in the death of the keratinocytes. Therefore, we propose that lead vitamin D derivatives can protect the epidermis against neoplastic transformation secondary to oxidative or UV-induced stress through activation of vitamin D-signaling. Furthermore, our data suggest that treatment with low calcemic vitamin D analogs or the maintenance of optimal level of vitamin D by proper supplementation, can enhance the anticancer efficacy of cisplatin

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

Cited by 59 publications

References 65 publications

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

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

Metabolism of 20-hydroxyvitamin D3 and 20,23-dihydroxyvitamin D3 by rat and human CYP24A1

Vitamin D derivatives enhance cytotoxic effects of H2O2 or cisplatin on human keratinocytes

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