title: 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 defense 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. This article is part of a special issue entitled '17th Vitamin D Workshop'.
authors.affiliation: Department of Pathology and Laboratory Medicine, Cancer Research Building, University of Tennessee HSC, Memphis, TN, USA; Department of Dermatology, University of Alabama Birmingham, Birmingham, AL 35294, USA. Electronic address: aslominski@uthsc.edu.
authors.forename: Andrzej T
authors.initials: AT
authors.lastname: Slominski
authors.affiliation: Department of Pathology and Laboratory Medicine, Cancer Research Building, University of Tennessee HSC, Memphis, TN, USA.
authors.forename: Zorica
authors.initials: Z
authors.lastname: Janjetovic
authors.affiliation: Department of Pathology and Laboratory Medicine, Cancer Research Building, University of Tennessee HSC, Memphis, TN, USA.
authors.forename: Tae-Kang
authors.initials: TK
authors.lastname: Kim
authors.affiliation: Department of Pathology and Laboratory Medicine, Cancer Research Building, University of Tennessee HSC, Memphis, TN, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Wasilewski
authors.affiliation: Department of Pathology and Laboratory Medicine, Cancer Research Building, University of Tennessee HSC, Memphis, TN, USA.
authors.forename: Sofia
authors.initials: S
authors.lastname: Rosas
authors.affiliation: Department of Pathology and Laboratory Medicine, Cancer Research Building, University of Tennessee HSC, Memphis, TN, USA.
authors.forename: Sherie
authors.initials: S
authors.lastname: Hanna
authors.affiliation: Rapid Precision Testing Laboratories, Cordova, TN, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sayre
authors.affiliation: Rapid Precision Testing Laboratories, Cordova, TN, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Dowdy
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee HSC, Memphis, TN, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA, Australia.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Tuckey
mesh_terms: D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects* / Q000528:radiation effects; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism* / Q000528:radiation effects; D006801:Humans; D006934:Hypercalcemia / Q000209:etiology / Q000517:prevention & control*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects; D018384:Oxidative Stress / Q000187:drug effects* / Q000528:radiation effects; D012632:Secosteroids / Q000494:pharmacology*; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D012632:Secosteroids
keywords: DNA damage; Epidermal keratinocytes; Epidermal melanocytes; Hydroxyvitamin D; Oxidative stress; UVB