title: CYP11A1 in skin: an alternative route to photoprotection by vitamin D compounds.
abstract: Topical 1,25-dihydroxyvitamin D (1,25D) and other vitamin D compounds have been shown to protect skin from damage by ultraviolet radiation (UVR) in a process that requires the vitamin D receptor. Yet, while mice which do not express the vitamin D receptor are more susceptible to photocarcinogenesis, mice unable to 1α-hydroxylate 25-hydroxyvitamin D to form 1,25D do not show increased susceptibility to UVR-induced skin tumors. A possible explanation is that an alternative pathway, which does not involve 1α-hydroxylation, may produce photoprotective compounds from vitamin D. The cholesterol side chain cleavage enzyme CYP11A1 is expressed in skin and produces 20-hydroxyvitamin D3 (20OHD) as a major product of vitamin D3. We examined whether topical 20OHD would affect UVR-induced DNA damage, inflammatory edema or immune suppression produced in Skh:hr1 mice. Photoprotection by 20OHD at 23 or 46pmol/cm(2) against cyclobutane pyrimidine dimers (DNA lesions) after UVR in mice was highly effective, up to 98±0.8%, (p<0.001) and comparable to that of 1,25D. Sunburn edema measured as skinfold thickness 24h after UVR was also significantly reduced by 20OHD (p<0.001). In studies of contact hypersensitivity (CHS), which is suppressed by UVR, topical application of 20OHD to mice protected against UVR-induced immunosuppression (p<0.05), similar to the effect of 1,25D at similar doses (46±0.6% protection with 20OHD, 44±0.5% with 1,25D). Both UVR-induced DNA damage and immunosuppression contribute to increased susceptibility to UVR-induced skin tumors. This study indicates a potentially anti-photocarcinogenic role of the naturally occurring vitamin D metabolite, 20OHD, which does not depend on 1α-hydroxylation for generation. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.
authors.affiliation: School of Medical Sciences and the Bosch Institute, University of Sydney, NSW, Australia.
authors.forename: Wannit
authors.initials: W
authors.lastname: Tongkao-On
authors.affiliation: School of Medical Sciences and the Bosch Institute, University of Sydney, NSW, Australia.
authors.forename: Sally
authors.initials: S
authors.lastname: Carter
authors.affiliation: Faculty of Veterinary Science, University of Sydney, NSW, Australia.
authors.forename: Vivienne E
authors.initials: VE
authors.lastname: Reeve
authors.affiliation: School of Medical Sciences and the Bosch Institute, University of Sydney, NSW, Australia.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Dixon
authors.affiliation: School of Medical Sciences and the Bosch Institute, University of Sydney, NSW, Australia.
authors.forename: Clare
authors.initials: C
authors.lastname: Gordon-Thomson
authors.affiliation: Dermatology and Bosch Institute, University of Sydney, NSW, Australia.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Halliday
authors.affiliation: School of Chemistry and Biochemistry, University of Western Australia, Crawley, WA, Australia.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Tuckey
authors.affiliation: School of Medical Sciences and the Bosch Institute, University of Sydney, NSW, Australia. Electronic address: rebeccam@physiol.usyd.edu.au.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Mason
mesh_terms: D000818:Animals; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism*; D006801:Humans; D051379:Mice; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D014466:Ultraviolet Rays / Q000009:adverse effects*; D014807:Vitamin D / Q000494:pharmacology*; D014815:Vitamins / Q000494:pharmacology*
chemical_list: D014815:Vitamins; D014807:Vitamin D; D002786:Cholesterol Side-Chain Cleavage Enzyme
keywords: 1α,25-Dihydroxyvitamin D(3); 20-Hydroxyvitamin D(3); CYP11A1; DNA damage; Photoprotection