title: 1,25-Dihydroxyvitamin D and three low-calcemic analogs decrease UV-induced DNA damage via the rapid response pathway.
abstract: 1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] is anti-apoptotic in human keratinocytes, melanocytes and fibroblasts after ultraviolet (UV)-exposure. To date, there is no published data on the effects of 1,25(OH)(2)D(3) or its analogs on DNA damage in irradiated skin cells. In these skin cells, 24h pre-treatment with 1,25(OH)(2)D(3) dose-dependently (10(-12) to 10(-8)M) decreased CPD damage by up to 60%. This photoprotective effect was also seen if the 1,25(OH)(2)D(3) was added immediately after irradiation and was mimicked by QW-1624F2-2 (QW), a low-calcemic 1beta-hydroxymethyl-3-epi-16-ene-24,24-difluoro-26,27-bis homo hybrid analog. The well-studied low calcemic, rapid acting agonist analogs 1alpha,25(OH)(2)lumisterol(3) (JN) and 1alpha,25(OH)(2)-7-dehydrocholesterol (JM) also protected skin cells from UV-induced cell loss and CPD damage to an extent comparable with that of 1,25(OH)(2)D(3). In contrast, the rapid response antagonist analog 1beta,25(OH)(2)D(3) (HL) completely abolished the photoprotective effects (reduced cell loss and reduced CPD damage) produced by treatment with 1,25(OH)(2)D(3), JN, JM and QW. Evidence for involvement of the nitric oxide pathway in the protection from CPD damage by 1,25(OH)(2)D(3) was obtained. These data provide further evidence for a role of the vitamin D pathway in the intrinsic skin defenses against UV damage. The data also support the hypothesis that the photoprotective effects of 1,25(OH)(2)D(3) are mediated via the rapid response pathway(s).
authors.affiliation: Department of Physiology and Institute for Biomedical Research, School of Biomedical Sciences, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Wong
authors.forename: R
authors.initials: R
authors.lastname: Gupta
authors.forename: K M
authors.initials: KM
authors.lastname: Dixon
authors.forename: S S
authors.initials: SS
authors.lastname: Deo
authors.forename: S M
authors.initials: SM
authors.lastname: Choong
authors.forename: G M
authors.initials: GM
authors.lastname: Halliday
authors.forename: J E
authors.initials: JE
authors.lastname: Bishop
authors.forename: S
authors.initials: S
authors.lastname: Ishizuka
authors.forename: A W
authors.initials: AW
authors.lastname: Norman
authors.forename: G H
authors.initials: GH
authors.lastname: Posner
authors.forename: R S
authors.initials: RS
authors.lastname: Mason
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects*; D006801:Humans; D014466:Ultraviolet Rays; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D