Differential photoprotective effects of 1,25-dihydroxyvitamin D3 and a low calcaemic deltanoid.
We have previously demonstrated that the active vitamin D hormone, 1α,25-dihydroxyvitamin D3 (1,25(OH)(2)D(3)) and a cis-locked non-genomic analogue, protect skin cells from ultraviolet radiation (UV)-induced skin cell loss, DNA damage, immunosuppression and skin carcinogenesis. Herein, we used a low-calcaemic analogue, 1α-hydroxymethyl-16-ene-24,24-difluoro-25-hydroxy-26,27-bis-homovitamin D3 (QW), which has some transactivating capacity and is approximately 80-100 times less calcaemic than 1,25(OH)(2)D(3). QW (0.1-10 nM) significantly (p < 0.05-0.01) reduced UV-induced DNA lesions (CPD) in skin fibroblasts and keratinocytes and reduced cell death after UV exposure. Moreover, both 1,25(OH)(2)D(3) and QW (1 nM) were equally effective in significantly (p < 0.01) increasing levels of tumour suppressive p53 in cultured human keratinocytes at 3 and 6 h after UV exposure. In a hairless mouse model, both 1,25(OH)(2)D(3) and QW (22.8 ρmol cm(-2)) reduced UV-immunosuppression from 13.7 ± 1.3% to 0.1 ± 1.1% (p < 0.01) and 5.4 ± 1.5% (p < 0.01) respectively. When tested alongside 1,25(OH)(2)D(3) in a murine model of skin carcinogenesis. QW (22.8 ρmol cm(-2)) was not as effective as 1α,25(OH)(2)D(3) or a cis-locked analogue in reducing tumour formation or inhibiting tumour progression. It is possible that the dose required for QW to be effective as an anti-photocarcinogenesis agent in vivo is higher than for protection against the acute effects of UV exposure, but the dissociation between clear acute photo-protective effects and limited long term photoprotection is as yet unexplained.
Discipline of Physiology, Bosch Institute, School of Medical Sciences, University of Sydney, NSW, Australia.
Katie M
KM
Dixon
Vanessa B
VB
Sequeira
Shivashni S
SS
Deo
Ritu
R
Mohan
Gary H
GH
Posner
Rebecca S
RS
Mason
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007165:Immunosuppression Therapy; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D051379:Mice; D008812:Mice, Hairless; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects* / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays
C580739:1alpha-hydroxymethyl-16-ene-24,24-difluoro-25-hydroxy-26,27-bis-homovitamin D3; D011837:Radiation-Protective Agents; D016159:Tumor Suppressor Protein p53; D002117:Calcitriol