The mechanism of the photoprotection byve effect of the active metabolite of vitamin D3, 1, 25 dihydroxyvitamin D (1,25(OH)2D) against UVR-induced DNA damage and immunosuppression is not completely understood. It has been shown that vitamin D-like compounds and analogues are similarly photoprotective without inducing hypercalcaemic toxicity and that photoprotection from UVR is affected by gender. The aim of the study was to test whether 20(OH)D, a CYP11A1biological metabolite of 1,25(OH)2D and tetrahydrocurcumin (THC), a vitamin D like compound, would reduce UVR-induced DNA damage in primary human keratinocytes and Skh:Hr1 mice, and inflammatory oedema and immune suppression in Skh:Hr1 mice. The mechanism of photoprotection by 1,25(OH)2D and 20(OH)D was tested using inhibitors of the Wnt signalling pathway (IWR-1) and chloride channels (DIDS). The influence of gender on photoprotection against DNA damage and immunosuppression was assessed using Skh:Hr1 mice and oestrogen receptor- knock out (ERβKO) mice. 20(OH)D and THC were as photoprotective as 1,25(OH)2D against UVR-induced DNA damage in vitro and in vivo 3 hours following UVR exposure. In primary human keratinocytes, DIDS reversed the protective effect of 1,25(OH)2D and 20(OH)D against UVR-induced DNA damage. IWR-1 alone was protective against UVR-induced DNA damage, and did not cause reversal of photoprotection by 1,25(OH)2D and 20(OH)D. 20(OH)D was as effective as 1,25(OH)2D in reducing UVR-induced skin inflammation and immunosuppression in Skh:Hr1 mice. UVR-induced immunosuppression and DNA damage was greater in males than females. ERβKO mice were more susceptible to UVR-induced immunosuppression than wild type controls and the photoprotective effect of 1,25(OH)2D and 20(OH)D was reduced. This study showed that that 20(OH)D is photoprotective against UVR-induced DNA damage, inflammation and immunosuppression in a non-genomic manner, and demonstrated a potential interaction between ERβ and the actions of VDR ligands in photoprotection
