Dixon K M, Deo S S, Norman A W, Bishop J E, Halliday G M, Reeve V E, Mason R S
Department of Physiology and Bosch Institute, University of Sydney, NSW 2006, Australia.
J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):451-6. doi: 10.1016/j.jsbmb.2006.11.016. Epub 2007 Jan 12.
Vitamin D is produced by exposure of 7-dehydrocholesterol in the skin to UV irradiation (UVR) and further converted in the skin to the biologically active metabolite, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and other compounds. UVR also results in DNA damage producing cyclobutane pyrimidine dimers (CPD). We previously reported that 1,25(OH)(2)D(3) at picomolar concentrations, protects human skin cells from UVR-induced apoptosis, and decreases CPD in surviving cells. 1,25(OH)(2)D(3) has been shown to generate biological responses via two pathways-the classical steroid receptor/genomic pathway or a rapid, non-genomic pathway mediated by a putative membrane receptor. Whether the rapid response pathway is physiologically relevant is unclear. A cis-locked, rapid-acting agonist 1,25(OH)(2)lumisterol(3) (JN), entirely mimicked the actions of 1,25(OH)(2)D(3) to reduce fibroblast and keratinocyte loss and CPD damage after UVR. The effects of 1,25(OH)(2)D(3) were abolished by a rapid-acting antagonist, but not by a genomic antagonist. Skh:hr1 mice exposed to three times the minimal erythemal dose of solar-simulated UVR and treated topically with 1,25(OH)(2)D(3) or JN immediately after UVR showed reduction in UVR-induced UVR-induced sunburn cells (p<0.01 and <0.05, respectively), CPD (p<0.01 for both) and immunosuppression (p<0.001 for both) compared with vehicle-treated mice. These results show for the first time an in vivo biological response mediated by a rapid-acting analog of the vitamin D system. The data support the hypothesis that 1,25(OH)(2)D(3) exerts its photoprotective effects via the rapid pathway and raise the possibility that other D compounds produced in skin may contribute to the photoprotective effects.
维生素D是皮肤中的7-脱氢胆固醇经紫外线照射（UVR）后产生的，并在皮肤中进一步转化为生物活性代谢物1,25-二羟基维生素D(3)（1,25(OH)(2)D(3)）及其他化合物。UVR还会导致DNA损伤，产生环丁烷嘧啶二聚体（CPD）。我们之前报道过，皮摩尔浓度的1,25(OH)(2)D(3)可保护人类皮肤细胞免受UVR诱导的凋亡，并减少存活细胞中的CPD。已证明1,25(OH)(2)D(3)可通过两条途径产生生物学反应——经典的类固醇受体/基因组途径或由假定的膜受体介导的快速非基因组途径。快速反应途径在生理上是否相关尚不清楚。一种顺式锁定的速效激动剂1,25(OH)(2)光甾醇(3)（JN）完全模拟了1,25(OH)(2)D(3)的作用，以减少UVR后成纤维细胞和角质形成细胞的损失以及CPD损伤。1,25(OH)(2)D(3)的作用可被速效拮抗剂消除，但不能被基因组拮抗剂消除。暴露于三倍最小红斑剂量的模拟太阳UVR下并在UVR后立即局部用1,25(OH)(2)D(3)或JN处理的Skh:hr1小鼠，与用赋形剂处理的小鼠相比，UVR诱导的晒伤细胞减少（分别为p<0.01和<0.05）、CPD减少（两者均为p<0.01）以及免疫抑制减少（两者均为p<0.001）。这些结果首次显示了维生素D系统的速效类似物介导的体内生物学反应。数据支持1,25(OH)(2)D(3)通过快速途径发挥其光保护作用的假设，并增加了皮肤中产生的其他D化合物可能有助于光保护作用的可能性。
