Evidence for Involvement of Nonclassical Pathways in the Protection From UV-Induced DNA Damage by Vitamin D-Related Compounds.
Evidence for Involvement of Nonclassical Pathways in the Protection From UV-Induced DNA Damage by Vitamin D-Related Compounds.
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作者：
De Silva WGM;Han JZR;Yang C;Tongkao-On W;McCarthy BY;Ince FA;Holland AJA;Tuckey RC;Slominski AT;Abboud M;Dixon KM;Rybchyn MS;Mason RS
维生素D激素1,25二羟基维生素D3 (1,25(OH)2D3)，以及通过CYP11A1酶代谢的维生素D3或lumisterol衍生的相关化合物，在紫外线照射前24小时或照射后立即应用，通过减少环丁烷嘧啶二聚体（CPD）和8‐氧‐7,8‐二氢‐2 '‐脱氧鸟苷（8‐OHdG）形式的氧化损伤，保护人体皮肤细胞和皮肤免受紫外线照射引起的DNA损伤。我们现在报道，通过小干扰RNA （siRNA）敲低维生素D受体或内质网蛋白ERp57，可以消除20‐羟维生素D3或24‐羟米斯特ol3对紫外线诱导的DNA损伤的减少，正如之前对1,25(OH)2D3的研究结果。1,25(OH)2D3降低了紫外线暴露和假暴露的人角质形成细胞的耗氧率，并降低了环AMP反应结合元件蛋白（CREB）的磷酸化。这两种作用都被证明可以抑制慢性紫外线照射后的皮肤癌变，这与1,25(OH)2D3的抗癌活性是一致的。1,25(OH)2D3和自然产生的CYP11A1衍生的维生素D相关化合物的光保护作用需要维生素D受体，这可能解释了为什么皮肤中缺乏维生素D受体的小鼠更容易患紫外线诱导的皮肤癌，而缺乏1α‐羟化酶的小鼠则不会更容易产生1,25(OH)2D3。©2021作者。JBMR Plus由Wiley期刊有限责任公司代表美国骨骼和矿物研究协会出版。
The vitamin D hormone, 1,25dihydroxyvitamin D3 (1,25(OH)2D3), and related compounds derived from vitamin D3 or lumisterol as a result of metabolism via the enzyme CYP11A1, have been shown, when applied 24 hours before or immediately after UV irradiation, to protect human skin cells and skin from DNA damage due to UV exposure, by reducing both cyclobutane pyrimidine dimers (CPD) and oxidative damage in the form of 8‐oxo‐7,8‐dihydro‐2′‐deoxyguanosine (8‐OHdG). We now report that knockdown of either the vitamin D receptor or the endoplasmic reticulum protein ERp57 by small, interfering RNA (siRNA) abolished the reductions in UV‐induced DNA damage with 20‐hydroxyvitamin D3 or 24‐hydroxylumisterol3, as previously shown for 1,25(OH)2D3. Treatment with 1,25(OH)2D3 reduced oxygen consumption rates in UV‐exposed and sham‐exposed human keratinocytes and reduced phosphorylation of cyclic AMP response binding element protein (CREB). Both these actions have been shown to inhibit skin carcinogenesis after chronic UV exposure, consistent with the anticarcinogenic activity of 1,25(OH)2D3. The requirement for a vitamin D receptor for the photoprotective actions of 1,25(OH)2D3 and of naturally occurring CYP11A1‐derived vitamin D–related compounds may explain why mice lacking the vitamin D receptor in skin are more susceptible to UV‐induced skin cancers, whereas mice lacking the 1α‐hydroxylase and thus unable to make 1,25(OH)2D3 are not more susceptible. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.