De Haes Petra, Garmyn Marjan, Verstuyf Annemieke, De Clercq Pierre, Vandewalle Maurits, Vantieghem Katleen, Degreef Hugo, Bouillon Roger, Segaert Siegfried
Laboratory for Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Gasthuisberg O&N9, Herestraat 49, 3000 Leuven, Belgium.
Arch Dermatol Res. 2004 May;295(12):527-34. doi: 10.1007/s00403-004-0451-x. Epub 2004 Mar 20.
In search of photoprotective agents, we recently demonstrated a protective effect of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] against different events mediated by ultraviolet B (UVB) in human keratinocytes. Pharmacological doses of 1,25(OH)(2)D(3) were required to obtain significant UVB protection; however, these doses cannot be used in vivo due to the calcemic properties of 1,25(OH)(2)D(3). Therefore, we evaluated the photoprotective capacities of two low-calcemic 14-epi analogues of 1,25(OH)(2)D(3), 19-nor-14-epi-23-yne-1,25(OH)(2)D(3) (TX 522) and 19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3) (TX 527). Using cultured human keratinocytes, we investigated the influence of TX 522 and TX 527 on two hallmark events in UVB-irradiated keratinocytes: the induction of apoptosis and the production of interleukin-6 (IL-6). Treatment of the keratinocytes with TX 522 or TX 527, 24 h before irradiation, resulted in a significant and dose-dependent reduction of both UVB-induced apoptosis and IL-6 production. Both analogues were equally efficient in their anti-UVB effects and at least 100 times more potent than 1,25(OH)(2)D(3). We further demonstrated that metallothionein (MT) mRNA expression was clearly induced by 1,25(OH)(2)D(3) and both analogues. MT acts as a radical scavenger in oxygen-mediated UVB injury and its induction may therefore be relevant for the anti-UVB effects of 1,25(OH)(2)D(3) and both analogues. Taken together, these findings create new perspectives for the use of active vitamin D analogues as photoprotective agents.
在寻找光保护剂的过程中，我们最近证明了1,25 - 二羟基维生素D(3)[1,25(OH)(2)D(3)]对人角质形成细胞中由紫外线B(UVB)介导的不同事件具有保护作用。需要药理剂量的1,25(OH)(2)D(3)才能获得显著的UVB保护作用；然而，由于1,25(OH)(2)D(3)的血钙升高特性，这些剂量不能在体内使用。因此，我们评估了两种低血钙的1,25(OH)(2)D(3)的14 - 表位类似物，即19 - 去甲 - 14 - 表 - 23 - 炔 - 1,25(OH)(2)D(3)(TX 522)和19 - 去甲 - 14,20 - 双表 - 23 - 炔 - 1,25(OH)(2)D(3)(TX 527)的光保护能力。利用培养的人角质形成细胞，我们研究了TX 522和TX 527对UVB照射的角质形成细胞中的两个标志性事件的影响：细胞凋亡的诱导和白细胞介素 - 6(IL - 6)的产生。在照射前24小时用TX 522或TX 527处理角质形成细胞，导致UVB诱导的细胞凋亡和IL - 6产生均显著且呈剂量依赖性降低。两种类似物在抗UVB作用方面同样有效，且效力至少比1,25(OH)(2)D(3)强100倍。我们进一步证明，金属硫蛋白(MT)mRNA表达明显受到1,25(OH)(2)D(3)和两种类似物的诱导。MT在氧介导的UVB损伤中作为自由基清除剂发挥作用，因此其诱导可能与1,25(OH)(2)D(3)和两种类似物的抗UVB作用有关。综上所述，这些发现为使用活性维生素D类似物作为光保护剂创造了新的前景。
