Medicinal and Natural Products Chemistry, Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Arizona Cancer Center, 1515 N. Campbell Ave., Tucson, AZ 85724, USA.
J Photochem Photobiol B. 2010 Apr 2;99(1):49-61. doi: 10.1016/j.jphotobiol.2010.02.003. Epub 2010 Feb 6.
Folate nutrition is critical in humans and a high dietary folate intake is associated with a diminished risk of many types of cancer. Both synthetic folic acid and the most biologically abundant extracellular reduced folate, 5-methyltetrahydrofolate, are degraded under conditions of ultraviolet radiation (UVR) exposure. Skin is a proliferative tissue with increased folate nutrient demands due to a dependence upon continuous epidermal cell proliferation and differentiation to maintain homeostasis. Regions of skin are also chronically exposed to UVR, which penetrates to the actively dividing basal layer of the epidermis, increasing the folate nutrient demands in order to replace folate species degraded by UVR exposure and to supply the folate cofactors required for repair of photo-damaged DNA. Localized folate deficiencies of skin are a likely consequence of UVR exposure. We report here a cultured keratinocyte model of folate deficiency that has been applied to examine possible effects of folate nutritional deficiencies in skin. Utilizing this model, we were able to quantify the concentrations of key intracellular folate species during folate depletion and repletion. We investigated the hypotheses that the genomic instability observed under conditions of folate deficiency in other cell types extends to skin, adversely effecting cellular capacity to handle UVR insult and that optimizing folate levels in skin is beneficial in preventing or repairing the pro-carcinogenic effects of UVR exposure. Folate restriction leads to rapid depletion of intracellular reduced folates resulting in S-phase growth arrest, increased levels of inherent DNA damage, and increased uracil misincorporation into DNA, without a significant losses in overall cellular viability. Folate depleted keratinocytes were sensitized toward UVR induced apoptosis and displayed a diminished capacity to remove DNA breaks resulting from both photo and oxidative DNA damage. Thus, folate deficiency creates a permissive environment for genomic instability, an early event in the process of skin carcinogenesis. The effects of folate restriction, even in severely depleted, growth-arrested keratinocytes, were reversible by repletion with folic acid. Overall, these results indicate that skin health can be positively influenced by optimal folate nutriture.
叶酸营养在人类中至关重要，高膳食叶酸摄入量与许多类型癌症的风险降低有关。合成叶酸和最具生物丰富性的细胞外还原叶酸，5-甲基四氢叶酸，在紫外线辐射（UVR）暴露下都会降解。皮肤是一种增殖组织，由于依赖于连续的表皮细胞增殖和分化来维持体内平衡，因此对叶酸营养物质的需求增加。皮肤区域也会受到 UVR 的慢性暴露，这种暴露会穿透到表皮的活跃分裂基底层，增加叶酸营养物质的需求，以替代因 UVR 暴露而降解的叶酸物质，并为修复光损伤的 DNA 提供所需的叶酸辅因子。皮肤的局部叶酸缺乏可能是 UVR 暴露的结果。我们在这里报告了一种叶酸缺乏的培养角质形成细胞模型，该模型已被应用于研究皮肤中叶酸营养缺乏的可能影响。利用该模型，我们能够在叶酸耗竭和补充过程中定量测定关键细胞内叶酸物质的浓度。我们研究了以下假设：在其他细胞类型中叶酸缺乏条件下观察到的基因组不稳定性扩展到皮肤，对细胞处理 UVR 损伤的能力产生不利影响，以及优化皮肤中的叶酸水平有利于预防或修复 UVR 暴露的致癌前效应。叶酸限制导致细胞内还原叶酸迅速耗竭，导致 S 期生长停滞、固有 DNA 损伤水平增加以及尿嘧啶错误掺入 DNA 增加，而细胞总体存活率没有显著降低。叶酸耗尽的角质形成细胞对 UVR 诱导的细胞凋亡敏感，并显示出去除光和氧化 DNA 损伤引起的 DNA 断裂的能力下降。因此，叶酸缺乏会导致基因组不稳定性的许可环境，这是皮肤癌变过程中的早期事件。即使在严重耗竭、生长停滞的角质形成细胞中，通过补充叶酸也可以逆转叶酸限制的影响。总的来说，这些结果表明，通过最佳叶酸营养可以对皮肤健康产生积极影响。
