Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
Am J Clin Nutr. 2010 Jan;91(1):160-5. doi: 10.3945/ajcn.2009.28527. Epub 2009 Nov 18.
Folate deficiency decreases thymidylate synthesis from deoxyuridylate, which results in an imbalance of deoxyribonucleotide that may lead to excessive uracil misincorporation (UrMis) into DNA during replication and repair.
We evaluated the relation between UrMis in different tissues and the effect of folate supplementation on UrMis.
We analyzed UrMis concentrations in rectal mucosa (n = 92) and white blood cells (WBCs; n = 60) among individuals randomly assigned to receive supplementation with 1 mg folate/d or placebo, who were then evaluated for colorectal adenoma recurrence.
As expected, total homocysteine was significantly lower among the study participants who received active folate treatment (Wilcoxon's P = 0.003) than among those in the placebo group. The median UrMis concentration in rectal mucosa and WBCs among individuals treated with folate was not significantly lower than that in those who received placebo (Wilcoxon's P = 0.17). UrMis concentrations in both rectal mucosa and WBCs did not correlate significantly with folate measured in plasma and red blood cells. UrMis in rectal mucosa was marginally associated with an increased risk of adenoma recurrence (odds ratio per SD: 1.43; 95% CI: 0.91, 2.25).
UrMis measurements in WBCs are not a robust surrogate for UrMis measurements in the rectal mucosa (Spearman correlation coefficient = 0.23, P = 0.08). Furthermore, folate supplementation in an already replete population (half treated with folic acid supplements and all exposed to folic acid fortification of the food supply) was not significantly associated with reduced UrMis in rectal mucosa cells or WBCs. Large-scale studies are needed to evaluate whether excessive UrMis concentrations are an important risk factor for colorectal neoplasia. This trial was registered at clinicaltrials.gov as NCT00272324.
叶酸缺乏会减少脱氧尿苷酸合成胸苷酸，导致脱氧核苷酸失衡，可能导致复制和修复过程中尿嘧啶错误掺入（UrMis）到 DNA 中。
我们评估了不同组织中的 UrMis 浓度与叶酸补充对 UrMis 的影响。
我们分析了随机分配接受 1 毫克叶酸/天或安慰剂治疗的个体的直肠黏膜（n = 92）和白细胞（WBC；n = 60）中的 UrMis 浓度，然后评估他们的结直肠腺瘤复发情况。
正如预期的那样，接受活性叶酸治疗的研究参与者的总同型半胱氨酸水平明显低于安慰剂组（Wilcoxon's P = 0.003）。接受叶酸治疗的个体的直肠黏膜和 WBC 中的 UrMis 浓度与接受安慰剂的个体相比没有显著降低（Wilcoxon's P = 0.17）。直肠黏膜和 WBC 中的 UrMis 浓度与血浆和红细胞中的叶酸测量值没有显著相关性。直肠黏膜中的 UrMis 与腺瘤复发的风险增加呈边缘相关（每 SD 的优势比：1.43；95%CI：0.91，2.25）。
WBC 中的 UrMis 测量值不是直肠黏膜中 UrMis 测量值的可靠替代指标（Spearman 相关系数 = 0.23，P = 0.08）。此外，在已经补充叶酸的人群（一半接受叶酸补充剂，所有人都暴露于食物供应中的叶酸强化）中补充叶酸与直肠黏膜细胞或 WBC 中的 UrMis 减少没有显著相关性。需要开展大规模研究来评估过高的 UrMis 浓度是否是结直肠肿瘤的重要危险因素。该试验在 clinicaltrials.gov 上注册为 NCT00272324。
