van den Donk Maureen, Pellis Linette, Crott Jimmy W, van Engeland Manon, Friederich Pieter, Nagengast Fokko M, van Bergeijk Jeroen D, de Boer Sybrand Y, Mason Joel B, Kok Frans J, Keijer Jaap, Kampman Ellen
Division of Human Nutrition, Wageningen University, 6700 EV Wageningen, The Netherlands.
J Nutr. 2007 Sep;137(9):2114-20. doi: 10.1093/jn/137.9.2114.
Adequate folate availability is necessary to sustain normal DNA synthesis and normal patterns of DNA methylation and these features of DNA can be modified by methylenetetrahydrofolate reductase (MTHFR) C677T genotype. This study investigated the effect of MTHFR C677T genotype and daily supplementation with 5 mg folic acid and 1.25 mg vitamin B-12 on uracil misincorporation into DNA and promoter methylation. Subjects (n = 86) with a history of colorectal adenoma and MTHFR CC or TT genotype were randomly assigned to receive folic acid plus vitamin B-12 or placebo for 6 mo. Uracil misincorporation and promoter methylation of 6 tumor suppressor and DNA repair genes were assessed in DNA from rectal biopsies at baseline and after the intervention. The biomarkers did not differ between the treated group and the placebo group after 6 mo compared with baseline. The uracil concentration of DNA increased in the treated group (5.37 fmol/microg DNA, P = 0.02), whereas it did not change in the placebo group (P = 0.42). The change from baseline of 4.01 fmol uracil/microg DNA tended to differ between the groups (P = 0.16). An increase in promoter methylation tended to occur more often in the intervention group than in the placebo group (OR = 1.67; P = 0.08). This study suggests that supplementation with high doses of folic acid and vitamin B-12 may not favorably influence uracil incorporation and promoter methylation in subjects with previous colorectal adenomas. Because such alterations may potentially increase the risk of neoplastic transformation, more research is needed to fully define the consequences of these molecular alterations.
充足的叶酸供应对于维持正常的DNA合成以及正常的DNA甲基化模式是必要的，并且DNA的这些特性可被亚甲基四氢叶酸还原酶（MTHFR）C677T基因型所改变。本研究调查了MTHFR C677T基因型以及每日补充5毫克叶酸和1.25毫克维生素B-12对尿嘧啶错误掺入DNA和启动子甲基化的影响。有结肠直肠腺瘤病史且为MTHFR CC或TT基因型的受试者（n = 86）被随机分配接受叶酸加维生素B-12或安慰剂，为期6个月。在基线和干预后，对直肠活检组织DNA中6个肿瘤抑制基因和DNA修复基因的尿嘧啶错误掺入及启动子甲基化进行评估。与基线相比，6个月后治疗组和安慰剂组之间的生物标志物没有差异。治疗组DNA中的尿嘧啶浓度增加（5.37 fmol/μg DNA，P = 0.02），而安慰剂组未发生变化（P = 0.42）。两组之间每微克DNA中尿嘧啶从基线的变化量4.01 fmol有差异趋势（P = 0.16）。干预组启动子甲基化增加的发生率往往高于安慰剂组（OR = 1.67；P = 0.08）。本研究表明，高剂量叶酸和维生素B-12补充剂可能不会对既往有结肠直肠腺瘤的受试者的尿嘧啶掺入和启动子甲基化产生有利影响。由于这种改变可能会潜在增加肿瘤转化的风险，因此需要更多研究来全面确定这些分子改变的后果。
