Cancer Prevention Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M4-B402, Seattle, WA 98019, USA.
Cancer Epidemiol Biomarkers Prev. 2011 Sep;20(9):1912-7. doi: 10.1158/1055-9965.EPI-10-1352. Epub 2011 Jul 13.
Folate is an essential B-vitamin that mediates one-carbon metabolism reactions, including nucleotide synthesis and others related to carcinogenesis. Both low- and high-folate status influences carcinogenesis.
We used a mathematical model of folate-mediated one-carbon metabolism to predict the effect of a range of intracellular epithelial folate concentrations (0.25-15.0 μmol/L) on methylation rate and purine and thymidylate synthesis. We also examined the interaction of these folate concentrations with polymorphisms in two enzymes [methylene tetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS)] in relation to the biochemical products.
TS enzyme reaction rate increased markedly in response to the modeled higher intracellular folate concentrations. Changes in methylation rate were modest, whereas purine synthesis was only minimally related to increases in folate concentrations with an apparent threshold effect at 5.0 to 6.0 μmol/L. The relationship between folate concentrations and thymidylate synthesis was modified by genetic variation in TS but less so by variation in MTHFR. These gene-folate interactions modestly influenced purine synthesis in a nonlinear manner but only affected methylation rate under conditions of very high MTHFR activity.
Thymidylate synthesis is very sensitive to changes in epithelial intracellular folate and increased nearly fivefold under conditions of high intracellular folate. Individuals with genetic variations causing reduced TS activity may present even greater susceptibility to excessive folate.
Our observation that thymidylate synthesis increases dramatically under conditions of very elevated intracellular folate provides biological support to observations that excessive folic acid intake increases risk of both precursor lesions (i.e., colorectal adenomas) and cancer.
叶酸是一种必需的 B 族维生素，可介导一碳代谢反应，包括核苷酸合成和其他与致癌作用相关的反应。叶酸的低水平和高水平状态均会影响致癌作用。
我们使用叶酸介导的一碳代谢的数学模型来预测一系列细胞内上皮叶酸浓度（0.25-15.0 μmol/L）对甲基化率以及嘌呤和胸苷酸合成的影响。我们还研究了这些叶酸浓度与两种酶（亚甲基四氢叶酸还原酶（MTHFR）和胸苷酸合成酶（TS））中的多态性之间的相互作用，以及这些多态性与生化产物之间的关系。
TS 酶反应速率随模型中较高的细胞内叶酸浓度显著增加。甲基化率的变化不大，而嘌呤合成仅与叶酸浓度的增加有最小的关系，在 5.0 至 6.0 μmol/L 时有明显的阈值效应。叶酸浓度与胸苷酸合成之间的关系受 TS 基因多态性的修饰，但受 MTHFR 基因多态性的修饰较小。这些基因-叶酸相互作用以非线性方式轻微影响嘌呤合成，但仅在 MTHFR 活性非常高的情况下影响甲基化率。
胸苷酸合成对细胞内上皮叶酸的变化非常敏感，在高细胞内叶酸条件下增加近五倍。由于 TS 活性降低而导致遗传变异的个体可能对过多的叶酸表现出更大的易感性。
我们的观察结果表明，在非常高的细胞内叶酸条件下，胸苷酸合成显著增加，为观察到过量叶酸摄入增加前体病变（即结直肠腺瘤）和癌症的风险提供了生物学支持。
