CSIRO Food and Nutritional Sciences, PO Box 10041 Adelaide BC, SA 5000, Australia.
Mutat Res. 2012 May 1;733(1-2):21-33. doi: 10.1016/j.mrfmmm.2011.11.003. Epub 2011 Nov 7.
Folate plays a critical role in the prevention of uracil incorporation into DNA and hypomethylation of DNA. This activity is compromised when vitamin B12 concentration is low because methionine synthase activity is reduced, lowering the concentration of S-adenosyl methionine (SAM) which in turn may diminish DNA methylation and cause folate to become unavailable for the conversion of dUMP to dTMP. The most plausible explanation for the chromosome-breaking effect of low folate is excessive uracil misincorporation into DNA, a mutagenic lesion that leads to strand breaks in DNA during repair. Both in vitro and in vivo studies with human cells clearly show that folate deficiency causes expression of chromosomal fragile sites, chromosome breaks, excessive uracil in DNA, micronucleus formation, DNA hypomethylation and mitochondrial DNA deletions. In vivo studies show that folate and/or vitamin B12 deficiency and elevated plasma homocysteine (a metabolic indicator of folate deficiency) are significantly correlated with increased micronucleus formation and reduced telomere length respectively. In vitro experiments indicate that genomic instability in human cells is minimised when folic acid concentration in culture medium is greater than 100nmol/L. Intervention studies in humans show (a) that DNA hypomethylation, chromosome breaks, uracil incorporation and micronucleus formation are minimised when red cell folate concentration is greater than 700nmol/L and (b) micronucleus formation is minimised when plasma concentration of vitamin B12 is greater than 300pmol/L and plasma homocysteine is less than 7.5μmol/L. These concentrations are achievable at intake levels at or above current recommended dietary intakes of folate (i.e. >400μg/day) and vitamin B12 (i.e. >2μg/day) depending on an individual's capacity to absorb and metabolise these vitamins which may vary due to genetic and epigenetic differences.
叶酸在防止尿嘧啶掺入 DNA 和 DNA 去甲基化方面起着至关重要的作用。当维生素 B12 浓度较低时，由于蛋氨酸合酶活性降低，导致 S-腺苷甲硫氨酸 (SAM) 浓度降低，从而可能降低 DNA 甲基化并使叶酸无法将 dUMP 转化为 dTMP，从而使这种活性受到损害。叶酸水平低导致染色体断裂的最合理解释是尿嘧啶错误掺入 DNA 过多，这是一种诱变损伤，在修复过程中会导致 DNA 链断裂。人体细胞的体外和体内研究清楚地表明，叶酸缺乏会导致染色体脆性部位、染色体断裂、DNA 中过多的尿嘧啶、微核形成、DNA 去甲基化和线粒体 DNA 缺失的表达。体内研究表明，叶酸和/或维生素 B12 缺乏以及血浆同型半胱氨酸升高（叶酸缺乏的代谢指标）与微核形成增加和端粒长度缩短分别显著相关。体外实验表明，当培养基中叶酸浓度大于 100nmol/L 时，人细胞中的基因组不稳定性最小化。人类干预研究表明：(a) 当红细胞叶酸浓度大于 700nmol/L 时，DNA 去甲基化、染色体断裂、尿嘧啶掺入和微核形成最小化；(b) 当血浆维生素 B12 浓度大于 300pmol/L 且血浆同型半胱氨酸小于 7.5μmol/L 时，微核形成最小化。这些浓度可以通过摄入水平达到或超过当前推荐的叶酸（即 >400μg/天）和维生素 B12（即 >2μg/天）的摄入量来实现，这取决于个体吸收和代谢这些维生素的能力，而这种能力可能因遗传和表观遗传差异而有所不同。
