Fenech M
CSIRO Health Sciences and Nutrition, Adelaide, Australia.
Mutat Res. 2001 Apr 18;475(1-2):57-67. doi: 10.1016/s0027-5107(01)00079-3.
Folic acid plays a critical role in the prevention of chromosome breakage and hypomethylation of DNA. This activity is compromised when Vitamin B12 (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 and DNA hypomethylation. In vivo studies show that Vitamin B12 deficiency and elevated plasma homocysteine are significantly correlated with increased micronucleus formation. In vitro experiments indicate that genomic instability in human cells is minimised when folic acid concentration in culture medium is >227nmol/l. Intervention studies in humans show: (a) that DNA hypomethylation, chromosome breaks, uracil misincorporation and micronucleus formation are minimised when red cell folate concentration is >700nmol/l folate; and (b) micronucleus formation is minimised when plasma concentration of Vitamin B12 is >300pmol/l and plasma homocysteine is <7.5micromol/l. These concentrations are achievable at intake levels in excess of current RDIs i.e. more than 200-400microgram folic acid per day and more than 2microgram Vitamin B12 per day. A placebo-controlled study with a dose-response suggests that based on the micronucleus index in lymphocytes, an RDI level of 700microgram/day for folic acid and 7microgram/day for Vitamin B12 would be appropriate for genomic stability in young adults. Dietary intakes above the current RDI may be particularly important in those with extreme defects in the absorption and metabolism of these Vitamins, for which ageing is a contributing factor.
叶酸在预防染色体断裂和DNA低甲基化方面起着关键作用。当维生素B12（B12）浓度较低时，这种活性会受到影响，因为甲硫氨酸合成酶的活性降低，导致S-腺苷甲硫氨酸（SAM）浓度降低，进而可能减少DNA甲基化，并使叶酸无法用于将dUMP转化为dTMP。低叶酸导致染色体断裂效应最合理的解释是尿嘧啶过多错误掺入DNA，这是一种诱变损伤，在修复过程中会导致DNA链断裂。对人类细胞进行的体外和体内研究均清楚表明，叶酸缺乏会导致染色体脆弱位点的表达、染色体断裂、DNA中尿嘧啶过多、微核形成以及DNA低甲基化。体内研究表明，维生素B12缺乏和血浆同型半胱氨酸升高与微核形成增加显著相关。体外实验表明，当培养基中叶酸浓度>227nmol/l时，人类细胞中的基因组不稳定性最小化。对人类进行的干预研究表明：（a）当红细胞叶酸浓度>700nmol/l叶酸时，DNA低甲基化、染色体断裂、尿嘧啶错误掺入和微核形成最小化；（b）当血浆维生素B12浓度>300pmol/l且血浆同型半胱氨酸<7.5μmol/l时，微核形成最小化。这些浓度在超过当前推荐膳食摄入量（RDI）的摄入水平时即可实现，即每天摄入超过200 - 400微克叶酸和超过2微克维生素B12。一项安慰剂对照的剂量反应研究表明，基于淋巴细胞中的微核指数，对于年轻人基因组稳定性而言，叶酸的RDI水平为每天700微克，维生素B12为每天7微克是合适的。对于那些这些维生素吸收和代谢存在极端缺陷（衰老就是一个促成因素）的人来说，高于当前RDI的膳食摄入量可能尤为重要。
