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 theconcentration 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 lowfolate 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 showthat 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 >227 nmol/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 >700 nmol/l folate; and (b) micronucleus formation is minimised when plasma concentration of Vitamin B12 is >300 pmol/l and plasma homocysteine is <7.5 umol/l. These concentrations are achievable at intake levels in excess of current RDIs i.e. more than 200–400 ug folic acid per day and more than 2 ug 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 700 ug/day for folic acid and 7 ug/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.