Folic acid under scrutiny

A consideration of the absorption and metabolism of folic acid in human subjects is timely, owing to the recent recommendation by the UK Government’s Scientific Advisory Committee on Nutrition that a mandatory folic acid fortification programme be implemented in the UK. In this issue of the British Journal of Nutrition, Wright et al. take us through the processes of absorption and metabolism of folic acid and conclude that there are grounds to propose that the use of this compound as a supplement or a fortificant may increase its concentration in the systemic circulation. They suggest that there may be associated risks. Folic acid is the most oxidised, monoglutamate, form of folate, and the form in which this vitamin is taken as a supplement or used as a fortificant. Because its lack of glutamate residues obviates the need for deconjugase at the brush-border membrane, and the presence in foodstuffs of dietary inhibitors of folate deconjugation, it has long been considered to have a much higher bioavailability than food folates. In reality, studies show a wide variation in the bioavailability of food folates, depending upon the particular food matrix, and a recent study suggests that the consumption of a mixed diet containing folate-rich foods can be almost as effective as folic acid supplements at improving folate status. With the advent of readily accessible stable isotope-labelled folates it became possible to study folate bioavailability and metabolism in human subjects with a high degree of accuracy. These studies now strongly suggest that a high proportion of folic acid undergoes initial reduction and methylation in the liver. On entering a cell folic acid is initially reduced by dihydrofolate reductase (DHFR) to dihydrofolate (DHF), which is subsequently reduced further to tetrahydrofolate (THF). THF is then available for further metabolism to a number of different biologically active forms of folate, with specific metabolic functions. Importantly, in human subjects, some tissues, including liver, have a limited ability to reduce folic acid, because of a low activity of DHFR, and are unable to reduce high concentrations of folic acid. This would be expected to increase the appearance of unmetabolised folic acid in the circulation in the situation of high or repeated doses of folic acid.