Neural tube defects and periconceptional folic acid in England and Wales: retrospective studyCommentary: Food should be fortified with folic acid

Food fortification with folic acid

Kadir et al1 assessed changes in the incidence of neural tube defects
(NTD) resulting from 1992 government recommendations on the use of
periconceptional folate supplementation. They found that despite 100-fold
increased folate consumption between 1991 and 1996, there was no
comcomitant fall in NTD of similar magnitude. Following on immediately
after this article Alberman and Noble indicate why this might be, and
suggest that this situation could be improved by mandatory fortification
of food designed to increase the average daily folic acid intake of every
women by 400 micrograms / day. The average intake currently being 200 micrograms / day.

The form of folate in pharmacological supplements and in fortified
foods is pteroylmonoglutamate (PteGlu). This form does not occur in
nature. However, it is both cheap and extremely stable, unlike many native
forms of the vitamin. The body metabolises PteGlu into methylfolate, the
normal transport form of the vitamin found in plasma. However, research
shows that this absorption and biotransformation process is saturated at
doses in the region of 266 - 400 micrograms PteGlu2,3. This raises the possibility
of a life times exposure to unmetabolised PteGlu, were mandatory PteGlu
fortification to go ahead in the UK. Although such exposure may present no
health risk at all, we can't know this for certain. At present the US
supplements at a level of 100 micrograms / day PteGlu, although moves are afoot to
increase this to 400 micrograms / day.

One of the major concerns of mandatory fortification is hindering the
diagnosis of B12 deficiency in pernicious anaemia, along with the
associated progression of neurological sequelae. Nobody yet knows what, if
any, the effect of mandatory fortification of flour, rice, pasta and other
grain products would be at the population level. Folate metabolism is
extraordinarily complex, underpinning several pathways crucial for life
processes such as nucleotide biosynthesis (ie DNA-thymine) and methionine
biosynthesis (ie de novo methyl group synthesis including those required
for DNA methylation and gene expression). The nutritional value of dietary
folate is therefore immense; supplements lower potentially atherogenic
homocysteine - particularly important in individuals with a common 677c®t
mutation of the folate dependent enzyme, 5,10methylenetetrahydrofolate
reductase, reduce NTD, play a beneficial role in general health and well
being that extends to certain cancers4 and may even influence Alzheimers
disease5. Despite this, unmetabolised non-native PteGlu should be assessed
for its in vivo effects on folate dependent enzymes: ie It is metabolised
by dihydrofolate reductase for which it has a higher Km (lower affinity)
than has dihydrofolate itself - could this have an antifolate effect via
competitive interaction? Could similar phenomena occur at other enzymes,
particularly allosteric enzymes where structurally similar dihydrofolate
plays a regulatory role. In vitro studies do show PteGlu acts to inhibit
certain enzymes including those associated with nucleotide biosynthesis.