The Emerging Role of Unmetabolized Folic Acid in Human Diseases: Myth or Reality?
Rima Obeid and Wolfgang Herrmann
Affiliation: University Hospital of Saarland, Department of Clinical Chemistry and Laboratory Medicine, Building 57, D-66421 Homburg/Saar, Germany.
Keywords: Folic acid, fortification, cancer, pregnancy, metabolism, dihydrofolate reductase, DHFR, FA dose, vitamin B9, 5-MTHF, homocysteine, unmetabolised FA, NTD.
An increase in folate intake before and during pregnancy can prevent many neural tube defects. This prompted over 50 countries
worldwide to mandate fortification of breakfast cereals or staple foods with folic acid (FA), which is the synthetic oxidised form of
the vitamin used in supplements and fortified foods. After ingestion, FA is reduced by dihydrofolate reductase (DHFR) and then converted
to the biologically active forms. The presence of detectable amounts of unmetabolised FA in blood of individuals who have consumed
supplements or fortified foods has attracted attention in recent years. A direct correlation exists between FA intake and unmetabolised
FA in serum and suggests that a saturable level of DHFR exists. Factors affecting FA reduction, such as age, intestinal pH, alcohol,
FA dose and duration of supplement usage, and possibly polymorphisms of folate-metabolising enzymes, can affect the presence of FA
in blood. However, minor amounts of FA might also be produced during sample preparation. In pregnant women taking supplements, FA
does not seem to accumulate in the newborns. Concentrations of unmetabolized FA are correlated to and predicted by those of total folate
or 5-MTHF. Evidence of a negative health effect of free FA in blood is not consistent and suggests rather artificial factors. FA has no
known cofactor function that would increase the likelihood of a causal role for free FA in disease development.
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