The emerging role of unmetabolized folic acid in human diseases: myth or reality?

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.