Molecular mechanisms underlying the potentially adverse effects of folate

Abstract

The importance of proper consumption of dietary folate for human health has been highlighted by an extensive number of publications over several decades. Fortification of grain products with folic acid was initiated with the specific intent to prevent neural tube defects, and the scope of this endeavor is unique in that its target population (women of the periconceptional period) is many times smaller than the population it affects (everyone who ingests fortified grain products). Folate fortification has been wildly successful in terms of its goal; since its inception, the incidence of neural tube defects has markedly decreased. In the wake of this public health triumph, it is important to catalog both the serendipitous benefits and potential side effects of folic acid supplementation. The vitamin is generally regarded as a harmless nutrient based on studies evaluating the safe upper limits of folate intake. In recent years, however, a concern has been raised with respect to a potential downside to folate supplementation; namely, its proposed ability to enhance proliferation of malignant tumors. The current review summarizes the available literature on the effects of folate supplementation and the molecular mechanisms by which high doses of folate may have negative consequences on human health, especially with regard to cancer.

Figure 1. Folate metabolism

Folate is taken up by the cell in forms of folic acid (FA, supplements or fortified foods) or 5-MTHF (natural diet). In the cell, FA is sequentially converted to dihydrofolate (DHF) and then to the active form of the coenzyme, tetrahydrofolate (THF). Both reactions are catalyzed by DHFR (dihydrofolate reductase). Upon accepting a one-carbon group (comes either from serine, glycine, histidine or formate), THF is converted to other forms of folate. For simplicity, only folate coenzymes directly participating in the biosynthesis of nucleotides and methionine are shown (10-FTHF, 10-formyl-THF; CH₂-THF, 5,10-methylene-THF). HCY, homocysteine; SAM, S-adenosylmethionine; MS, methionine synthase; TS, thymidylate synthase; MTHFR, methylenetetrahydrofolate reductase. Reaction catalyzed by MS converts 5-MTHF to THF (indicated by dotted arrow) and requires vitamin B₁₂.