Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate

Abstract

Adequate levels of folates are essential for homeostasis of the organism, prevention of congenital malformations, and the salvage of predisposed disease states. They depend on genetic predisposition, and therefore, a pharmacogenetic approach to individualized supplementation or therapeutic intervention is necessary for an optimal outcome. The role of folates in vital cell processes was investigated by translational pharmacogenetics employing lymphoblastoid cell lines (LCLs). Depriving cells of folates led to reversible S-phase arrest. Since 5,10-methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in the biosynthesis of an active folate form, we evaluated the relevance of polymorphisms in the MTHFR gene on intracellular levels of bioactive metabolite, the 5-methyltetrahydrofolate (5-Me-THF). LCLs (n = 35) were divided into low- and normal-MTHFR activity groups based on their genotype. They were cultured in the presence of folic acid (FA) or 5-Me-THF. Based on the cells’ metabolic activity and intracellular 5-Me-THF levels, we conclude supplementation of FA is sufficient to maintain adequate folate level in the normal MTHFR activity group, while low MTHFR activity cells require 5-Me-THF to overcome the metabolic defects caused by polymorphisms in their MTHFR genes. This finding was supported by the determination of intracellular levels of 5-Me-THF in cell lysates by LC-MS/MS. FA supplementation resulted in a 2.5-fold increase in 5-Me-THF in cells with normal MTHFR activity, but there was no increase after FA supplementation in low MTHFR activity cells. However, when LCLs were exposed to 5-Me-THF, a 10-fold increase in intracellular levels of this metabolite was determined. These findings indicate that patients undergoing folate supplementation to counteract anti-folate therapies, or patients with increased folate demand, would benefit from pharmacogenetics-based therapy choices.

Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism and Infant’s Anthropometry at Birth

“…It appears that unfavorable MTHFR(677) genotypes require additional factors to overcome the metabolic defects caused by low MTHFR activity, otherwise the genetic factor by itself would impair fetal growth. An experimental study showed that folate supplementation in a cell line with low MTHFR activity did not significantly increase the concentration of 5-MTHF, the biologically active folate, when compared with normal MTHFR activity cells [ 43 ]. Thus, the metabolic defects caused by genetic polymorphisms of the gene encoding the MTHFR enzyme may require supplemental 5-MTHF to overcome such defects [ 43 ].…”

“…An experimental study showed that folate supplementation in a cell line with low MTHFR activity did not significantly increase the concentration of 5-MTHF, the biologically active folate, when compared with normal MTHFR activity cells [ 43 ]. Thus, the metabolic defects caused by genetic polymorphisms of the gene encoding the MTHFR enzyme may require supplemental 5-MTHF to overcome such defects [ 43 ]. Moreover, previous studies have demonstrated the excellent safety profile for the Calcium L-5-methyltetrahydrofolic acid (L-5-MTHF-Ca).…”

The Timing and Duration of Folate Restriction Differentially Impacts Colon Carcinogenesis

“…The L. casei microbiological assay was used in this study. However, methods of folate detection, such as LC–MS/MS, could produce more accurate and specific measurements of folate and its metabolites in serum and tissues, while being less susceptible to interference from antibiotics and contaminants [ 38 , 39 ].…”

Folic Acid, Folinic Acid, 5 Methyl TetraHydroFolate Supplementation for Mutations That Affect Epigenesis through the Folate and One-Carbon Cycles

“…FA, FLA and 5MTHF share the same transporter and receptor. In vitro experiments have shown that cells with low MTHFR activity require 5-MTHF [ 19 ]; 5-MTHF cannot bypass mutations at the levels of methionine synthase or the receptors/transporters.…”

“…Unmetabolized FA in plasma occurs regularly following FA supplementation, but rarely with 5-MTHF [ 31 ]. High doses of folic acid can induce a pseudo MTHFR syndrome simply via a Michaelis and Menten effect on enzymes that have a weak/slow activity [ 18 , 19 , 40 ]. Determining the real impact of UMFA in infants is important: it is a common feature in countries that implement an FA fortification program.…”