Folate Metabolism; plasma

Overview:

Folate is a generic term that includes the various derivatives of naturally occurring physiologically important forms of folate (b-9), and synthetic folic acid. Naturally occurring folates are derived mostly from dark green leafy vegetables while synthetic folic acid is used under mandate in fortified cereals and other processed foods. Folic acid is also the most common form found in nutritional supplements and prescribed prenatally for women to prevent serious birth defects of the fetal spinal cord and brain. There is much debate regarding synthetic folic acid as it is not considered biologically active unless converted into activated folates. Folic acid can impede essential folate metabolism by means of blocking folate receptors and transporters, along with inhibiting the enzyme dihydrofolate reductase (DHFR), which initiates the reductive activation of folates. High levels of unmetabolized folic acid (UMFA) may also promote the growth of existing cancers, and have been associated with decreased natural killer cell activity and increased cancer risk. Activated forms of folate in their reduced chemical form are obligatory cofactors in the metabolism of amino acids, DNA and biopterin (BH₂ to BH₄). Various genetic and epigenetic factors may adversely affect folate metabolism; e.g. methotrexate and excessive intake of polyphenols. The level of total folates in red blood cells (RBC) has traditionally been used to assess long-term folate status, but the test does not provide clinically important information regarding specific forms of folate. Folate levels in RBC and plasma reflect hepatic folate stores. Although plasma folates are cleared rapidly, the analysis of plasma folates allows for the distinction between the different forms to help identify and aberrant folate metabolism. Five-methyltetrahydrofolate (5-MTHF) is the predominate folate in plasma and is the bioactive derivative with respect to donation of a methyl group to homocysteine using cobalamin (B-12) bound to MTR (methionine synthase). Tetrahydrofolate (THF) is a byproduct of MTR activity and can be recycled back to other bioactive reduced forms of folate. Folinic acid (5-formylTHF) supports purine biosynthesis (DNA nucleobases), and can be converted to 5-MTHF under normal conditions; an abnormal ratio of folinic acid to 5-MTHF might be clinical significant and indicative of aberrant folate metabolism. Folinic acid can be effective in patients with inherited disorders of folate transport or with folate receptor autoantibodies as it readily crosses the blood-brain-barrier. Folinic acid may thereby normalize the level of active folate derivatives and has been shown to normalize folate concentrations and improve various social interactions in cerebral folate deficiency, including mood, behavior, and verbal communication in children with autistic spectrum disorders. The Plasma Folate test reports the levels of THF, UMFA, folinic acid and 5-MTHF and an be used to monitor clinical intervention, or as a "folate challenge test" in assessing folate levels before and one hour post-folate supplementation. It can also be a useful add on to the functional Plasma Methylation Profile.