James Odell, OMD, ND, LAc
This article will outline the importance of eating foods rich in folate and differentiate the difference between natural folate and synthetic folic acid. The intention is to highlight folate supplementation, such as 5-methyltetrahydrofolate (5-MTHF), that can assist in treating and preventing many diseases.
What Is Folate?
Folate, also known as vitamin B9, is the term given to a family of chemically similar compounds recognized as an essential nutrient for numerous metabolic pathways and the prevention of many adverse health conditions. Adequate folate intake is critical in preventing neural tube defects, certain forms of anemia (megaloblastic), cardiovascular disease, dementia, and certain cancers. 1, 2, 3, 4
The Folate Family of Compounds
Folate is the generic term for a family of compounds that include 5-methyltetrahydrofolate (5-MTHF), 5-formyltetrahydrofolate (5-FTHF or folinic acid), 10-formyl-tetrahydrofolate, and 5,10-methylene- tetrahydrofolate. Methyl THF (CH 3 -THF) is the most common form of folate in blood and tissues. However, other folate forms in which the bound carbon has a higher oxidation state also have vital important cellular roles. For example, 5,10-methylene-THF is used by the enzyme thymidylate synthase to produce deoxythymidine monophosphate (dTMP) from deoxyuridine monophosphate (dUMP), an important step in DNA synthesis. At the same time, 10-formyl-THF is required as a carbon donor for two steps in purine synthesis. THF is also a cofactor for enzymes that metabolize histidine, serine, glycine, and methionine. 5
The interconversion between different folate forms occurs through the folate-mediated one-carbon metabolic pathway, such that the amount of a particular oxidation state of one-carbon-bound THF produced can be tailored according to cellular needs. This pathway is mainly compartmentalized between the cell’s cytosol and mitochondria, with smaller folate amounts in the nucleus.
Folate Metabolism and Biochemistry
Folate metabolism is influenced by several processes, especially its dietary intake and certain associated gene’s polymorphisms. The methionine cycle is highly dependent upon adequate folate status as demonstrated in the diagram below.
Folate and Homocysteine
The amino acid homocysteine is an essential intermediate in folate metabolism. Substantial evidence indicates that elevated plasma homocysteine is an independent risk factor for heart disease and stroke. Plasma homocysteine levels can be reduced by consuming foods containing folate and folate supplements. Thus, when folate status is poor, the ability of the cell to re-methylate cellular homocysteine is impaired, resulting in increased plasma homocysteine levels. Elevated homocysteine levels relate to various pathologies both in adult and child populations. Specifically, elevated levels of homocysteine (hyperhomocysteinemia) are correlated to occlusive artery disease, especially in the brain, the heart, and the kidney, in addition to venous thrombosis, chronic renal failure, megaloblastic anemia, osteoporosis, depression, Alzheimer’s disease, pregnancy problems, and numerous other conditions.
Hyperhomocysteinemia can be caused by deficiencies in folate, cobalamin (vitamin B12), and to a lesser extent, deficiency in pyridoxine (vitamin B6).
MTHFR Genetic Mutations (Polymorphisms)
Other common causes of hyperhomocysteinemia include genetic mutations and enzyme deficiencies in 5, 10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MS), and cystathionine β-synthase. It is shown that plasma homocysteine levels indirectly indicate folate levels and B12 levels. These methylation reactions play important roles in development, gene expression, and genomic stability. In short, studies show plasma levels of folate are inversely related to plasma homocysteine levels which demonstrate a strong connection between folate intake and reduced risk of inflammatory and vascular disease.
Genetic polymorphism may also impair the MTHFR activity and the related metabolization of food folates and folic acid in 5-MTHF. MTHFR is highly polymorphic in the general population, with multiple MTHFR gene alterations having been identified. Today, 35 rare but deleterious mutations in MTHFR, polymorphisms, and nine common variants have been reported. The two most common are C677T and A1298C. The numbers refer to their location on the gene.
A polymorphic MTHFR (5, 10-methylenetetrahydrofolate reductase) enzyme may function with approximately 55% to 70% efficiency as compared to a normal MTHFR enzyme. The incidence of people presenting a form of polymorphism of MTHFR is about 40% worldwide. This polymorphism is associated with a reduced specific activity of MTHFR, resulting in a residual enzyme activity of 65% for heterozygous carriers and only 30% for homozygous carriers. 6, 7, 8, 9
It’s valuable to get an MTHFR genetic test and is especially recommended for women of childbearing age. This is because MTHFR mutations may increase the risk of miscarriage and birth defects. Getting an MTHFR test is also important if you have a history of thyroid or autoimmune disease. MTHFR polymorphisms contribute to those conditions as well.
Cancer
Colorectal cancer represents a major leading cause of death due to malignancies. There is reasonable evidence to implicate low folate status in the specific case of colorectal cancer. In particular, folate supplementation may substantially reduce the risk of colorectal cancer substantially. 10, 11, 12, 13, 14
Megaloblastic Anemia
As the name suggests, Megaloblastic anemia is characterized by large, nucleated (most red blood cells do not have a nucleus), immature red blood cells. Megaloblastic anemia is most commonly due to a deficiency of folate or cobalamin (vitamin B12). Folate deficiency is usually nutritional in origin and may be seen in alcoholics and the elderly poor but also in patients on hyperalimentation or hemodialysis. Megaloblastic anemia is also common in developing countries as a result of low folate foods. Over the last two to three decades, the incidence of megaloblastic anemia seems to be increasing. This occurs because folate is needed for DNA synthesis and without it, red blood cells are not able to divide properly. 15
As a result, fewer and poorer functioning red blood cells are produced that cannot carry oxygen as efficiently as normal red blood cells. 16
Cobalamin (B12) deficiency leads not only to megaloblastic anemia but also to a demyelinating disease that manifests itself as peripheral neuropathy, spastic paralysis with ataxia (so-called combined system disease of the spinal cord), dementia, psychosis, or a combination of the foregoing. “Subtle” cobalamin deficiency, manifested as neurologic symptoms without anemia, appears to be relatively widespread among the elderly.
All megaloblastic anemias share certain general clinical features. Because the anemia develops slowly, it produces few symptoms until the hematocrit is severely depressed. When symptoms appear, they are those of anemia: weakness, palpitation, fatigue, light-headedness, and shortness of breath. Severe pallor and slight jaundice combine to produce a telltale lemon-yellow skin. Leukocyte and platelet counts may also be low but rarely cause clinical problems.
The Difference Between Folic Acid and Folate
Unfortunately, much of the research literature confuses folate with folic acid and does not distinguish the important metabolic differences between naturally occurring folate and synthetic folic acid. Folic acid, or pteroylglutamic acid, is a synthetic, oxidized water-soluble molecule which was created in a laboratory in 1943. Being synthetic, it does not exist in nature. It is composed of two main units: a pteroyl group linked to a glutamic acid residue. Thus, folic acid refers to the synthetic form, while folate refers to the natural form. Folic acid is only found in certain foods because they have been fortified with it, not because they produce it.
The structure of folic acid is shown below.
A key structural difference between folate and folic acid is the number of glutamates in their tails. Notice that glutamate is boxed in the structure of folic acid above. Folic acid always exists as a monoglutamate, meaning it only contains 1 glutamate. On the other hand, about 90% of the natural folate found in foods are polyglutamates, meaning there is more than 1 glutamate in their tail.
Folic acid itself is not active as a coenzyme and must undergo several metabolic steps to be converted into the metabolically active THF (H4PteGlu) form. These steps rob methyl molecules necessary for converting methionine into homocysteine and homocysteine into cysteine. Specifically, folic acid is first reduced to dihydrofolate (H2PteGlu) by the enzyme dihydrofolate reductase (DHFR) and then to tetrahydrofolate (THF). This rate-limiting step leads to DHFR’s weak activity in humans, with considerable interindividual variations. Even minimal quantities of folic acid can lead to a rapid saturation or inhibition of the DHFR enzyme, resulting in an accumulation of unmetabolized folic acid causing unmetabolized folic acid (UMFA) syndrome.
Concerns of Unmetabolized Folic Acid
There are increasing concerns that exposure to unmetabolized folic acid, which results from folic acid intakes that overwhelm the liver’s metabolic capacity, may be associated with adverse effects. The rate of folate metabolism is different for everyone, but generally, the body breaks down folic acid slower than folate from natural sources. Most of the burden to metabolize folic acid falls onto the liver. This is where the bulk of the DHFR enzyme is made. The liver has a limited capacity to reduce folic acid into THF due to natural biological limitations. Only people who are supplementing with or consuming folic acid-fortified foods are at risk for having UMFA present in their blood. UMFA can cause a variety of problems within the body including: 17, 18
Impairment of the immune system
Cancer grows more easily due to lower natural killer cell activity Impairs iron metabolism leading to anemia.
Cognitive and memory impairment and memory
Also, unmetabolized folic acid may compete with natural folate (5-MTHF) for the folate transporter and the folate receptor, thus depleting active folate for participation in the metabolic cycles. 19, 20, 21 For instance, both folic acid and dihydrofolate (H 2 PteGlu) are substrates for dihydrofolate reductase (DHFR). Although the affinity of DHFR for dihydrofolate is higher than its affinity for folic acid, in the presence of high concentrations of folic acid, folic acid could competitively inhibit the conversion of dihydrofolate to THF (H 4 PteGlu). 22
Intracellular Folate Deficiency
Neither folic acid nor dihydrofolate is metabolically active, this can create an intracellular folate deficiency. Another study observed the downregulation of folate transporters in intestinal and renal epithelial cells cultured in growth media that were over-supplemented with folic acid. 23
Two studies have demonstrated the presence of detectable levels of unmetabolized folic acid in fasting plasma samples after eight to 14 weeks of supplementation with 400 μg/day of folic acid. 24, 25
This suggests that daily ingestion of more than 400 mcg of synthetic folic acid saturates not only hepatic DHFR activity but also cellular uptake and renal clearance mechanisms. Thus, naturally occurring folate has important advantages over synthetic folic acid. First, it is well absorbed even when gastrointestinal pH is altered, and its bioavailability is not affected by metabolic defects.
Supplemental folate
Supplemental folate is available as 5-methyltetrahydrofolate (5-MTHF). Using this form instead of folic acid reduces the potential for masking hematological symptoms of vitamin B12 deficiency, reduces interactions with drugs that inhibit dihydrofolate reductase, and overcomes metabolic defects caused by methylenetetrahydrofolate reductase polymorphism. The use of 5-MTHF also prevents the potential negative effects of unconverted folic acid in the peripheral circulation.
Folic Acid Addition to Food
In 1996, the U.S. Food and Drug Administration issued a regulation requiring that all enriched cereal-grain products be fortified with synthetic folic acid by January 1998. An average increase in folic acid intake of 100 μg/d was projected because of this “fortification”. Thus in 1998, the U.S. government mandated the addition of folic acid to certain staple grain products (flour, rice, breads, rolls and buns, pasta, corn grits, corn meal, farina, macaroni, and noodle products). Iron, thiamin, riboflavin, and niacin had already been added to these enriched cereal-grain products.
The added level of folic acid was set at 140 micrograms per 100 grams of grain product, targeting these foods due to their widespread consumption in the American diet. Beyond mandatory fortification, many food manufacturers voluntarily add folic acid to other products like breakfast cereals and corn tortillas. However, there remain many unanswered questions regarding the safety and importance of the additional folic acid in the American diet. 26
This decision was based on evidence that natural folate intake before and during early pregnancy significantly reduces the risk of neural tube defects in newborns, such as spina bifida. Even though folic acid is metabolically vastly different than naturally occurring folate, this addition of synthetic folate continues to date.
Folate bioavailability is defined as the proportion of an ingested amount of folate that is absorbed in the gut and that becomes available for metabolic processes. To sell the idea that folic acid should be added to food, the government’s Dietary Reference Intake (DRI) committee arbitrarily and erroneously propagated that the bioavailability of folate was believed to be much lower than synthetic folic acid. 27
To make it appear folic acid was more bioavailable than it was, in 1998 the DRI committee created dietary folate equivalents (DFEs) as follows:
DFE = ug food folate + (ug folic acid X 1.7) The 1.7 came from questionable research suggesting that folic acid from fortified food was 85% bioavailable, compared to 50% for folate (85%/50% = 1.7). 28
There is now newer evidence suggesting folate’s bioavailability from food is much higher than previously published. 29, 30 This means that food folate levels are contributing much more towards our dietary needs than currently estimated, but the DRI for folate/folic acid has not yet been updated. 31
Conclusion
An abundance of data reflects the need to distinguish between naturally occurring folates and synthetic folic acid, as these terms are often mistaken and used interchangeably, both by practitioners and consumers, causing considerable confusion. Folic acid can interfere with the metabolism, cellular transport, and regulatory functions of the natural folates that occur in the body by competing with the reduced forms for binding with enzymes, carrier proteins, and binding proteins.
Folic acid is not a normal metabolite and must be reduced, first to dihydrofolate and then to tetrahydrofolate, primarily in the liver, before it can enter the folate cycle.
This multistep process robs methyl molecules necessary for the all-important methylation process leading to high levels of homocysteine and reduced methionine. High homocysteine creates inflammation that affects blood vessels, the central nervous system, as well as other organs, glands, and tissues.
Other concerns include whether the increased uptake of folic acid rather than 5-methyl-THF during cell division could reduce the methionine supply at a critical time and whether the long-term intake of relatively high doses of folic acid can change the gene expression of the folate-dependent enzymes or influence metabolic flux in the pathways involving one-carbon units. Fortification of folic acid in foods raises the concentration of unmetabolized folic acid, above that occurring with normal diets. Unmetabolized folic acid leads to impairment of the immune system, cancer, certain types of anemia, and cognitive and memory impairment. For a significant proportion of the population, the concentrations are likely to be particularly high because of dietary habits. These groups include children and the elderly, for whom bread, and breakfast cereals are a major part of their diet, and the increasing number who take multivitamin supplements that include folic acid.
Because folic acid can accumulate and interfere with methylation and detoxification of chemicals it may cause neurological injury. It can also mask pernicious anemia and even cause drug-related interference to epileptic-treated patients because seizure control may be affected. Also, because antifolate medications are now being used to treat a wide range of malignant and nonmalignant 7 disorders, further investigation is needed concerning the safety of folic acid supplements in patients with these disorders.
Tips:
In short, eat foods rich in folate and avoid foods fortified with folic acid.
Always choose folate over folic acid as a food supplement.
If you need to supplement, 5-methyltetrahydrofolate has been shown as a superior alternative to folic acid supplementation. Particularly when taken together with methylcobalamin (the methylated form of b-12) and a good b-complex.
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