What Is Folic Acid? Other Names: 5′-methyltetrahydrofolate, Folate, Vitamin B9

What is Folic Acid?

This post was written with Consensus AI Academic Search Engine – please read our Disclaimer at the end of this article. Folic acid, also known as vitamin B9, is a water-soluble vitamin that plays a crucial role in various bodily functions, including DNA synthesis, repair, and methylation. It is essential for the formation of red blood cells and the proper development of the neural tube in embryos. This article explores the biochemical properties of folic acid, its health benefits, and its role in disease prevention and management. Other names include: 5′-methyltetrahydrofolate, 5′-methyltetrahydrofolic acid, 5′-MTHF, Acide Folique, Acide Ptéroylglutamique, Acide Ptéroylmonoglutamique, Acido Folico, B Complex Vitamin, Complexe de Vitamines B, Complexe Vitaminique B, Dihydrofolate, Dihydrofolic Acid, Folacin, Folacine, Folate, Folinic Acid, L-methylfolate, Methylfolate, Méthylfolate, Methylfolic Acid, Pteroylglutamic Acid, Pteroylmonoglutamic Acid, Pteroylpolyglutamate, Tetrahydrofolate, Tétrahydrofolate, Vitamin B9, Vitamine B9.

Biochemistry and Metabolism

Folic acid is the synthetic form of folate, which naturally occurs in foods such as dark green leafy vegetables. Once ingested, folic acid is converted into its active form, tetrahydrofolate (THF), which participates in one-carbon metabolism. This metabolic pathway is vital for the synthesis of nucleotides and the remethylation of homocysteine to methionine, a process crucial for DNA synthesis and repair.

Health Benefits of Folic Acid

Prevention of Neural Tube Defects

One of the most well-documented benefits of folic acid is its role in preventing neural tube defects (NTDs) such as spina bifida. Adequate folic acid intake before conception and during early pregnancy significantly reduces the risk of these congenital malformations . Studies have shown that increasing folic acid intake can lead to a substantial reduction in the incidence of NTDs, with higher doses providing greater protective effects.

Cardiovascular Health

Folic acid is also known for its ability to lower homocysteine levels in the blood, a risk factor for cardiovascular diseases. Elevated homocysteine levels are associated with an increased risk of arterial disease, dementia, and Alzheimer’s disease. Supplementation with folic acid, often in combination with vitamin B12, has been shown to reduce homocysteine levels, potentially lowering the risk of these conditions .

Cognitive Function

There is ongoing research into the effects of folic acid on cognitive function, particularly in the elderly. While some studies have found no significant benefit of folic acid supplementation on cognitive measures, others suggest that it may help in reducing serum homocysteine concentrations, which is linked to cognitive decline.

Role in Disease Processes of Folic Acid

Cancer

Folic acid plays a dual role in cancer prevention and progression. While it helps in DNA synthesis and repair, thereby preventing cancer initiation, high levels of folic acid may facilitate the growth of existing preneoplastic cells. This dual effect necessitates a cautious approach to folic acid supplementation, especially in populations at risk for cancer.

Chronic Inflammatory and Autoimmune Diseases

Folic acid deficiency is common in chronic inflammatory and autoimmune conditions such as rheumatoid arthritis and psoriasis. Supplementation can help manage these conditions by reducing homocysteine levels and potentially lowering the risk of cardiovascular events associated with these diseases.

Safety and Recommendations

Fortification and Supplementation

Many countries have implemented folic acid fortification programs to reduce the incidence of NTDs. However, there is ongoing debate about the optimal levels of fortification and supplementation. Excessive intake of folic acid, particularly from supplements, may lead to unmetabolized folic acid in the blood, which has been associated with potential adverse effects, including masking vitamin B12 deficiency and influencing DNA methylation .

Special Populations

Pregnant women and those planning to conceive are advised to take folic acid supplements to prevent NTDs. The recommended dose varies, with some guidelines suggesting higher doses for women with a history of NTD-affected pregnancies .

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Adverse Effects of Folic Acid

Exacerbation of Vitamin B-12 Deficiency Symptoms

High folic acid intake can worsen clinical and biochemical signs of vitamin B-12 deficiency, such as anemia and cognitive impairment, particularly in the elderly .

Cancer Risk

Some studies suggest that excessive folic acid intake may increase the risk of certain cancers, although the evidence is not conclusive .

Neurocognitive Health

There are concerns that high folic acid levels might affect neurocognitive health, potentially exacerbating conditions like cognitive impairment and dementia, especially in individuals with low vitamin B-12 levels .

Insulin Resistance and Gestational Diabetes

High maternal folate levels have been linked to increased insulin resistance in offspring and a higher risk of gestational diabetes mellitus (GDM) .

Unmetabolized Folic Acid (UMFA)

The presence of unmetabolized folic acid in the bloodstream is a potential issue, with unclear health implications, but it is a concern for its possible role in adverse health outcomes .

Other Health Concerns

Excessive folic acid intake may interfere with zinc absorption, affect seizure control in epileptic patients, and lower natural killer cell activity in elderly women .

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How has Folic Acid Improved Patient Outcomes?

Cardiovascular Health and Homocysteine Levels

Folic acid supplementation significantly reduces plasma homocysteine levels, which is associated with improved endothelial function in patients with high homocysteine concentrations . However, it does not significantly reduce clinical endpoints in patients with stable coronary artery disease on statin treatment.

Diabetes Management

Folic acid, especially when combined with vitamin B12, improves glycemic control, insulin resistance, and serum adiponectin levels in patients with type 2 diabetes mellitus.

Schizophrenia Treatment

Folic acid supplementation, when added to antipsychotic treatment, improves negative symptoms in schizophrenia patients and is well-tolerated, though it does not significantly affect other symptom domains.

Prevention of Birth Defects

Periconceptional folic acid supplementation significantly reduces the risk of neural tube defects (NTDs) in newborns. It does not have a clear effect on other birth defects such as cleft palate or congenital cardiovascular defects .

Cognitive Function in the Elderly

Folic acid supplementation improves cognitive performance and reduces peripheral inflammatory cytokine levels in elderly individuals with mild cognitive impairment (MCI).

Chronic Kidney Disease (CKD)

Folic acid, when combined with enalapril, significantly slows the progression of chronic kidney disease and reduces the rate of renal function decline in patients with mild-to-moderate CKD.

Uric Acid Levels in Hypertensive Patients

Folic acid supplementation reduces serum uric acid levels and the incidence of new-onset hyperuricemia in hypertensive patients.

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Folic Acid Mechanisms of Action

DNA Synthesis and Repair

Folic acid is converted into tetrahydrofolate, which acts as a carrier for one-carbon units in enzymatic reactions essential for DNA and RNA synthesis and repair .

Homocysteine Regulation

Folic acid helps lower homocysteine levels, which is beneficial for cardiovascular health. This is achieved through its role in the remethylation cycle, converting homocysteine to methionine .

Nitric Oxide Synthesis

Folic acid enhances endothelial nitric oxide (eNO) synthesis, which is crucial for vascular health. It stimulates the regeneration of tetrahydrobiopterin (H4B), a cofactor necessary for eNO synthesis, and inhibits superoxide generation, thereby increasing the half-life of nitric oxide .

Cell Growth and Division

Folic acid is vital for rapid cell division and growth, particularly during fetal development. It is involved in the synthesis of nucleotides and amino acids, which are building blocks for new cells .

Immunomodulation

Folic acid has immunomodulatory effects, such as increasing the frequency of regulatory T cells (Treg) and altering DNA methylation patterns, which can help in conditions like alcoholic liver disease.

Cancer and Neural Tube Defects

Folic acid can activate the pro-oncogene STAT3 via the Folate Receptor alpha (FRα), contributing to cell proliferation in cancer cells. It also plays a preventive role in neural tube defects by ensuring proper cell division and growth during early fetal development .

Absorption and Bioavailability

Folic acid is absorbed more efficiently than natural folates. It is converted into its active forms in the liver, which are then utilized in various metabolic processes.

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Common Complaints Associated with Folic Acid Use

Exacerbation of Vitamin B12 Deficiency Symptoms

High folic acid intake can worsen clinical and biochemical signs of vitamin B12 deficiency, such as anemia and cognitive impairment, especially in the elderly .

Cognitive Decline and Dementia

There is no significant benefit of folic acid supplementation on cognitive function or mood in elderly individuals, whether healthy or with mild to moderate cognitive impairment or dementia. High doses may even lead to a decline in cognitive function in some cases .

Insulin Resistance in Offspring

Maternal high folic acid intake has been linked to increased insulin resistance in offspring, particularly in populations with high prevalence of vitamin B12 deficiency .

Potential Genetic and Ethnic Variations

Certain genetic polymorphisms, such as the 19 bp deletion in the DHFR gene, can increase the risk of adverse effects like unilateral retinoblastoma in offspring and lower cognitive scores in the elderly when high folic acid intake is involved.

Reduced Natural Killer Cell Activity

Excessive folic acid intake may be associated with lower natural killer cell activity, which could impact immune function, particularly in elderly women.

General Safety Concerns

Despite the benefits of folic acid in preventing neural tube defects, there are concerns about its safety in high doses, with potential side effects including variations in epigenetic programming and long-term health effects .

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Disclaimer

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