Folic acid

Alternative Medicine Review, Sept, 2005

Introduction

Folic acid, also known generically as folate or folacin, is a member of the B-complex family of vitamins, and works in concert with vitamin B 12. Folic acid functions primarily as a methyl-group donor involved in many important body processes, including DNA synthesis. Therapeutically, folic acid is instrumental in reducing homocysteine levels and the occurrence of neural tube defects. It may play a key role in preventing cervical dysplasia and protecting against neoplasia in ulcerative colitis. Folic acid also shows promise as part of a nutritional protocol to treat vitiligo, and may reduce inflammation of the gingiva. Furthermore, certain neurological, cognitive, and psychiatric presentations may be secondary to folate deficiency. Such presentations include peripheral neuropathy, myelopathy, restless legs syndrome, insomnia, dementia, forgetfulness, irritability, endogenous depression, organic psychosis, and schizophrenia-like syndromes.

Biochemistry

Folic acid is a water-soluble member of the B-complex family of vitamins. Folic acid is composed of three primary structures, a hetero-bicyclic pteridine ring, para-aminobenzoic acid (PABA), and glutamic acid. Because humans cannot synthesize this compound, it is a dietary requirement.

Although folic acid is the primary form of folate used in dietary supplements or fortified foods, it comprises only 10 percent or less of folates in the diet. Dietary folic acid, or the form naturally found in foods, is actually a complex and variable mixture of folate compounds, such as polyglutamate (multiple glutamate molecules attached) conjugate compounds, reduced folates, and tetrahydrofolates. Although folates are abundant in the diet, cooking or processing destroys these compounds. The best folate sources in foods are green, leafy vegetables; sprouts, fruits, brewer's yeast, liver, and kidney also contain high amounts of folates.

Pharmacokinetics

Human pharmacokinetic studies indicate folic acid has very high bioavailability, with large oral doses of folic acid substantially raising plasma levels in healthy subjects in a time- and dose-dependent manner. Subsequent to high-dose oral administration of folic acid (ranging from 25-1,000 mg/day), red blood cell (RBC) folate levels remain elevated for periods in excess of 40 days following discontinuation of the supplement. Folic acid is poorly transported to the brain and rapidly cleared from the central nervous system. The primary methods of elimination of absorbed folic acid are fecal (through bile) and urinary. (1-4)

After ingestion, the process of conversion of folic acid to the metabolically active coenzyme forms is relatively complex. Synthesis of the active forms of folic acid requires several enzymes, adequate liver and intestinal function, and adequate supplies of riboflavin (B2), niacin (B3), pyridoxine (B6), zinc, vitamin C, and serine. After the formation of the coenzyme forms of the vitamin in the liver, these metabolically active compounds are secreted into the small intestine with bile (the folate enterohepatic cycle), where they are reabsorbed and distributed to tissues throughout the body. Despite the biochemical complexity of this process, evidence suggests oral supplementation with folic acid is able to increase the body's pool of the active reduced folate metabolites (such as methyltetrahydrofolate) in healthy individuals. (5)

Enzyme defects, malabsorption or digestive system pathology, and liver disease can result in impaired ability to activate folic acid to the required coenzyme forms in the body. Evidence indicates some individuals have a severe congenital deficiency of the enzyme methyltetrahydrofolate reductase, which is needed to convert folic acid to the 5-methyltetrahydrofolate coenzyme form of the vitamin. The existence of milder forms of this enzyme defect is strongly suspected and likely interacts with dietary folate status to determine risk for some disease conditions. (6-10) In individuals with a genetic defect of this enzyme (whether mild or severe), greater dietary exposure to foods rich in folates and supplemental folates in the form of folinic acid or 5-methyltetrahydrofolate might be preferable to folic acid supplementation.

Mechanisms of Action

Folic acid's primary mechanisms of action are through its role as a methyl donor in a range of metabolic and nervous system biochemical processes, as well as being necessary for DNA synthesis. Serine reacts with tetrahydrofolate, forming 5,10-methylenetetrahydrofolate, the folate derivative involved in DNA synthesis. A methyl group is donated to cobalamin (B12) by 5-methyltetrahydrofolate, forming methylcobalamin. With the help of the enzyme methionine synthase, methylcobalamin donates a methyl group to the amino acid metabolite homocysteine, converting it to the amino acid methionine.

Methionine subsequently is converted to S-adenosylmethionine (SAMe), a methyl donor involved in numerous biochemical processes.

Deficiency States and Symptoms