Folic acid/folate metabolism

Folic acid appears in the plasma approximately 15 to 30 minutes after an oral dose peak levels are generally reached within 1 hour. After IV administration, the drug is rapidly cleared from the plasma. Folic acid is metabolized in the liver. Normal serum levels of total folate have been reported to be 5 to 15 ng/mL normal CSF levels are approximately 16 to 21 ng/mL. In general, folate serum levels less than 5 ng/mL indicate folate deficiency, and levels less than 2 ng/mL usually result in megaloblastic anemia. A majority of the metabolic products appeared in the urine after 6 hours excretion was generally complete within 24 hours. 

I. Pharmacology. Folic acid is a B-complex vitamin that is essential for protein synthesis and erythropoiesis. In addition, the administration of folate to patients with methanol poisoning may enhance the elimination of the toxic metabolite formic acid, based on studies in folate-deficient primates. Note Folic acid requires metabolic activation and is not effective for treatment of poisoning by dihydrofolate reductase inhibitors (eg, methotrexate and trimethoprim). Leucovorin (see p 460) is the proper agent in these situations. 

Folic acid (folate) is found in green leafy vegetables and is involved in one-carbon metabolism. Folate supplements are vital during pregnancy. Groups of women who are prescribed folic acid show a significant decrease in the incidence of neural tube defects in their newborns (5b). 

J. R. Bertino, P. F. Nixon, and A. Nahas, Mechanism of uptake of folate monoglutamates and their metabolism. In Folic Acid Biochemistry and Physiology in Relation to Human Nutrition Requirements, National Academy of Sciences, Washington, D. C. 1977, p. 178. 

Figure 22.6 How various factors increase the risk of atherosclerosis, thrombosis and myocardial infarction. The diagram provides suggestions as to how various factors increase the risk of development of the trio of cardiovascular problems. The factors include an excessive intake of total fat, which increases activity of clotting factors, especially factor VIII an excessive intake of saturated or trans fatty acids that change the structure of the plasma membrane of cells, such as endothelial cells, which increases the risk of platelet aggregation or susceptibility of the membrane to injury excessive intake of salt - which increases blood pressure, as does smoking and low physical activity a high intake of fat or cholesterol or a low intake of antioxidants, vitamin 6 2 and folic acid, which can lead either to direct chemical damage (e.g. oxidation) to the structure of LDL or an increase in the serum level of LDL, which also increases the risk of chemical damage to LDL. A low intake of folate and vitamin B12 also decreases metabolism of homocysteine, so that the plasma concentration increases, which can damage the endothelial membrane due to formation of thiolactone.

Folate, the anion of folic acid, is made up of three different components—a pteridine derivative, 4-aminobenzoate, and one or more glutamate residues. After reduction to tetrahydrofolate (THF), folate serves as a coenzyme in the Q metabolism (see p. 418). Folate deficiency is relatively common, and leads to disturbances in nucleotide biosynthesis and thus cell proliferation. As the precursors for blood cells divide particularly rapidly, disturbances of the blood picture can occur, with increased amounts of abnormal precursors for megalocytes megaloblastic anemia). Later, general damage ensues as phospholipid... 

Both the sulfonamides and trimethoprim interfere with bacterial folate metabolism. For purine synthesis tetrahydrofolate is required. It is also a cofactor for the methylation of various amino acids. The formation of dihydrofolate from para-aminobenzoic acid (PABA) is catalyzed by dihydropteroate synthetase. Dihydrofolate is further reduced to tetrahydrofolate by dihydrofolate reductase. Micro organisms require extracellular PABA to form folic acid. Sulfonamides are analogues of PABA. They can enter into the synthesis of folic acid and take the place of PABA. They then competitively inhibit dihydrofolate synthetase resulting in an accumulation of PABA and deficient tetrahydrofolate formation. On the other hand trimethoprim inhibits dihydrofolate... 

All patients with methanol toxicity should be given folic acid 50 milligrams intravenously every 4 hours to increase the metabolism of formic acid. In ethylene glycol ingestion, folate, thiamine and pyri-doxine should all be administered, to enhance the metabolism of the poison to non-toxic products, and minimize oxalic acid production. Calcium supplements are required for symptomatic hypocalcaemia. 

Since sulfasalazine inhibits the absorption of folic acid, patients may become folate deficient during longterm therapy. Sulfasalazine decreases the bioavailabiUty of digoxin. Cholestyramine reduces the metabolism of sulfasalazine. Sulfasalazine causes a reversible decrease in sperm counts. Sulfasalazine is safe in pregnancy. 

Because both drugs may interfere with folic acid metabolism, their use during pregnancy is usually contraindicated by the potential for effects on the fetus, such as the development of neural tube defects associated with folate deficiency. The use of trimethoprim is contraindicated in patients with blood dyscrasias, hepatic damage, and renal impairment. 

The compound sulfanilamide exhibits a structural similarity to para-amino benzoic acid (PABA). Woods and Fields proposed the theory that sulfonamides, being structurally similar to PABA, inhibit bacterial folate synthetase so that folic acid is not formed which is needed for a number of metabolic reactions. Folic acid derived from PABA is essential for bacterial metabolism. Sulfonamides inhibit the enzyme folic acid synthetase which is... 

Gamble MV Folate and arsenic metabolism A double-blind, placebo-controlled folic acid supplementation trial in Bangladesh. Am J Clin Nutr 2006 84 1093. [PMID 17093162]... 

Folic acid (or folate), which plays a key role in one-carbon metabolism, is essential for the biosynthesis of several compounds. Folic acid deficiency is probably the most common vitamin deficiency in the United States, particularly among pregnant women and alcoholics. 

The evaluation of folic acid status must often also include evaluation of vilamin B1 because of its effect on folate metabolism. A vilamin Bu-dependenl reaction is necessary for an cit/vmc involved in the catabolism of branchcd-chain amino acids (mclhylmalonyl CoA to succinyl CoA). This reaction may provide the basis for a functional assessment method for vitamin Biz status. See also Hormones and Vitamin. 

Folacin bioavailability varies among the vitamers (120,125). Folic acid is more readily available than the naturally occurring food folates but may be less available from fortified foods than in aqueous solution or tablet form. Food folates have been reported to be 30-80% as available as folic acid. Folacin availability, absorption, and metabolism were recently reviewed (20,120,122). 

Anyone taking diuretics for longer than six months may experience a folate, or folic acid, deficiency. Folic acid plays a part in the health and reproduction of virtually every cell in the body. It is responsible for protein metabolism, the prevention of neural tube defects in pregnancy, blood cell production, and the synthesis of neurotransmitters. Individuals with folate deficiencies may suffer from anemia, depression and other mood disorders, and may give birth to babies with neural tube defects. Supplementation with folic acid may be useful in reversing these effects. 

Folic acid deficiency, unlike vitamin B12 deficiency, is often caused by inadequate dietary intake of folates. Alcoholics and patients with liver disease develop folic acid deficiency because of poor diet and diminished hepatic storage of folates. There is also evidence that alcohol and liver disease interfere with absorption and metabolism of folates. Pregnant women and patients with hemolytic anemia have increased folate requirements and may become folic acid-deficient, especially if their diets are marginal. Evidence implicates maternal folic acid deficiency in the occurrence of fetal neural tube defects, eg, spina bifida. (See Folic Acid Supplementation A Public Health Dilemma.) Patients with malabsorption syndromes also frequently develop folic acid deficiency. Folic acid deficiency is occasionally associated with cancer, leukemia, myeloproliferative disorders, certain chronic skin disorders, and other chronic debilitating diseases. Patients who require renal dialysis also develop folic acid deficiency, because folates are removed from the plasma each time the patient is dialyzed. 

Folic acid deficiency can be caused by drugs that interfere with folate absorption or metabolism. Phenytoin, some other anticonvulsants, oral contraceptives, and isoniazid can cause folic acid deficiency by interfering with folic acid absorption. Other drugs such as methotrexate and, to a lesser extent, trimethoprim and pyrimethamine, inhibit dihydrofolate reductase and may result in a deficiency of folate cofactors and ultimately in megaloblastic anemia. 

Oxidized folate is not only metabolically dead buyt may even be neurotoxic. For example, a patient with epilepsy who has not had a convulsion in years because dilantin has produced complete control, can be thrown into an immediate convulsion with a megadose of folic acid, because folic acid and dilantin compete for absorption at the brain cell surface, and too much oxidized folic acid will block the ability of the brain cell to take up dilantin, similar to the competition between dilantin and folic acid for uptake by the gutcell (22). 

Folic acid participates in the activation of single carbons and in the oxidation and reduction of single carbons. Folate-dependent single-carbon reactions are important in amino acid metabolism and in biosynthetic pathways leading to DNA, RNA, membrane lipids, and neurotransmitters. 

Methotrexate [meth oh TREX ate] (MTX) is structurally related to folic acid and acts as an antagonist of that vitamin by inhibiting dihydrofolate reductase1, the enzyme that converts folic acid to its active, coenzyme form, tetrahydrofolic acid (FH4) it therefore acts as an antagonist of that vitamin. Folate plays a central role in a variety of metabolic reactions involving the transfer of one-carbon units. (Figure 38.7)2. 

Vitamin B12 is required by only two enzymes in human metabolism methionine synthetase and L-methylmalonyl-CoA mutase. Methionine synthetase has an absolute requirement for methylcobalamin and catalyzes the conversion of homocysteine to methionine (Fig. 28-5). 5-Methyltetrahydrofolate is converted to tetrahydrofolate (THF) in this reaction. This vitamin B12-catalyzed reaction is the only means by which THF can be regenerated from 5-methyltetrahydrofolate in humans. Therefore, in vitamin B12 deficiency, folic acid can become trapped in the 5-methyltetrahydrofolate form, and THF is then unavailable for conversion to other coenzyme forms required for purine, pyrimidine, and amino acid synthesis (Fig. 28-6). All folate-dependent reactions are impaired in vitamin B12 deficiency, resulting in indistinguishable hematological abnormalities in both folate and vitamin B12 deficiencies. 

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