In this article we will discuss about Folic Acid:- 1. Introduction to Folic Acid 2. Chemistry on Folic Acid 3. Absorption and Transport 4. Excretion 5. Folic Acid 6. Normal Level in Serum 7. Source 8. Physiological Functions 9. Antagonists 10. Importance 11. Deficiency Symptoms 12. Management 13. Toxic Effects.
- Introduction to Folic Acid
- Chemistry on Folic Acid
- Absorption and Transport of Folic Acid
- Excretion of Folic Acid
- Folic Acid in Tissues
- Normal Level of Folic Acid in Serum
- Source of Folic Acid
- Physiological Functions of Folic Acid
- Folic Acid Antagonists
- Importance of Folic Acid
- Deficiency Symptoms of Folic Acid
- Management of Folic Acid
- Toxic Effects of Folic Acid
1. Introduction to Folic Acid:
a. In 1934, Wills showed that tropical macrocytic anemia in human beings was cured by a vitamin present in autolysed yeast extract.
b. In 1947, Pifiner et al isolated folic acid in a crystalline form from liver.
2. Chemistry on Folic Acid:
a. Folic acid (folacin, pteroylglutamic acid) is a compound made up of the Pteridine nucleus, P-amino-benzoic acid and glutamic acid. There are at least three nutritionally important and chemically related compounds which occur in natural products belong to the folic acid group. These three compounds only differ in the number of glutamic acid residues attached to the Pteridine-amino-benzoic acid complex. The chemical structure of folic acid is given (Fig. 15.19). Folic acid is synonymous with vitamin Bc.
b. Folinic acid (leucovorin, folinic acid-SF [synthetic factor] is the reduced form of folic acid with a formyl group on position 5 (N5-formyl-tetrahydrofolic acid).
c. Folic acid is soluble in water.
d. It is stable to heat at neutral pH.
e. Its activity is not lost if it is heated at 120°C for 30 minutes at neutral pH.
f. Riboflavin accelerates the photo-oxidation of folic acid.
3. Absorption and Transport of Folic Acid:
a. Absorption of folic acid takes place along the whole length of the mucosa of the small intestine.
b. Mono-glutamates are produced from poly-glutamates which is ingested within the intestinal mucosa and di-hydro-folates are further reduced to tetra-hydro-folates by folic acid reductases.
c. The tetra-hydrofolates are then converted to methyl-tetrahydrofolate which enters the portal blood to be transported to the liver.
d. The vitamin then appears in the systemic circulation to supply the tissue.
e. The vitamin is transported to the plasma as methyl-tetrahydrofolate bound to protein. The folate level of plasma obtained from umbilical cord blood is about 3 times that of the maternal plasma.
4. Excretion of Folic Acid:
a. 20% of ingested folate that remains unabsorbed is excreted in the feces.
b. 2-5 µg of folic acid is excreted in the urine daily. This may be increased after an oral dose of folate if the tissues are saturated.
c. Some folates are also excreted in saliva, sweat and bile.
5. Folic Acid in Tissues:
a. Tissue folate is about 70 mg in the whole body.
b. About one-third (5-15 µg/g) is in the liver.
c. Folate is incorporated into the erythrocytes during erythropoiesis.
6. Normal Level of Folic Acid in Serum:
3-25 µg/1 of serum in healthy subjects.
7. Source of Folic Acid:
8. Physiological Functions of Folic Acid:
a. Folic acid as a coenzyme is involved in the transfer and utilization of the single carbon (C -1) moiety.
Before functioning as a C- 1 carrier, folic acid is first reduced to 7, 8-dihydrofolic acid (H2 folate) and then to the tetra-hydro compound (H4 folate) catalyzed by folic acid reductase which uses NADPH as hydrogen donor.
The “one carbon” moiety may be formyl (-CHO), formate(H+COO–), methyl (CH3–) or hydroxymethyl (-CH2OH). These are metabolically interchangeable.
Folinic acid (formyl tetrahydrofolate, f5 – H4 folate) is involved in the formylation of glutamic acid during the metabolic degradation of histidine; otherwise, it is metabolically inert. But f10-H4 folate is metabolically active.
However, f5 can be converted to f5-10 by formyl tetrahydrofolic acid isomerase as:
F5-10-H4 folate is also converted to N5– methyl-tetrahydrofolic acid by an NAD- dependent reductase and this methyl group is then transferred to de-oxy-adenosyl —B12 (cobamide coenzyme) to form methyl B12 which is an important donor of methyl group in the formation of methionine from homocysteine.
The other sources of the one-carbon moiety are the methyl groups of methionine, choline (by way of betaine) and thymine. These methyl groups are oxidized to -CH2OH groups and carried as such on f5-10-H4 folate. The beta carbon of serine contributes hydroxymethyl group to the formation of a single carbon moiety.
The single (formyl) carbon present on the tetrahydrofolic acids is utilized in the following ways:
(i) As a source of carbons 2 and 8 in the purine nucleus.
(ii) As a source of the formyl group on N- formyl methionine-tRNA which initiates synthesis of peptide chains on ribosomes in microorganisms.
(iii) As a source of the formyl carbon in the formation of the beta carbon of serine in conversion of glycine to serine.
(iv) In the synthesis of methyl groups for methylation of homocysteine to form methionine or methylation of uracil to form thymine and for the synthesis of choline by the way of methyl groups from methionine.
b. Since the folic acid coenzymes take part in the synthesis of purines and thymine (the methylated pyrimidine of DNA) they are fundamentally involved in growth and reproduction of cells.
c. Folic acid coenzymes are not only confined to the hematopoietic system but are also generalized throughout the body.
d. In the metabolism of histidine, there is a folic acid-dependent step at the point where formiminoglutamic acid (Figlu) is converted to glutamic acid.
9. Folic Acid Antagonists:
1. The competitive inhibitor aminopterin (4-amino folic acid) is the most potent folic acid inhibitor.
2. Another antagonist is amethopterine (4-amino-10-methyl folic acid).
3. In animals the inhibitory effect of amtnopterin cannot be reversed by folic acid but only by folinic acid.
10. Importance of Folic Acid:
a. They have got clinical application in the treatment of malignant disease and confirmation of the action of folic acid in cell growth.
b. Aminopterine has been used in the treatment of leukemia, particularly in children. A remission is temporarily observed in some patients but after a time the leukemic cells acquire the power to overcome the effects of the antagonist.
11. Deficiency Symptoms of Folic Acid:
Folic acid deficiency can result from low dietary intake, in intestinal malabsorption syndromes and during pregnancy. A similar deficiency can occur as a result of prolonged administration of anticonvulsant drugs (phenytoin sodium and primidone). Folic acid antagonists also cause deficiency of folic acid.
The deficiency gives rise to a megaloblastic anemia. The nuclei of the neutrophil polymorphonuclear leukocytes contain more than the normal number of lobes. Other deficiency manifestations include retardation of growth, weakness, infertility, inadequate lactation in females and increased output of formiminoglutamic acid (FIGLU) in the urine after histidine loading.
12. Management of Folic Acid:
(a) In folic acid deficiency, treatment with a daily dose of 5 mg of folic acid by mouth is sufficient; 5 mg once a week is always adequate for maintenance therapy.
(b) Folic acid must never be given other than with vitamin B12 in Addisonian pernicious anemia or other vitamin B12 deficiency anemia’s because of the risk of aggravating or precipitating neurological features of vitamin B12 depletion.
(c) Megaloblastic change due to vitamin B12 deficiency is very rare in pregnancy. Therefore, it is reasonable to give folic acid supplements (350 µg daily) to all pregnant women.
(d) When a drug methotrexate inhibits dihydrofolate reductase, it is better to employ folinic acid to overcome the metabolic block. Folinic acid may be given as tablets, 15 mg daily orally or as an injection intravenously or intramuscularly at a dose of 3 mg per ml.
(e) Folinic acid mouthwashes are used to counteract the oral side-effects of folate antagonist drugs.
(f) Megaloblastic disorder caused by other cytotoxic drugs which inhibit DNA synthesis is not reversed by either vitamin B12 or folic acid administration.
(g) Severe hemolytic crises require treatment by blood transfusion. Folic acid 5 mg daily orally is prescribed to support the increased erythropoiesis.
(h) Following splenectomy, resistance to some infections may be impaired and daily penicillin V, 250 mg 12 hourly, is prescribed for at least 5 years.
13. Toxic Effects of Folic Acid:
Renal injury has been observed in animals receiving large doses (50 mg./kg. body wt.) of folic acid intravenously.
Excess intake of folic acid may hasten the development of the nerve damage found in B12 deficiency.