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Folic Acid Stokstad (1943) isolated folic acid as a result of inves- tigations of the properties of factors present in yeast or liver that would promote the growth of lactic acid bacte- ria (Snell and Peterson, 1940~. Subsequent studies dem- onstrated that the active factor was identical to, or related to, antianemia factors and animal growth factors discovered by other investigators (Brody et al., 1984~. Mowat et al. (1948) showed that folic acid is composed of a pteridine ring linked through a methylene bridge to p-aminobenzoic acid to form pteroic acid, which is in turn linked as an amide to glutamic acid. Early studies of the ability of purines or thymine to partially satisfy bac- terial requirements for folic acid pointed to the involve- ment of this vitamin in purine and thymine biosynthesis. Early studies using i4C-labeled formate and formalde- hyde suggested a role of folic acid in the metabolism of one-carbon units. NUTRITIONAL ROLE Dietary Requirements of Various Species from 0.25 to 1.0 mg/kg of diet for chickens and 1 to 6 ma/ kg of diet for rats and guinea pigs. Sulfa drugs, which are often added to commercial chick diets, increase the folate requirement. Folate requirements for ruminant animals and horses have not been established. The swine requirement is less than 1 mg/kg of diet. The folate requirement for the human is about 50 ,ug/day and is increased during pregnancy and lactation. Biochemical Functions The pteridine ring is completely oxidized in folic acid and can be enzymatically reduced to the dihydro- and tetrahydrofolate forms. The coenzyme forms of the vi- tamin are the various one-carbon derivatives of the te- trahydrofolate (see Figure 141. These include the 5-methyl-, 5- and 10-formyl-, 5-formimino-, 5,10 methyl- idene-, and 5-10 methylene- derivatives (Wagner, 1984~. They encompass one-carbon units at the oxidation state of methanol, formaldehyde, or formate. These one- carbon derivatives are generated from free formate or from the metabolism of glycine, serine, and histidine. The derivatives can be oxidized and reduced as folate coenzymes. The various one-carbon units carried on fo The nutritional status of an~mals w~th respect to folate . , . . adequacy is most often assessed through an estimation of folate concentrations in serum or red cells. These determinations have historically been carried out . . . . . through m1croblolog1cal assays, but protein-binding as- says are used increasingly. Functional tests are used as well. For example, excretion of formiminoglutamate (FIGLU) following a histidine load is often used as a clinical measure of folate adequacy. Growth rate and the maintenance of normal hematological responses have also been used as a measure of folate adequacy in animal studies. Folate requirements have been determined to range late coenzymes are used to synthes~ze meth~on~ne ano purine rings and convert deoxyuridinemonophosphate to deoxythymadinemonophosphate. The folate coen- zymes, S-adenosyl methionine and vitamin B~2, are therefore responsible for the movement of one-carbon units in metabolic pathways. FORMS OF THE VITAMIN Folacin is the generic descriptor of all compounds that exhibit the biological activity of folic acid. Pteroylglu 64

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Folic Acit1 65 COOH OH , O CHCH2 CH2 COOH Nit s ~ CH2-NH ~ C-AH H2NN N Folic acid (PteGlu) OH CH3 1~ ACHE-NH~C-Glu-~-Glu-~-Clu-~-Glu-~-Glu H2N N N H H H Methyl-tetrahydrofolate pentaglutamate (S-methyl-H4PteGlus ~ tamic acid (2-amino-4-hydroxy-6-methyleneaminio- benzoyl-~-glutamic acid pteridine) was the first form of folate isolated and synthesized. In almost all tissues, however, the predominant forms are polyglutamates. These forms may have up to eight additional glutamic acid residues attached to the terminal glutamate of folic acid in an amide linkage as a poly-^y-amide. The polyglu- tamates are the reduced active coenzyme forms in ani- mal tissues. The monoglutamate is used in the supplementation of animal feeds. Animals convert the absorbed monoglutamate form to polyglutamates. Sub- sequent metabolism of the reduced polyglutamates pro- duces the various one-carbon derivatives that function in metabolic reactions. ABSORPTION AND METABOLISM Foods contain a mixture of the mono- and polygluta- mate forms of folate. These forms are predominantly in the reduced state. The polyglutamates are hydrolyzed by a ~y-glutamylhydrolase prior to absorption as the monoglutamate. The occurrence of folate deficiency in celiac sprue is the result of disturbance of the proximal small intestine mucosa and a failure of the normal intes- tinal transport process. Absorbed monoglutamates are transported in plasma to cells that use specific transport systems to take up the vitamin (Herbert et al., 1980~. The majority of body folate occurs in the liver in the form of the 5-methyl- or 10-formyl-tetrahydro deriva- tives of the penta or hexaglutamate. Both free folate and folate degradation products are excreted in the bile. There is a substantial enterohepatic circulation of the vitamin, which leads to a significant fecal loss. FIGURE 14 Chemical structures of folic acid and 5-methyl-tetrahydrofolate. HYPERVITAMINOSIS Adverse effects following the ingestion of elevated amounts of folic acid to animals have not been observed. The vitamin is generally regarded as nontoxic. Pharma- cological responses to massive doses of folic acid have, however, been reported (Omaye, 1984; Preuss, 1978~. Single intravenous doses of 250 mg/kg of BW of sodium folate caused an epileptic response in rats (Hommes and Obbens, 1973~. This response is decreased in partially hepatectomized rats. These data suggest that metabo- lism is required for the toxic response, but the nature of the metabolic change has not been identified. Threlfall et al. (1966) observed that parenteral administration of 250 mg folate/kg of BW causes a renal hypertrophy in the rat. This effect is not seen in the villi of the small bowel (Tilson, 1970), and it is likely that the renal effect is due to tubular obstruction rather than to any meta- bolic effect. Schmidt and Dubach (1976) and Schubert (1976) have investigated the morphological and meta- bolic changes associated with the pteridine-induced stimulus of renal growth in some detail. PRESUMED UPPER SAFE LEVELS No adverse responses to the ingestion of folic acid have been documented. Therefore, the upper limits of presumed safe dietary levels cannot be established. SUMMARY 1. Administration of massive doses of folic acid in the diet has not been reported to cause adverse effects.

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66 Vitamin Tolerance of Animals 2. Single parenteral doses of folic acid have been re- ported to induce epileptic responses and renal hypertro- phy in rats. The doses employed to produce this response have been about 1,000 times greater than the dietary requirements for the vitamin. REFERENCES Brody, T., B. Shane, and R. Stokstad. 1984. Folic acid. Pp.459-496 in Handbook of Vitamins, L. J. Machlin, ed. New York: Marcel Dekker. Herbert, V., N. Colman, and E. Jacob.1980. Folic acid and vitamin Bit. Pp. 229-258 in Modern Nutrition in Health and Disease, R. S. Goodhart and M. E. Shils, eds. Philadelphia: Lea & Febiger. Hommes, O. R., and E. A. M. T. Obbens. 1973. Liver function and folate epilepsy in the rat. I. Neurol. Sci. 20:269. Mowat, J. H., J. H. Boothe, B. L. Hutchings, E. L. R. Stokstad, C. W. Wailer, R. B. Angler, J. Semb, D. B. Cosulich, and Y. Subbarow. 1948. The structure of liver L. cased factor. J. Am. Chem. Soc.70:14. Omaye, S. T. 1984. Safety of megavitamin therapy. Adv. Exp. Med. Biol. 177:169. Preuss, H. 1978. Effect of nutrient toxicities-Excess in animals and man: Folic acid. Pp. 61-62 in Handbook in Nutrition and Food, M. Rechcigl, ed. New York: CRC Press. Schmidt, U., and U. C. Dubach.1976. Acute renal failure in the folate- treated rat: Early metabolic changes in various structures of the nephron. Kidney Int. 10:S39. Schubert, G. E.1976. Folic acid-induced acute renal failure in the rat: Morphological studies. Kidney Int. 10:S46. Snell, E. E., and W. H. Peterson.1940. Growth factors for bacteria. X. Additional factors required by certain lactic acid bacteria. J. Bacte- riol. 39:273. Stokstad, E. L. R. 1943. Some properties of a growth factor for Lacto- bacillus cases. J. Biol. Chem. 149:573. Threlfall, G., D. M. Taylor, and A. T. Buck. 1966. The effect of folic acid on growth and deoxyribonucleic acid synthesis in the rat kid- ney. Lab. Invest. 15:1477. Tilson, M. D.1970. A dissimilar effect of folic acid upon the growth of the rat kidney and small bowel. Proc. Soc. Exp. Biol. Med. 134:95. Wagner, C. 1984. Folic acid. Pp. 332-346 in Present Knowledge in Nutrition, R. E. Olsen, ed. Washington, D.C.: The Nutrition Foun- dation.