Folic acid nutritional requirements

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. 

In a totally different field, studies were being carried out on children who had a deficiency of methionine synthase and an impaired ability to convert homocysteine to methionine, so that they had increased blood levels of homocysteine. It was noted that these children had an increased incidence of thrombosis in cerebral and coronary arteries. This led to a study which eventually showed that an increased level of homocysteine was a risk factor for coronary artery disease in adults. Since methionine synthase requires the vitamins, folic acid and B12, for its catalytic activity, it has been suggested that an increased intake of these vitamins could encourage the conversion of homocysteine to methionine and hence decrease the plasma level of homocysteine. This is particularly the case for the elderly who are undernourished (see Chapter 15 for a discussion of nutrition in the elderly). 

Studies on growth factors required by certain microorganisms, for example Streptococcus faecalis and Lactobacillus casei, and of their relevance in animal nutrition, led to the isolation and characterization of folic acid, pteroylglutamic acid (104), the structure of which was determined in 1946. It is an essential vitamin for man and together with vitamin B12 it is involved in the development of blood cells. Deficiency causes macrocytic anaemia. Many microorganisms do not use exogenous folic acid, but synthesize their own, and some... 

Folacin has recently been implicated in a number of nonvitamin functions, including roles in various types of cancer, coronary heart disease, and the prevention of birth defects, such as neural tube abnormalities (109,121,131-144). Investigations into these functions are ongoing and have generated controversy concerning the exact nature of the nonvitamin functions, human nutritional requirements for folacin, and the wisdom of food fortification or supplementation of selected population groups with pharmacological doses of folic acid (131,132,145-150). 

In many animals, dietary deprivation of choline leads to liver dysfunction and growth retardation, and some patients maintained on choline-free total parenteral nutrition develop liver damage that resolves when choline is provided, suggesting that endogenous synthesis may be inadequate to meet requirements (Zeisel, 2000). There is inadequate information to permit the setting of reference intakes, but the Acceptable Intake for adults is 550 mg (for men) or 425 mg (for women) per day (Institute of Medicine, 1998). In experimental animals choline deficiency is exacerbated by deficiency of methionine, folic acid, or vitamin B12, which impairs the capacity for de novo synthesis. 

It is estimated that the minimum daily requirement of folate is 5 micrograms/kg. Liver stores are about 160 micrograms in premature children, and 220 micrograms in full-term infants. Infants who require parenteral nutrition will rapidly become folate deficient unless fohc acid is included in the regimen. Since many multivitamin supplements do not contain folic acid, its inclusion should be ensured by the addition of folic or folinic acid. 

Although requirements for vitamins and trace elements are known in health (Table 30-1), the effects of illness on these requirements are poorly understood and quantified. However, it is now apparent that as an individual develops progressively more severe depletion in vitamin or trace element status, the person passes through a series of stages with biochemical or physiological consequences. The metabolic or physiological penalty of such suboptimal nutritional status is usually not clear, but the assumption remains that the suboptimal metabolism is likely to have detrimental effects (e.g., subclinical deficiency of folic acid is associated with an increase in serum homocysteine concentration, which is an independent risk factor for coronary artery disease—see Chapter 26). Similarly, subclinical deficiency of chromium may be associated with impaired glucose tolerance in certain types of diabetes. 

Based on folate concentrations in liver biopsy samples, and assuming that the liver contains about half of ail body stores, total body stores of folate are estimated to be between 12 and 28 Kinetic studies that show both fast-turnover and very-slow-turnover folate pools indicate that about 0.5% to 1% of body stores are catabolized or excreted daily,suggesting a minimum daily requirement of between 60 and 280)Llg to replace losses. In calculating nutritional requirement, the concept of dietary folate equivalents (DFE) has been used to adjust for the nearly 50% lower bioavailabihty of food folate compared with supplemental folic acid, such that 1 p.g DFE = 0.6 Llg of folic acid from fortified food = 1 j,g of food folate 0.5 p.g foUc acid supplement taken on an empty stomach. Before the fortification program of cereal grains with folic acid conducted between 1988 and 1994, the median intake of folate from food in the United States was approximately 250p.g/day this figure is expected to increase by about 100 Llg/day after fortification. Recommendations... 

There are many causes of folic acid deficiencies. Inadequate nutrition during periods of increased requirements is one of the main causes of megaloblastie anemia of pregnaney and neural tube defects. Alcoholism is considered the leading cause of folic acid deficiency... 

Little information is available concerning alterations in vitamin requirements in ARF. Reduced plasma concentrations of vitamin A, ascorbate, vitamin D, and vitamin E have been reported in patients with ARF, whereas vitamin K concentrations are relatively increased. Losses of vitamins via dialysis also must be considered. Traditional HD clears several water-soluble vitamins such as folic acid, vitamins C and B12, and pyridoxine, but not the highly protein-bound vitamins A and D. The clinical significance of these findings in ARF is unknown. Currently, it seems prudent to administer vitamins at least daily in doses recommended by the Nutrition Advisory Group of the American Medical Association for patients receiving PN (see Chap. 137)." Administration of ascorbic acid should be restricted to under 200 mg/day to avoid secondary oxalosis which may worsen renal function." If the enteral route is used for nutritional support, vitamin administration should at least meet the recommended daily allowances (RDAs). 

C4. Cooper, B. A., Physiology of absorption of mono utamyl folates from the gastrointestinal tract. In Folic Acid Biochemistry and Physiology in Relation to Human Nutrition Requirement (C. E. Butterworth, ed.)p. 188. Nad. Acad. Sci., Washington, D.C.,... 

H16. Herbert, V, Nutritional requirements for vitamin B12 and folic acid. Proc. Congr. Int. 

Folic acid/cobalamin/pyridoxine hydrochloride are nutritional combinations. Folic acid and cobalamin reduce homocysteine by metabolizing it to methionine. Pyridox-ine facilitates breakdown of homocysteine to cysteine and other by-products. They are indicated for nutritional requirement of patients with end-stage renal failure, dialysis, hyperhomocysteinemia, homocystinuria, nutrient malabsorption or inadequate dietary intake, particularly for patients with or at risk for cardiovascular disease, cerebrovascular disease, peripheral vascular disease, arteriosclerotic... 

Considerable uncertainty and controversy exists concerning the folate requirement for humans. Hie review of data concerning the human folate requirement by the Food and Nutrition Board (1989) suggests that the daily maintenance requirement is 100-200 fig of avaUable folic acid equivalents. The 1989 RDAs were reduced to 200 and 180 fig for adult men and women, respectively, from the previous RDA of 400 on the basis of such evidence (Food and Nutrition Board, 1989). Similarly, the Canadian RDA for folate was set at 3 /ig/kg body wt or 210 fig for a 70-kg individual. These lower RDAs may be inadequate for certain population groups, however (Sauberlich, 1990 Bailey, 1992 McPartlin etai, 1 3). It is currently difficult or impossible to predict the quantitative effect on folate nutritional status of factors such as (a) changes in folate intake, (b) differences in folate bioavailability, (c) effects of pregnancy and lactation on folate requirements, and (d) pharmaceuticals with antifolate properties. In addition, the development of mathematical models would improve our ability to evaluate methods of nutritional status assessment for this vitamin. 

It is true that when the selenium and/or methionine in the diet is suboptimum, there is a marked increase in the requirement for vitamin E. However, many stresses and other nutritional deficiencies are also known to increase the tocopherol requirement. For example, carbon tetrachloride toxicity, protein, B12 and folic acid deficiencies (Hove and Hardin, 1951a,b), and Be deficiency (Day and Dinning, 1956), all increase the requirement for a-tocopherol. As for the relationship of ubiquinone to tocopherol, here also, one wonders whether the decreased amount of ubiquinone found in vitamin E deficiency is specific or an incidental effect of one form of inanition, since a deficiency of pantothenic acid, and possibly other deficiencies that affect liver function, will produce similar decreases in ubiquinone. 

Reference Intakes for folate have been reported (Food and Nutrition Board 1998) (Table 44.2). The high frequency of folate deficiency has led the Food and Drug Administration in the United States to require folic acid fortification of all enriched cereals and grain products since January 1998. Folate deficiency is a major public health concern both northern and southern countries, and affects both industrialized and non-industrialized nations. In non-industrialized countries, it is particularly accentuated by poverty, limited access to food resources, and infectious diseases (Change and Abdennebi-Najar, 2011). 

The evidence that (- )-shikimic acid plays a central role in aromatic biosynthesis was obtained by Davis with a variety of nutritionally deficient mutants of Escherichia coli. In one group of mutants with a multiple requirement for L-tyrosine, L-phenylalanine, L-tryptophan and p-aminobenzoic acid and a partial requirement for p-hydroxybenzoic acid, (—)-shikimic acid substituted for all the aromatic compounds. The quintuple requirement for aromatic compounds which these mutants displayed arises from the fact that, besides furnishing a metabolic route to the three aromatic a-amino acids, the shikimate pathway also provides in micro-organisms a means of synthesis of other essential metabolites, and in particular, the various isoprenoid quinones involved in electron transport and the folic acid group of co-enzymes. The biosynthesis of both of these groups of compounds is discussed below. In addition the biosynthesis of a range of structurally diverse metabolites, which are derived from intermediates and occasionally end-products of the pathway, is outlined. These metabolites are restricted to certain types of organism and their function, if any, is in the majority of cases obscure. 

HISTORY. Carnitine was first isolated from meat extract in 1905, but its structure was not established until 1927. Then, another 20 years elapsed before Fraenkel, in 1947, while investigating the role of folic acid in the nutrition of insects, found that the meal worm (Tenebrio moli-tor) required a growth factor present in yeast. Frankel called this factor Vitamin BT vitamin B because of its water-soluble property, and the T standing for Tenebrio. Because of not being recognized as a vitamin, the name was subsequently changed to carnitine. 

This field of study was opened by the recognition that the organism Leuconostoc dtrovorum 8081 (now renamed Pediococcua cereviaiae) bad a special nutritional requirement for citrovomm factor, a modified form of folic acid that was found to be 5-formyl-FH4. This was synthesized and received the name leucovorin. Leucovorin has one-half the biological activity of natural 5-formyl-FH4 due to it being a racemic mixture with respect to the configuration of the carbon 6 atom. 

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