Folate depletion

The gastritis and chronic pancreatitis associated with chronic alcoholism may result in a reduction of the amount of vitamin B12 absorbed but this has not been found to result in a clinical deficiency (M4). Alcohol can also cause damage to the ileum. Lindenbaum and Lieber gave alcohol to human volunteers for periods of 13—37 days and found that absorption of the vitamin was impaired in six of eight volunteers and this was not corrected by the addition of intrinsic factor or pancreatin (L10,L11). Biopsy of the ileum showed ultra-structural evidence of mitochondrial damage (Rll). It has been shown previously that folate deficiency may result in a reduction in the serum vitamin B12 level (H16) and the low serum vitamin B12 levels found in some alcoholics is probably secondary to folate depletion, which is common in this condition (L12). How folate is able to influence the serum vitamin B12 level is not clear. 

Although folate is widely distributed in foods, dietary deficiency is not uncommon, and a number of commonly used drugs can cause folate depletion. Marginal folate status is a factor in the development of neural tube defects and supplements of 400 fj,g per day periconceptually reduce the incidence of neural tube defects significantly. High intakes of folate lower the plasma concentration of homocysteine in people genetically at risk of hyperhomo-cysteinemia and may reduce the risk of cardiovascular disease, although as yet there is no evidence from intervention studies. There is also evidence that low folate status is associated with increased risk of colorectal and other cancers and that folate may be protective. Mandatory enrichment of cereal products with folic acid has been introduced in the United States and other countries, and considered in others. 

Free formate can react with tetrahydrofolate to form 10-formyl-tetrahy-drofolate the plasma concentration of formate rises in folate deficiency and the ability to metabolize [ Cjformate has been used as an index of folate depletion in experimental animals. 

It is probable from the evidence available so for that oral contraceptives marginally depress the body folate pool. In many, if not most women, this is probably of little consequence however, this folate-depleted state is important should pregnancy take place shortly after ceasing the oral contraceptive agent because the vitamin has an important role in the early stage of fetal development. 

Most of the folate abnormalities observed have been associated with active disease. Patients in remission usually have a normal serum folate provided their dietary intake is adequate. Folate depletion associated with active neoplastic disease is in the main due to a poor diet and this may be made worse by an increased demand due to rapidly growing tissue. Although up to 85% of patients with malignant disease have been found to have a low serum folate, most have had a normal erythrocyte concentration of the vitamin (M15). 

Whether folate deficiency predisposes to infection is not clear. Certainly many folate-depleted patients develop infections and there is little doubt that infection tends to place fiirther demands on folate reserves. 

Little is known about other aspects of folate metabolism, such as the factors that determine plasma clearance, in either normal subjects or users of oral contraceptive steroids. As described earlier, maximum serum folate concentrations after oral folate polyglutamate are lower in contraceptive users than in nonusers, when subjects are not presaturated (S19). This may be due to increased clearance from plasma, because poor absorption was not found. Stephens et al. (S19) felt that this was probably not due to tissue folate depletion because there was no correlation with initial fasting serum folate concentrations. However, erythrocyte folate concentrations were not measured and might have been a better index of tissue saturation with the vitamin. 

Price and Kerr, 1985). Alcohol has been fonnd to interfere with the active transport of thiamine in the gastrointestinal system, at least in rodents (Knmar et al, 2000). Thiamine absorption may be significantly decreased in the setting of folate depletion but may return to normal with 4-6 weeks of folate repletion therapy. A deficiency in magnesium, required for the conversion of thiamine to thiamine pyrophosphate, may also cause thiamine deficiency (Bishai and Bozzetti, 1986 Lonsdale, 2006). 

R.J. Hayman and M.B. Van Der Weyden. Phytohemagglutinin stimulated normal human peripheral blood lymphocytes in folate depleted medium an in vitro model for megaloblastic hemopoiesis. Blood 55 803, 1980. 

Folate seems to have a significant, but poorly defined, role in brain function. It is concentrated two- to fourfold in CSF, as opposed to serum, by a saturable, presumably active process (Lipton et al., 1979). Brain levels decrease less rapidly than serum and peripheral nerve levels during folate depletion (Fehling, 1976). Dihydrofolate reductase is present in rat brain (Pollock and Kaufman, 1978), and brain folate depletion may impair central nucleic acid metabolism (Haltia, 1970). Folate is associated with central amine metabolism. It is concentrated in the synaptic region (McClain et al., 1975) and may function as a coenzyme in monoamine biosynthesis. Korevaar et al. (1973) found the highest brain folate levels in the median raphe and corpus striatum, areas also rich in serotonin neurons. 

Figure 44.2 Analysis of 5-methyl cytosine (% 5-metC) and dUTP/dTTP (dU/dT) ratio in genomic DNA of HepG2 cell line. Folate depletion results in decrease of 5-metC% and elevation of dU/dT into genomic DNA extracted from HepG2 cell lines grown in complete medium (ECM) or in folate depleted medium (FDM) for 72h (T72) control (TO). (Chango et al. 2009a).

Moretti, R., Torre, P., and Antonello, R.M., 2008. Vitamin B12, folate depletion and homocysteine What do they mean for cognition In Vitamin B New Research. Nova Science Publishers, Hauppage, NY, USA, pp. 139-152. 

Although folate is widely distributed in foods, dietary deficiency is not uncommon, and a number of commonly used drugs can cause folate depletion. More importantly. 

The antagonism of bactericidal sulfanilamides by p-aminobenzoic acid (PABA), a precursor of the vitamin folic acid, has been well documented in the pharmacological literature. More recently, it was shown that the phytotoxic activity of asulam, a herbicidal sulfanilamide derivative, also results from an inhibition of the biosynthesis of the vitamin folic acid. " In particular, asulam inhibits competitively the enzyme 7,8-dihydropteroate synthase, which catalyzes the conversion of 2-amino-4-hydroxy-6-hydroxy-methyl-7,8-dihydropteridine and PABA to dihydropteroic acid, leading to folate depletion. A consequence of the depletion of folic acid derivatives is the buildup of intermediates of the de novo synthesis of purine nucleo-tides. ° Such intermediates include 5 -phosphoribosyl glycineamide (GAR) or 5 -phosphoribosyl-5-amino-4-imidazole (AICAR). The accumulation of GAR and AICAR in asulam-treated pea seedlings has been reported. 

Clifford, A.J., Wilson, D.S. and Bills, N.D. (1989) Repletion of folate-depleted rats with an amino acid-based diet supplemented with folic acid. JNutr 119,1956—1961. 

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