Turnover folate

In addition to the methods described here, measurement of urinary ac-etamido p-aminohenzojd glutamate will reflect folate turnover (Section 10.2.3) and incorporation of uracil, instead of thymidine into the DNA in leukocytes or lymphocytes may provide a sensitive index of folate status. 

Fohc acid is a precursor of several important enzyme cofactors required for the synthesis of nucleic acids (qv) and the metaboHsm of certain amino acids. Fohc acid deficiency results in an inabiUty to produce deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and certain proteins (qv). Megaloblastic anemia is a common symptom of folate deficiency owing to rapid red blood cell turnover and the high metaboHc requirement of hematopoietic tissue. One of the clinical signs of acute folate deficiency includes a red and painhil tongue. Vitamin B 2 folate share a common metaboHc pathway, the methionine synthase reaction. Therefore a differential diagnosis is required to measure foHc acid deficiency because both foHc acid and vitamin B 2 deficiency cause... 

With investigations of phytochemicals and functional foods, the outcome measure is generally going to be a biomarker of disease, such as serum cholesterol level as a marker of heart disease risk, or indicators of bone turnover as markers of osteoporosis risk. Alternatively, markers of exposure may also indicate the benefit from a functional food by demonstrating bioavailability, such as increased serum levels of vitamins or carotenoids. Some components will be measurable in both ways. For instance, effects of a folic acid-fortified food could be measured via decrease in plasma homocysteine levels, or increase in red blood cell folate. 

Most dietary folate is reduced and methylated to methyl-tetrahydro-folate in the intestinal mucosa (Section 10.2.1). Intestinal mucosal ceUs have a rapid turnover, typicaUy 48 hours from proliferation in the crypt to shedding at the tip of the vUlus. This means that an unstable variant of the enzyme, which loses activity over a shorter time than the normal enzyme, is probably irrelevant in ceUs that have such a rapid turnover. A high intake of folate would therefore result in a relatively high rate of supply of methyl-tetrahydrofolate to cells, arising from newly absorbed folate, so that impaired turnover of folate within cells would be less important. 

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... 

Gregory JF, III, Williamson J, Liao JF, Bailey LB, Toth JR Kinetic model of folate metabolism in nonpregnant women consuming [2H2]folic acid isotopic labeling of urinary folate and the catabolite para-acetamidobenzoylglutamate indicates slow, intake-dependent, turnover of folate pools. J Nutr 1998 128 1896-906. 

Folic acid Megaloblastic anemia, diarrhea, glossitis Serum folate Decreased with increased cellular/tissue turnover (pregnancy, malignancy, hemolytic anemia) masks neurologic complications of vitamin B12 deficiency decreases risks of neural tube defects... 

Many patients with infection have a reduced serum level of folate, particularly those with chronic bacterial infections. However, the development of a megaloblastic anemia is uncommon and when it does occur is perhaps more often associated with the treatment. It is probable that the folate deficiency is the result of a combination of fiictors including poor dietary intake, low reserves, an increased demand due to an increased cell turnover, impaired absorption, vomiting, and impaired metabolism due to the toxic state of the patient (C17, M16, W25). Pyrexia may also inhibit the reduction of folate. Panders and Rupert (P13) found that if folic acid was incubated with a chicken liver enzyme preparation at an elevated temperature the reduction of folic acid to tetrahydrofolic acid was inhibited. 

The demand for folate is increased in people with thalassemia because of a more rapid cell turnover due to ineffective erythropoiesis. Where this demand cannot be met, a megaloblastic anemia may be superimposed on the thalassemia (R14, G8). This may be difficult to recognize because the abnormal synthesis of the globin moiety of hemoglobin may prevent the development of characteristic megaloblasts. A similar situation may occur in iron-deficiency anemia where characteristic megaloblasts will not develop until... 

FOLATE DEFICIENCY Folate deficiency is a common complication of diseases of the small intestine, which interfere with the absorption of dietary folate and the recirculation of folate through the enterohepatic cycle. In acute or chronic alcohohsm, daily intake of dietary folate may be severely restricted, and the enterohepatic cycle of the vitamin may be impaired by toxic effects of alcohol on hepatic parenchymal cells this is the most common cause of folate-deficient megaloblastic erythropoiesis. However, it also is the most amenable to therapy, inasmuch as the reinstitution of a normal diet is sufficient to overcome the effect of alcohol. Disease states characterized by a high rate of cell turnover, such as hemolytic anemias, also may be complicated by folate deficiency. Additionally, drugs that inhibit dihydrofolate reductase (e.g., methotrexate and trimethoprim) or that interfere with the absorption and storage of folate in tissues (e.g., certain anticonvulsants and oral contraceptives) can lower the concentration of folate in plasma and may cause a megaloblastic anemia. 

FIG. 3. Two-pool model of folate metabolism with output only from the rapid turnover pool. Output represents the sum of urinary, fecal, and catabolic losses. 

The excretion of folate and its metabolites by both urinary and fecal routes was demonstrated in a study with [2- C]folic acid administered to a single adult woman as several daily doses followed by periodic urine and fecal collection over several months (Knimdieck et al, 1978). Fecal excretion accounted for nearly half of the isotope elimination. From excretion of urinary C, two pools were readily apparent with half times of 31.5 hr and 100 days. Periodic administration of diphenylhydantoin to this subject (a Hodgkin s disease patient in remission) did not notably alter the turnover kinetics. 

FIG. 6. Expanded model of in vivo folate metabolism. Tbe pools are defined as follows 1, rapid turnover folate 6, slow turnover folate (tissues) 2, irretrievable losses by fecal excretion and catabolism 3, cumulative excretion of urinary folate 4, fractional (daily) excretion of urinary folate. Analysis was performed with parallel models for labeled and nonlabeled folate. 

FCR and MRT values of approximately 0.0088 day" and 114 days, respectively. The mean masses of folate in pool 1 (rapidly exchanging folate) and pool 6 (slow turnover tissue folates) were 10.9 and 76.8 mg, respectively. These masses were greater than those estimated from the previous study with one female subject, which may reflect the larger body mass of the male subjects as well as their greater folate intake in this study. 

The use of animal models will be of help in this area as various tissues may be sampled over time to determine folate stores and turnover. This information can then be extrapolated to a human kinetic model based on known similarities and differences in metabolism between the species. 

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