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PubMed2004

99mTc-Tetraethylenepentamine-Folate--a new 99mTc-based folate derivative for the detection of folate receptor positive tumors: synthesis and biological evaluation.

A new radiopharmaceutical, 99mTc-Tetraethylenepentamine(TEPA)-Folate has been synthesized introducing TEPA to the gamma-carboxyl group of folic acid. This binds with 99mTc high efficiency at ambient temperature. The resulting 99mTc-N5-Folate is stable under physiological conditions at least for 24 h after radiocomplexation. TEPA is a known open chain pentamine (N5) chelator, its four-nitrogen act as the binding site for 99mTc. The folate membrane receptor binding of the 99mTc-TEPA-Folate by established human tumor cell lines (KB, U-87MG and MDA-MB-468) showed Kd in microM range in normal DMEM (10% serum, 10 microM folic acid). The blood kinetic studies showed more than 70% clearance within five minutes from the circulation. The KB cell line tumors in mice were readily identifiable in the gamma images and revealed major accumulation of radiotracer in liver, kidneys and intestines. High tumor uptake was shown in the tumor bearing nude mice; tumorto-blood ratios reached 2.68 +/- 0.52 and 5.5 +/- 1.47 at 1 and 4 h after post injection respectively. Surviving fractions as obtained in clonogenic assay were 1.02 +/- 0.07 and 1.03 +/- 0.05 in U-87MG and MDA-MB-468 cell lines respectively. The 99mTc-N5-Folate conjugate have promising utility as a receptor specific radiopharmaceutical for imaging neoplastic tissues known to over express folate-binding protein.

Animals↗
PubMed1989

Folate (pteroylglutamate) uptake in human red blood cells, erythroid precursors and KB cells at high extracellular folate concentrations. Evidence against a role for specific folate-binding and transport proteins.

Membrane-associated folate (pteroylglutamate, PteGlu)-binding proteins (FBPs) play an important role as PteGlu-transport proteins in malignant and normal human cells. Since high extracellular folate (PteGlu) concentrations (EFC) profoundly influenced uptake and toxicity of the anti-PteGlu methotrexate in malignant KB cells, we studied human cells to determine additional mechanisms for PteGlu uptake when the EFC was varied. At low EFC (less than 10 nM), the predominant mechanism for folate uptake in mature erythrocytes was through binding to externally oriented FBPs which were quantitatively insignificant (4-6 orders of magnitude lower) and of no apparent physiological relevance when compared with KB cells. However, the predominant mechanism of PteGlu accumulation at high EFC [10-250 nM] in intact erythrocytes and sealed right-side-out (RSO) ghosts was not FBP-mediated and non-specific. This conclusion was based on the findings that radiolabelled PteGlu uptake: (i) continued even in the presence of a 1000-fold excess of unlabelled PteGlu and was linear and not saturable up to 250 nM; (ii) was two-fold higher at pH 4.5 than 7.5; (iii) was less than 2-fold increased at 37 degrees C compared with 4 degrees C; and (iv) was unaffected after trypsin-mediated proteolysis of greater than 75% FBPs. The [3H]PteGlu and 125I-PteGlu (histamine derivative) accumulated intracellularly through the non-specific PteGlu-uptake mechanism was unaltered biochemically and in a soluble compartment. Raising the EFC 500-fold higher than controls during erythropoiesis in vitro resulted in reversal of the expected anti-(placental folate-receptor)-antiserum-induced megaloblastic changes in orthochromatic normoblasts derived from burst-forming unit-erythroid colonies. Furthermore, at EFC greater than 0.1 microM, KB-cell accumulation of [3H]PteGlu was also predominantly through a mechanism that did not involve specific FBPs. Thus, at high EFC, a major component of PteGlu transport in human cells is not mediated through FBPs and is likely to be a passive diffusion process.

Carrier Proteins↗
PubMed1991

The conversion of the human membrane-associated folate binding protein (folate receptor) to the soluble folate binding protein by a membrane-associated metalloprotease.

The membrane-associated (M-FBP) and soluble (S-FBP) forms of human folate binding proteins (FBP) have been well characterized. Although related in a precursor-product manner, the mechanism of conversion and the basis for differences between M-FBP and S-FBP are not known. The conversion of M-FBP to S-FBP in crude human nasopharyngeal carcinoma (KB) cell preparations is demonstrated based on characteristic gel filtration elution profiles of M-FBP and S-FBP (Ve/V0 = 1.3 and 1.7, respectively) in Triton X-100. M-FBP is stoichiometrically converted to S-FBP in a time- and temperature-dependent reaction by a metalloprotease which is: heat-labile; particulate; contained in human KB cell and placental membranes, and rat kidney homogenates; inhibited by EDTA, 1,10-phenanthroline, and parahydroxymercuribenzoate; requires divalent cations; is maximally active at neutral pH; and is active in the presence or absence of detergent. The purified soluble FBP product appears to be identical to S-FBP. Conversion of purified endogenously [3H]leucine-labeled M-FBP yields a soluble FBP characterized by a 45% decrease in specific activity (moles of 3H/mol folate bound) relative to M-FBP and a non-folate binding fragment which contains 45% of the [3H]leucine from M-FBP, requires detergent and/or urea to remain soluble, and migrates aberrantly on gel filtration in 1% (v/v) Triton X-100 and 8 M urea. Based on changes in the specific activity and the gel filtration elution profiles of purified labeled M-FBP associated with conversion to S-FBP, the endoproteolytic cleavage site is predicted between residues 226 and 229 of the cDNA predicted human FBP amino acid sequence. These results suggest that the cDNA predicted hydrophobic carboxyl terminus (residues 227-257) remains intact on the fully processed, membrane-anchored M-FBP, contains the Triton binding domain, and is involved in the formation of the membrane anchor of M-FBP.

Animals↗
PubMed1966

Method of assay of red cell folate activity and the value of the assay as a test for folate deficiency.

A simplified microbiological assay for determining the folate content of red cells is described. As in previously reported methods Lactobacillus casei is used as test organism but two modifications are introduced. First, haemolysis is carried out in water containing 1 g.% of ascorbic acid; secondly, haemolysates are not incubated before the assay. Using this assay, recovery of pteroylglutamic acid added in two different concentrations to five different whole blood samples was 97.0 +/- 1.9 S.E. % and 106.1 +/- 4.7 S.E. % respectively. The coefficient of variation of the assay was between 11.2 and 15.0%. Haemolysates were best stored deep frozen, showing no significant loss of L. casei activity for three to five months at -20 degrees C. On the other hand, non-haemolysed blood samples were best stored at 4 degrees C. when there was no loss of activity for seven to 10 days. Experiments confirmed that plasma is necessary for the maximum release of red cell L. casei activity, and showed that only small amounts of plasma are necessary; folate- and B(12)-deficient plasma released slightly lower L. casei activities from red cells than did normal plasma. The red cell folate levels of 40 healthy normal subjects ranged from 160 to 640 mmug. per ml. of packed red cells. One hundred and twenty patients with subnormal serum folate levels due to idiopathic steatorrhoea, nutritional folate deficiency and Crohn's disease, partial gastrectomy, myelosclerosis, and polycythaemia vera were studied. Red cell folate levels were subnormal (range from 7 to 143 mmug. per ml.) in 40 patients with megaloblastic anaemia, the lowest levels occurring in the most anaemic patients. Subnormal red cell folate levels also occurred in 23 (29%) of the 80 non-anaemic patients. There was a good correlation between red cell folate level and severity of folate deficiency assessed by polymorph nuclear lobe counts, and, in the non-anaemic patients bone marrow morphology. It is concluded that, in the absence of B(12) deficiency, the red cell folate level is a precise guide to the severity of folate deficiency. Patients with serum folate levels less than 3.0 mmug. per ml. almost always had megaloblastic anaemia or obvious morphological changes of folate deficiency. In patients with borderline serum folate levels (3.0-5.9 mmug. per ml.) haematological changes varied widely. The degree of change correlated with the red cell folate level in these patients. The formiminoglutamic acid (Figlu) test was positive (range 20-660 mg. excreted in eight hours) in all 30 patients with megaloblastic anaemia due to folate deficiency tested and also in 17 (31%) of 54 non-anaemic patients who were folate deficient. The amount of Figlu excreted paralleled the red cell folate level in both the anaemic and non-anaemic, folate-deficient patients tested. Figlu excretion, like the red cell folate level, appeared to be a satisfactory index of tissue folate stores. In 46 patients with pernicious anaemia, the red cell folate levels ranged from 26 to 396 mmug. per ml., 29 (63%) of them having subnormal levels. The ratio of mean red cell to mean serum folate level, 13.0:1, was lower than that of normal subjects. As in folate deficiency the patients with the lowest haemoglobin concentrations had the lowest red cell folate levels. Figlu was positively excreted in 10 (59%) of 17 patients with pernicious anaemia tested, being particularly increased in those with low red cell folate levels. Reticulocytes of patients with pernicious anaemia on treatment and with haemolytic anaemia were shown to have higher folate levels than their corresponding mature cells. It is concluded that reticulocytes in general have relatively high folate levels.

Anemia, Macrocytic↗
PubMed2000

Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects.

BACKGROUND: Neural tube defects arise during the development of the brain and spinal cord. OBJECTIVES: The objective of this review was to assess the effects of increased consumption of multivitamins or folate on the prevalence of neural tube defects before pregnancy and in the first two months of pregnancy (periconceptionally). SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing periconceptional supplementation by multivitamins with placebo, folate with placebo, or multivitamins with folate; different dosages of multivitamins or folate; prepregnancy dietary advice and counselling in primary care settings to increase the consumption of folate-rich foods, or folate-fortified foods, with standard care; increased intensity of information provision with standard public health dissemination. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trial quality and extracted data. MAIN RESULTS: Four trials involving 6425 women were included. The trials all addressed the question of supplementation and they were of variable quality. No dissemination trials were identified. Periconceptional folate supplementation reduced the incidence of neural tube defects (odds ratio 0.28, 95% confidence interval 0.15 to 0.53). Folate supplementation did not significantly increase spontaneous abortion, ectopic pregnancy or stillbirth, although there was a possible increase in multiple gestation. Multivitamins alone were not associated with prevention of neural tube defects and did not produce preventive effects when given with folate. REVIEWER'S CONCLUSIONS: Periconceptional folate supplementation has a strong protective effect against neural tube defects. Information about folate should be made more widely available throughout the health and education systems. Women whose fetuses or babies have neural tube defects should be offered continuing folate supplementation. The benefits and risks of fortifying basic food stuffs, such as flour, with added folate remain unresolved.

Dietary Supplements↗
PubMed1992

Effects of ethanol on tissue folate incorporation and recovery from folate deficiency in rats.

Studies in folate-deficient alcoholics suggest that ethanol interferes with the recovery of folate status and the hematopoietic response to folate. Previous animal studies have suggested diverse effects of ethanol on intestinal absorption, hepatic metabolism, and urinary excretion of folate. In order to examine the effects of ethanol on folate distribution during folate deficiency, tissue incorporation of a tracer dose of folate was studied in rats chronically fed ethanol-containing and/or folate-deficient diets. Rats fed these diets were also used to study the effect of chronic ethanol consumption on the dietary reversal of folate deficiency by changing the diets (adding folate or replacing ethanol) from 12 to 16 weeks. After 16 weeks, tissue folate depletion was severe in rats fed folate-deficient diets. Plasma and whole body retention of the tracer dose of folate was decreased in folate-deficient rats consuming ethanol. In folate-deficient rats, ethanol consumption increased the incorporation of folate by the kidney and brain, but had no effect in other tissues (liver, lung, spleen, intestine, testis). In ethanol-fed folate-deficient rats that continued to consume ethanol, but with added folate in their diets, urine, plasma, liver, and kidney folate levels returned to control levels in 4 weeks. In the rats that stopped ethanol, but continued low folate diet consumption, no recovery of tissue folate levels was seen in 4 weeks. These results suggest that chronic ethanol consumption can exacerbate folate requirements by inhibiting body retention of small doses of folate. However, these effects are minor because ethanol consumption does not block recovery from folate deficiency when rats are fed sufficient amounts of folate.

Alcohol Drinking↗
PubMed2002

Dietary monoglutamate and polyglutamate folate are associated with plasma folate concentrations in Dutch men and women aged 20-65 years.

Dietary folate consists of monoglutamate and polyglutamate folate species. In the small intestine, folate polyglutamate is deconjugated to the monoglutamate form before absorption takes place. This enzymatic deconjugation might limit the bioavailability of polyglutamate folate. Until now, no data have been available on dietary intake of both folate forms and their associations with folate status. Therefore, we estimated the intake of monoglutamate and polyglutamate folate in the Dutch population and studied whether the association with plasma folate is different for these two folate forms. Dietary intake of monoglutamate and polyglutamate folate from nonfortified foods was estimated for 2435 subjects (1275 men; 1160 women) aged 20-65 y. The intake of monoglutamate folate was about one third of total folate intake, derived mainly from bread (approximately 20%) and meat (approximately 18%), whereas two thirds consisted of polyglutamates, derived mainly from vegetables (approximately 25%). The predictive power of the regression model with total folate intake as the independent variable adjusted for age, smoking and alcohol intake, did not increase when including the ratio of monoglutamate to polyglutamate folate intake. In addition, linear regression models showed that both monoglutamate and polyglutamate folate intake were associated positively with plasma folate levels. However, in men, the monoglutamate folate form appeared to be a threefold stronger determinant of plasma folate levels than polyglutamate folate, whereas in women, both folate forms were equally strong determinants. This might be explained by different food intake patterns of men and women, including alcohol intake. At present, it does not seem necessary to distinguish between food folate forms in advising an increase in folate intake from nonfortified foods.

Adult↗
PubMed2000

Characterization of a human alternatively spliced truncated reduced folate carrier increasing folate accumulation in parental leukemia cells.

Human CEM-7A cells established by gradual deprivation of leucovorin from the growth medium, display 100-fold overexpression of methotrexate transport activity. We found that this was associated with 10-fold reduced folate carrier gene amplification and 50-fold overexpression of both the principal 3 kb reduced folate carrier transcript and, surprisingly, a novel truncated 2 kb reduced folate carrier mRNA poorly expressed in parental CEM cells. The molecular basis for the generation of this truncated reduced folate carrier transcript and its potential functional role in folate accumulation were studied. Reduced folate carrier genomic and cDNA sequencing revealed that the truncated transcript had an internal deletion of 987 nucleotides which was a result of an alternative splicing utilizing a cryptic acceptor splice site within exon 6. This deletion consisted of the 3'-most 480 nucleotides of the reduced folate carrier ORF and the following 507 nucleotides of the 3'-UTR. These resulted in a truncated reduced folate carrier protein, which lacks the C-terminal 160 amino acids, but instead contains 58 new C-terminal amino acids obtained from reading through the 3'-UTR. Consequently, a truncated reduced folate carrier protein is generated that lacks the 12th transmembrane domain and contains a new and much shorter C-terminus predicted to reside at the extracellular face. Western analysis with plasma-membrane fraction from CEM-7A cells revealed marked overexpression of both a broadly migrating approximately 65-90 kDa native reduced folate carrier and a approximately 40-45 kDa truncated reduced folate carrier, the core molecular masses of which were confirmed by in vitro translation. However, unlike the native reduced folate carrier, the truncated reduced folate carrier protein failed to bind the affinity labels NHS-[3H]MTX and NHS-[3H]folic acid. Stable transfection of the truncated reduced folate carrier cDNA into mouse L1210 leukemia cells: increased folate accumulation, decreased their leucovorin and folic acid growth requirements, and increased their sensitivity to methotrexate. This constitutes the first documentation of an expressed alternatively spliced truncated reduced folate carrier that, when coexpressed along with the native carrier, augments folate accumulation and consequently decreases the cellular folate growth requirement. The possible mechanisms by which the truncated reduced folate carrier may increase folate accumulation and/or metabolism in cells coexpressing the truncated and native reduced folate carrier are discussed.

3' Untranslated Regions↗
PubMed2005

Renal tubular reabsorption of folate mediated by folate binding protein 1.

Renal tubular reabsorption of filtered folate is essential for the conservation and normal homeostasis of this important vitamin. Different molecular mechanisms have been implicated in epithelial folate transport, including folate receptors. Defective expression or antibody inactivation of these is associated with embryonic defects also correlated with low folate intake; however, their contribution to renal tubular folate reabsorption has not been established. With the use of targeted inactivation of the folate binding protein 1 (folbp1) and folate binding protein 2 (folbp2) genes in mice, the role of folate receptors in renal epithelial folate reabsorption was evaluated during low and normal folate intake. Inactivation of folbp1 was associated with (1) loss of (3)H-folic acid binding to crude kidney membranes, (2) increase in renal folate clearance, and (3) increase in urinary excretion and decrease in renal uptake of injected (3)H-methyltetrahydrofolate. No changes in renal folate handling were observed as a result of folbp2 inactivation. Thus, folbp1 is essential for normal renal tubular folate reabsorption, preventing excessive urinary folate loss. Folbp1 is heavily expressed in choroid plexus, yolk sac, and placenta, supporting a role of folbp1 in folate transport in other tissues. The greatest significance of folbp1 for renal folate uptake was observed at conditions of low folate intake, providing a possible explanation for the ability of folate supplementation to prevent developmental defects associated with folbp1 inactivation.

Animals↗
PubMed1998

Colonic mucosal concentrations of folate correlate well with blood measurements of folate status in persons with colorectal polyps.

BACKGROUND: Estimates of habitual dietary folate intake are known to be imprecisely correlated with systemic measures of folate status. Furthermore, measurements of blood folate concentrations may not accurately reflect the concentration of folate in tissues of interest. This issue is important for assessing folate status in the colorectal mucosa because low dietary intake or blood concentrations of folate are associated with an increased risk of colorectal neoplasia. OBJECTIVE: We examined whether conventional measures of folate in blood and a more sensitive, inverse indicator of systemic folate status, serum homocysteine, accurately reflected folate concentrations in human colonic mucosa obtained by endoscopic biopsy. DESIGN: In 30 persons with colorectal polyps, blood samples were taken and biopsies of normal rectosigmoid mucosa performed at the time of colonoscopic polypectomy. Serum, red blood cell, and colonic mucosal folate and serum homocysteine concentrations were measured. RESULTS: Serum and red blood cell folate and serum homocysteine concentrations accurately reflected colonic mucosal folate concentrations; among these, serum homocysteine correlated best with mucosal concentrations. Folate concentrations in the normal rectosigmoid mucosa were significantly lower in persons with adenomatous polyps than in those with hyperplastic polyps (P=0.04). Conventional measures of systemic folate status were not significantly lower in those with adenomas, although serum homocysteine was mildly elevated (P=0.04). CONCLUSIONS: Our data underscore the ability of systemic measures of folate status, particularly serum homocysteine, to reflect folate concentrations in the colonic mucosa. Nevertheless, future studies that examine the ability of folate to modulate colorectal carcinogenesis may benefit from direct measurement of folate in the colon.

Adenoma↗
PubMed1989

Effects of chronic ethanol and diet treatment on urinary folate excretion and development of folate deficiency in the rat.

Because the folate deficiency of chronic alcoholism has been proposed to result from ethanol-induced effects on metabolism or urinary excretion of folate, the present study was designed to evaluate the role of chronic ethanol-induced urinary folate loss on folate homeostasis in the rat. Male Sprague-Dawley rats were fed nutritionally sufficient liquid diets for 12 wk with or without ethanol, folate and sulfonamide. Urinary folate excretion was increased in ethanol-fed rats consuming folate-containing diets, but not in rats fed folate deficient diets. Consumption of folate-deficient diets led to a rapid decrease in urinary folate excretion, suggesting renal adaptation to conserve folate. Tissue and plasma levels of folate were mostly unaffected by ethanol ingestion in rats fed folate-containing diets. Ethanol treatment did not consistently enhance tissue folate depletion in rats fed folate-deficient diets. The results suggest that in rats consuming diets containing high levels of folate, chronic ethanol ingestion increased urinary folate excretion, but not to a sufficient magnitude to consistently affect folate homeostasis.

Alcoholism↗
PubMed1988

Mediated uptake of folate by a high-affinity binding protein in sublines of L1210 cells adapted to nanomolar concentrations of folate.

An L1210 cell line (JT-1), which can grow in medium supplemented with 1 nM folate, has been isolated. These cells exhibit a slower growth rate than folate-replete parental cells and have a lower ability to transport folate or methotrexate via the reduced folate transport system. Measurements at nanomolar concentrations of folate revealed that the adapted cells have acquired a high-affinity folate-binding protein. Binding to this component at 37 degrees C was rapid and reached a maximum value after 30 min which corresponded in amount to 0.23 +/- 0.3 pmol/mg protein, and excess unlabeled folate added 30 min subsequent to the [3H]folate led to a rapid release of the bound substrate. Radioactivity bound to or released from the cells after 30 min at 37 degrees C remained as unmetabolized folic acid. Binding was also rapid at 0 degrees C but uptake at the plateau was only one-half the value obtained at 37 degrees C. Half-maximal saturation of the binding component (KD) occurred at a folate concentration of 0.065 nM at pH 7.4, while the affinity for folate decreased 30-fold when the pH was reduced to 6.2 (KD = 2.0 nM). 5-Methyltetrahydrofolate was also bound by this component (Ki = 13 nM at pH 7.4) but with a much lower affinity than for folate, while progressively weaker interactions were observed with 5-formyltetrahydrofolate (Ki = 45 nM) and methotrexate (Ki = 325 nM). When the same adaptation procedure was performed with limiting amounts of 5-formyltetrahydrofolate, two additional cell lines, JT-2 and JT-3, were isolated which expressed elevated levels of the folate-binding protein. The binding activity of the latter cells was 0.46 and 1.4 pmol/mg protein, respectively. When the level of binding protein was compared in cells grown at different concentrations of folate, an increase in medium folate from 1 to 500 nM caused a sevenfold reduction in binding activity in the JT-3 cell line, while these same growth conditions had no effect on binding by the other cells. These results indicate that L1210 cells adapted to low concentrations of folate or 5-formyltetrahydrofolate contain elevated levels of a high-affinity binding protein and that this protein is able to mediate the intracellular accumulation of folate compounds. L1210 cells thus appear to have two potential uptake routes for folate compounds, the previously characterized anion-exchange system and a second route mediated by a high-affinity binding protein.(ABSTRACT TRUNCATED AT 400 WORDS)

Adaptation, Physiological↗
PubMedDate not supplied

Synthesis of [(99m)Tc]DTPA-folate and its evaluation as a folate-receptor-targeted radiopharmaceutical.

A DTPA-folate conjugate was radiolabeled with (99m)Tc by stannous chloride reduction of [(99m)Tc]sodium pertechnetate in an aqueous solution of DTPA-folate. The radiochemical purity of the product consistently exceeded 97%, as assessed by thin-layer chromatography employing conditions analogous to those for radiochemical quality control of the radiopharmaceutical [(99m)Tc]DTPA. HPLC demonstrated that the radiolabeled product resulted from the intact DTPA-folate conjugate and not unconjugated DTPA. The ability of [(99m)Tc]DTPA-folate to target folate receptors in vivo was assessed in biodistribution studies with athymic mice bearing subcutaneous folate-receptor-positive human KB cell tumors. As an internal control, previously studied [(111)In]DTPA-folate was coinjected with the [(99m)Tc]DTPA-folate, along with varying amounts of DTPA-folate (0.38 mg/kg, 1.6 mg/kg, or 14 mg/kg). At each DTPA-folate dose, [(99m)Tc]DTPA-folate exhibited tumor uptake comparable to that of the coadministered [(111)In]DTPA-folate, with radiotracer levels declining at the higher DTPA-folate doses due to competitive receptor binding of the unlabeled conjugate. Tumor uptake of both tracers was also competitively blocked by preadministered folic acid dihydrate (2.9 mg/kg). Tumor-to-background tissue contrast obtained with [(99m)Tc]DTPA-folate was generally similar to that obtained with [(111)In]DTPA-folate. The (99m)Tc-labeled DTPA-folate conjugate may have utility as a targeted radiopharmaceutical for imaging neoplastic tissues known to overexpress the folate receptor.

Animals↗
PubMed2006

Folate intakes and folate biomarker profiles of pregnant Japanese women in the first trimester.

OBJECTIVE: To assess the status of dietary folate intake, serum and red blood cell (RBC) folate, and related nutritional biomarkers in healthy Japanese women in early pregnancy. DESIGN: A cross-sectional, observational study. SUBJECTS: Pregnant women in the first trimester, at 7-15 weeks gestation (n=70), who were not consuming any folate supplements or folate fortified foods. METHODS: Three-day dietary records were obtained from each subject to assess dietary folate intake. Blood samples were collected for measurement of biomarkers. Biomarkers and nutrient intake were analyzed in two groups defined by their serum folate concentrations: the low folate group (serum folate < 9 ng/ml) and the high folate group (serum folate > or = 9 ng/ml). RESULT: Mean serum and RBC folate concentrations in all subjects were 10.3 and 519 ng/ml, respectively. These levels were remarkably higher than the reported values from many other countries despite our subjects receiving no folic acids supplements. However, mean folate intake by our subjects from natural foods was 289 microg/day, which is thought to be low according to the Japanese dietary recommendation specified for pregnant women. The intake of spinach and fruits was significantly greater in the high folate group than in the low folate group. CONCLUSION: Folate intake was thought to be adequate to maintain a desirable level of serum folate concentration in Japanese pregnant women in the first trimester, although the intake of folate from natural food was not high enough to meet the recommended daily intake.

Adolescent↗
PubMed2005

Association between dietary folate-rich food intake and folate status of elderly Taiwanese.

To investigate the relationship between folate status and dietary folate intake in the Taiwanese elderly, we analyzed plasma folate levels and dietary folate intake in 725 males and 705 females aged 65-90 years, sampled from the Elderly Nutrition and Health Survey in Taiwan (1999-2000) (Elderly NAHSIT). Results showed that the mean plasma folate levels were 22.9+/-1.4 nmol/L (10.1+/-0.6 ng/ml) for males and 29.5+/-1.6 nmol/L (13.0+/-0.7 ng/ml) for females. The average plasma folate concentrations of males from all age groups were significantly lower than those of females (P<0.0001). None of the study subjects had a plasma folate below 7 nmol/L (3 ng/ml). However, 18.6% of males and 12.1% of females had marginal folate deficiency, with plasma folate between 7-14 nmol/L (3-6 ng/ml). This suggests that elderly males have a poorer folate status than elderly females in the Taiwanese population. The percentage of marginal folate deficiency tended to increase with age among females (P trend=0.0137). The average estimated folate intakes were 379+/-18 microg/d in males and 351+/-27 microg/d in females. However, 45.5% of males and 48.8% of females had a dietary folate intake below 2/3 of the RDA of 400 microg/d. Our results indicated that dietary folate intake is positively correlated with plasma folate levels (r=0.10, P<0.05). In addition, dietary folate intake increased with increased intakes of vegetables, mushrooms and fruit. A lower intake of fruit appeared to be responsible for the higher prevalence of marginal folate deficiency among females over the age of 80 years.

Age Factors↗
PubMed1983

Effect of orange juice, folic acid, and oral contraceptives on serum folate in women taking a folate-restricted diet.

The effect of folate intake from orange juice on serum folate was evaluated in 60 women (age 20-39) during 9 weeks of a folate-restricted diet. Twenty-one were users of oral contraceptives (OCA). Folate intake from the restricted diet was 159 +/- 5 micrograms/day, as assessed by dietary surveys. Serum folate of women taking OCA was lower than in nonusers at the inception of the study (P less than 0.01). During the initial 2 weeks of restricted diet, serum folates decreased significantly (13.8 +/- 1.8 to 8.5 +/- 0.4 ng/ml; P less than 0.002). This decrease was further prevented by supplementation of the diet for 7 weeks with 100 micrograms/day of total folate from reconstituted frozen orange juice or synthetic folic acid (PteGlu). Both folate supplements were effective (P less than 0.05) in increasing serum folate (9.4 +/- 1.0 to 14.5 +/- 1.4 ng/ml, orange juice; 8.4 +/- 0.7 to 20.5 +/- 5.8 ng/ml, folic acid). Serum folates were similar in women taking either orange juice or folic acid. Serum folate of nonsupplemented women decreased from 10.2 +/- 0.8 to 8.3 +/- 0.4 ng/ml (P less than 0.05). No difference between serum folates of OCA users and nonusers was detected during the restricted diet or folate supplementation. These data indicate that folate in reconstituted orange juice was as available as folic acid, and that utilization of both folate forms and folate in a mixed diet was unaffected by oral contraceptives.

Adolescent↗
PubMedDate not supplied

Synthesis and biological evaluation of diethylenetriamine pentaacetic acid-polyethylene glycol-folate: a new folate-derived, (99m)Tc-based radiopharmaceutical.

(99m)Technetium-labeled diethylenetriamine pentaacetic acid-polyethylene glycol-folate (DTPA-PEG-folate) was synthesized and tested as a radiopharmaceutical agent, which targeted the lymphatic system with metastatic tumor. Folic acid was reacted with H2N-PEG-NH2 to yield H2N-PEG-folate. After purification by anion-exchange chromatography, the product was reacted with cyclic DTPA. By removal of unreacted DTPA by size-exclusion chromatography, DTPA-PEG-Folate was obtained. Fluorescein-5-isothiocyanate (FITC)-labeled DTPA-PEG-folate and DTPA-PEG-OCH3 were prepared via a dicyclohexylcarbodiimide-mediated coupling. In vitro competitive binding test showed that the uptake of [125I] folic acid was inhibited by DTPA-PEG-folate and the 50% inhibitory concentration was 4.37 pmol/L (R2 = 0.9922). The relative affinity of DTPA-PEG-FITC was 0.18 for human folate receptor comparing with folic acid. In cultured tumor cells, uptake of fluorescence-labeled DTPA-PEG-folate was found to increase significantly in folate-deficient medium compared with that of untargeted DTPA-PEG-OCH3 and FITC-ethylenediamine. The competition with free folic acid blocked the cell uptake of DTPA-PEG-folate. These results confirmed the DTPA-PEG-folate entered into KB cells through the folate receptor endocytosis pathway in vitro. The radiolabeled yield of [(99m)Tc] DTPA-PEG-folate was in excess of 98%, and specific activities of 7.4 kBq (0.2 microCi/microg) were achieved. After subcutaneous injection, [(99m)Tc] DTPA-PEG-folate exhibited an initial increase and successive decline of accumulation in popliteal nodes in normal Wistar rats. Expect for the kidney, uptake by other tissues was rather low. In a normal rabbit imagine study, the lymphatic vessels were readily visualized by single-photon-emission computed tomography following subcutaneous injection of [(99m)Tc] DTPA-PEG-folate. In conclusion, the [(99m)Tc] DTPA-PEG-folate conjugate may have a potential as a lymphatic tumor-targeted radiopharmaceutical.

Animals↗
PubMed1975

Serum and erythrocyte folates in combined iron and folate deficiency.

A high incidence of iron and folate deficiency was found in 80 female subjects living in a private institution. Iron therapy in individuals with low serum iron values resulted in a significant increase in hemoglobin levels. An improvement in serum and RBC folate levels was also found following iron therapy but this could not be attributed to treatment since a similar increase was observed in untreated control subjects, probably due to an increased dietary intake of folates during the study period. In subsequent studies small amounts of pteroylglutamic acid were given to all patients and their response to therapy was related to initial serum and RBC folate values. No correlation between serum folate levels and response to folate therapy could be demonstrated. Red cell folate levels on the other hand correlated well with response to therapy. A significant increase in hemoglobin was found following folate therapy in patients with low RBC folates, but not increase in subjects with normal RBC folates. Conversely, the increase in hemoglobin following iron therapy in subjects with normal RBC folates was three times as much as in patients with low RBC folates. Thus, unlike serum folate determinations, RBC folate measurements are a reliable index of tissue folate stores, and useful in the prediction of response to folate therapy in both the iron-deficient and iron-replete states.

Adult↗