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PubMed1998

Endogenous folic acid is essential for normal development of preimplantation embryos.

Preimplantation mammalian embryos develop with a high degree of autonomy. To date, there have been no unequivocal demonstrations of a requirement for vitamins in preimplantation embryo development. Reduced folic acid acts as an important methyl donor in many reactions including the synthesis of thymidine. Thymidine does not accumulate in cells so it might be expected that significant amounts of reduced folate would be required to support the exponential increase in DNA synthesis that occurs during early embryo development. The reduction of folate is catalysed by dihydrofolate reductase (EC 1.5.1.3) which is selectively inhibited by the anti-cancer drug methotrexate. Methotrexate caused a dose-dependent inhibition of cell division in 1-cell, 2-cell and 8-cell mouse embryos with 50% inhibition of division occurring at concentrations of 1-10 microM. At a concentration of 0.1 microM only minimal inhibition of the initial cell division occurred, but continuous culture in this concentration of methotrexate completely inhibited further cell divisions. This suggests that most of the exogenous store of reduced folates was used in the first round of cell division. The effects of methotrexate were apparently primarily due to thymidine starvation, since a 10-fold excess of thymidine over methotrexate in culture media reversed the inhibition of development. Supplementing media with folic acid had no beneficial effect on the rate at which zygotes produced by in-vitro fertilization developed to the blastocyst stage. It is concluded that the development of the early embryo has an absolute requirement for reduced folate for thymidine synthesis which is met entirely by endogenous sources.

Animals↗
PubMed2004

Neural tube defect rates before and after food fortification with folic acid.

BACKGROUND: Since 1998, enriched cereal grains sold in the United States have been fortified with folic acid, to reduce the incidence of neural tube defects (NTDs). The Centers for Disease Control and Prevention (CDC) recently reported that NTD rates have decreased 26% since fortification, but that additional effort is needed to achieve the national goal of a 50% reduction. However, accurate determination of NTD rates requires counting antenatally detected cases; the CDC study noted that the number of prenatally diagnosed cases was likely underestimated. METHODS AND RESULTS: We examined studies from the United States and Canada that compared rates of NTDs before and after very similar fortification programs were instituted in each country. U.S. studies had incomplete ascertainment of prenatally diagnosed NTD cases, and as a result, underreported the number of NTDs prevented. Canadian studies, in which ascertainment was more complete, showed decreases in NTD rates up to 54%. CONCLUSIONS: There is a strong correlation between the completeness of ascertainment and the percentage decrease in NTD rates. Studies that identify cases best show that folic acid fortification is preventing around 50% of NTDs. The percentage of NTDs that are folate-preventable in the United States is uncertain, but is probably 50-60%. Thus, we may be quite close to achieving the optimum level of protection at current fortification levels.

Female↗
PubMed2002

Use of folic acid supplements in the first trimester of pregnancy.

Folic acid supplementation in the periconceptual period is known to reduce the risk of neural tube defects. High dose supplementation prevents a high proportion of recurrent defects, whilst low doses reduce the risk of first occurrences. The Department of Health advises all women considering pregnancy to take folate supplements for 12 weeks prior to conception and in the first trimester of pregnancy. Surveys of the British population indicate that the uptake of this advice is poor. The aim of the present study was to evaluate the uptake of advice in a group of Northampton women between January and June 2001. A total of 301 Caucasian women were recruited through an antenatal dating scan clinic. The women were aged between 16 and 42 years and completed a questionnaire concerning nutritional supplements prior to and during pregnancy and a five-day food diary, which was used to estimate dietary folate intakes. Of the women 67% consumed folate-containing supplements in the first trimester of pregnancy and 43% reported taking folate before becoming pregnant. Women under the age of 21 years were less likely to take folate supplements than women over the age of 21 years (p = 0.007), as were smokers (p < 0.001) and women from lower social classes. Mean folate intakes, including supplements, were 511 +/- 17 micrograms per day and unsupplemented dietary intakes were 237 +/- 5 micrograms per day. Of the women interviewed, 24.5% had folate intakes below the reference nutrient intake for pregnancy (300 micrograms per day). The data supports the assertion that neural tube defects are more likely to be prevented through the fortification of staple foods than through supplementation, but highlights the fact that young women from poor social backgrounds may still require close monitoring and support.

Adult↗
PubMed2002

Nitration and chlorination of folic acid by peroxynitrite and hypochlorous acid, and the selective binding of 10-nitro-folate to folate receptor beta.

The aim of this work was to characterize folates modified by ONOO(-) and HOCl and to evaluate the binding capacity of folates modified by ONOO(-) to folate receptor alpha and beta. For the modification of folate by ONOO(-), folic acid was reacted with the combination of PMA activated PMN and PAPA NONOate or chemically synthesized ONOO(-). For the modification of folate by HOCl, folic acid was reacted with the combination of MPO and H(2)O(2) or NaOCl. The structures of products were determined by 1H-NMR and MALDI-TOF mass. Nitrated folate species were identified as 10-nitro-folate and 12-nitro-folate, and chlorinated folate was identified as 12-chloro-folate. The 10-nitro-folate showed the selective binding to FR-beta, compared to folic acid.

Carrier Proteins↗
PubMed1993

Effect of withdrawal of folic acid supplementation in maintenance hemodialysis patients.

The requirement of patients on maintenance hemodialysis for dietary supplements of folic acid is controversial. High levels of folate carry the risk of toxicity as well as being unnecessary. We followed a group of 41 patients, not receiving erythropoietin, for 16 months after the cessation of folate supplementation (5 mg/day). Diet supplied 60-80 g protein and 120-260 micrograms folic acid/day. Red cell folate levels decreased linearly from a mean of 1931 +/- 888 micrograms/l (+/- SD) to 676 +/- 294 micrograms/l after 6 months before levelling off at 455 +/- 222 micrograms/l after 9 months. Mean values were unchanged 7 months later (491 +/- 319 micrograms/l). No patient developed folate deficiency. Hemoglobin values at 6, 9 and 16 months were slightly higher than the baseline value of 8.3 +/- 1.8 g/dl (p < 0.05). Mean corpuscular volumes were generally within normal limits, and vitamin B12 status was satisfactory. We conclude that folic acid supplements are unnecessary in adequately nourished hemodialysis patients who are not receiving erythropoietin.

Adult↗
PubMed1975

Depressed cell-mediated immunity in megaloblastic anemia due to folic acid deficiency.

Cell-mediated immunity has been studied in patients with 1) megaloblastic anemia of folic acid deficiency, 2)megaloblastic anemia of pregnancy, or 3) iron-deficiency anemia. Using dinitrochlorobenzene skin tests, phytohemagglutinin-stimulated lymphocyte transformation, and rosette inhibition by antilymphocyte globulin, we have shown that cell-mediated immunity is depressed in megaloblastic anemia due to folate deficiency; this depression was reversed by folate treatment. Cell-mediated immunity was not impaired by iron-deficiency anemia. Suggested interactions between iron deficiency and folate metabolism were not clarified by these studies.

Adolescent↗
PubMed1979

[Plasma B12 vitamin and folic acid during chronic renal failure and hemodialysis (author's transl)].

Thirty-one patients suffering from very advanced degrees of chronic renal insufficiency were studied. Ten received a hypoproteic diet as the only treatment and the remaining 21 were on a program of hemodialysis with a free diet and no vitamin supplements. Basal and pre- and post-dialysis plasma determinations of B12 vitamin and folic acid were carried out on them. Looking at the results it was verified that there was a significant reduction in the plasma values of both B12 vitamin and folic acid in the cases of low protein intake. In dialysis we saw that although folic acid was lost during sessions the free dietetic intake was enough to compensate for these losses. As for B12 vitamin, although it is described as dialyzable, we did not observe that its post-dialysis values disminished. Our conclusions indicate that a supplementary vitamin contribution is not necessary for patients who are on a program of hemodialysis.

Adult↗
PubMed1989

Inhibition of mammalian folylpolyglutamate synthetase and human dihydrofolate reductase by 5,8-dideaza analogues of folic acid and aminopterin bearing a terminal L-ornithine.

Six new 5,8-dideaza analogues of folic acid and aminopterin containing a terminal L-ornithine residue were prepared by using multistep synthetic sequences. Each was evaluated as an inhibitor of hog liver folylpolyglutamate synthetase and human dihydrofolate reductase. Structural modifications at positions 2, 4, 5, and 10 were included to help define structure-activity relationships for compounds of this type. The compound N alpha-(4-amino-4-deoxy-5-chloro-5,8-dideazapteroyl)-L-ornithine (3f) was identified as the most potent inhibitor of mammalian folylpolyglutamate synthetase reported thus far (Ki congruent to 2 nM). Its 4-oxy counterpart, N alpha-(5-chloro-5,8-dideazapteroyl)-L-ornithine, was only 5-fold less inhibitory than 3f toward folylpolyglutamate synthetase but was found to be a much weaker inhibitor of dihydrofolate reductase than 3f.

Aminopterin↗
PubMed2006

Influence of folic acid, vitamin B2 and B6 supplementation on feed intake, body and organs weight, and liver fatty acids composition in rats subjected to severe protein deprivation.

Growing rats fed for 3 months a low-protein (LP) diet (4.5% of energy from protein), possessed about 29% lower body weight than animals consuming adequate-protein diet (20% energy from protein). The LP diet feeding caused an increase in daily feed intake followed by a decrease in feed conversion efficiency. The enrichment of LP diet with folic acid, vitamin B2 and B6 (3 times above the level applied in the control diet) did not have any impact on rats BW and supplementation with these vitamins minimize the effect of LP diet on feed intake. The use of examined vitamins had a tendency to diminish an increase in feed conversion ratio caused by the LP nutrition. This effect was significant when all vitamins were added together. Rats fed the LP diet had higher relative weights of lungs, heart, liver and testis. Vitamins enriching the LP diet were observed to decrease a relative weight of lungs (folic acid, vitamin B6 and vitamin mixture), and liver (vitamin B6 and vitamin mixture). A tendency of increasing relative testis weight was also revealed in rats given the LP diet enriched with vitamins. The lower content of hepatic polyunsaturated fatty acids (FA) and a tendency for monounsaturated FA content to be higher were found in rats fed the LP diet. The LP diet enrichment with folic acid caused that these changes were more pronounced and statistically significant. Enrichment of LP diet with vitamins tested may cause a partial reverse of changes observed in the hepatic FA composition.

Animals↗
PubMed2005

The significance of folic acid for epilepsy patients.

The following is a comprehensive review of the current understanding of the many important roles of folic acid in the health of patients with epilepsy. A review of past and current literature reveals that folic acid plays important roles in the areas of hematology, neurology, development, and reproduction. Also highlighted are new areas for exploration.

Anticonvulsants↗
PubMed1977

A study of folic-acid-binding protein in normal subjects.

6 normal females were found to have a level of folic-acid-binding protein (FABP) in their sera (mean level 345 pg/ml). Lysates of their various leucocytes were assayed and FABP found exclusively in the polymorph fraction. The sera and lysates were fractionated by Sephadex G-200 gel column chromatography and the molecular weight of the FABP appeared to be approximately 40,000. A hitherto unreported inhibitory effect of heparin on folate binding was noticed. Studies have been performed on folic-acid-binding protein (FABP) in various pathological states, but the levels found in normal people are usually considered too low to permit investigation. In an earlier study [3], 6 normal females were found to have levels in excess of 300 pg/ml whilst the mean level of 94 controls was 76 pg/ml. Sera and leucocyte lysates from these people have been used to estimate the molecular weight of FABP in normal people.

Adult↗
PubMed2003

Amelioration of sodium valproate-induced neural tube defects in mouse fetuses by maternal folic acid supplementation during gestation.

Infants of epileptic women treated with valproic acid (VPA) during pregnancy have a higher risk of developing spina bifida than those of the general population. VPA induces exencephaly in experimental animal embryos. But the pathogenetic mechanism remains rather elusive. Antiepileptic drugs (AED) in general accentuate pregnancy-imposed fall in maternal folate levels. Periconceptional folic acid supplementation is reported to protect embryos from developing neural tube defects (NTD). Conflicting results have been reported by experimental studies that attempted to alleviate VPA-induced NTD by folic acid. Our objectives were to determine the critical developmental stages and an effective dose of folic acid for the prevention of VPA-induced exencephaly in mouse fetuses. A single teratogenic dose of 400 mg/kg of VPA was administered to TO mice on gestation day (GD) 7 or 8. It was followed by (1) a single dose of 12 mg/kg of FA (folinic acid) or (2) 3 doses of FA 4 mg/kg each. In experiment (3), FA (4 mg/kg) was administered thrice daily starting on GD 5 and continued through GD 10. These animals received VPA on GD 7 or 8. VPA and B12 concentrations were determined by radioimmunoassay. The single heavy dose of FA had no rescue effect on NTD. Three divided doses of FA on GD 7 and continuous dosing of FA from GD 5 through GD 10 substantially reduced the VPA-induced exencephaly in the fetuses. In the later experiments, the neural folds elevated faster than the non-supplemented group. VPA considerably reduced maternal plasma folate and B12 concentrations. The heavy dose of FA only moderately improved vitamin levels. Three divided doses of FA elevated the vitamin levels slightly better but it was the prolonged dosing of FA that was associated with sustained elevation of plasma levels higher than the control levels and acceleration of neural tube closure thus accounting for the pronounced protection against VPA-induced NTD development. These data suggest that plasma levels of FA and B12 have to be kept substantially elevated and maintained high throughout organogenesis period to protect embryos against VPA-induced NTD in this mouse model.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Specific antitumor targetable beta-cyclodextrin-poly(ethylene glycol)-folic acid drug delivery bioconjugate.

The tumor targeting properties of a new drug carrier synthesized by bioconjugation of folic acid (FA) to beta-cyclodextrins through a poly(ethylene glycol) (PEG) spacer (CD-PEG-FA) were investigated. Surface plasmon resonance demonstrated that CD-PEG-FA specifically interacts with immobilized folate binding protein (FBP) while the naked beta-cyclodextrins do not display any specific interaction. In vitro studies demonstrated that CD-PEG-FA was devoid of cell toxicity. [(3)H]-folic acid/CD-PEG-FA competition binding investigations performed with folate receptor overexpressing human epidermal carcinoma KB cells showed that CD-PEG-FA had about 14 times lower tumor cell binding capacity than free folic acid. The carrier cell trafficking properties were investigated using rhodamine-B as fluorescent probe, which possesses 3000 and 4580 M(-)(1) inclusion constants for CD-PEG-FA and beta-cyclodextrins, respectively. Cell-associated fluorescence measurements showed that CD-PEG-FA does not promote the rhodamine-B uptake into non-folate receptor expressing human lung carcinoma MCF7 cells while 19% higher accumulation in KB cells was found with respect to rhodamine-B loaded beta-cyclodextrins. Confocal laser scanning microscopy indicated the presence of cytosolic red fluorescent spots after 2 h of incubation of KB cells with rhodamine-B included CD-PEG-FA. The fluorescent dye resided primarily in small spots, namely, endosomes and multivesicular bodies. At 1 h after pulsed incubation, wider red fluorescent cellular structures appeared as a fusion of previous structures.

Antineoplastic Agents↗