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PubMed2006

The effect of folic acid on porphyrin synthesis in tumors and normal skin of mice treated with 5-aminolevulinic acid or methyl 5-aminolevulinate.

5-Aminolevulinic acid (ALA) or its derivative methyl 5-aminolevulinate (MAL) combined with folic acid was applied in nude mice bearing human colon adenocarcinoma. The aim of the study is to see whether folic acid may increase biosynthesis of porphyrins in tumor tissue after systemic or topical administration of ALA or MAL. The production of porphyrins was determined by spectrofluorometric measurements with an optical fibre probe. It was found that the porphyrin production after i.p injection of 200 mg kg(-1) ALA or MAL was significantly increased by i.p injection of 100 mg kg(-1) folic acid. However, in the case of topically applied 20% ALA, folic acid had no effect. In the case of topically applied 20% MAL, folic acid (i.p or topically applied) reduced the porphyrin synthesis. This might be used for the protection of normal skin against photosensitization. The effects of folic acid were similar in tumors and normal skin. Two mechanisms may explain the results: enhancement of the efficiency of the rate-limiting enzyme porphobilinogen deaminase by folic acid or interference of folic acid with the transport of ALA and MAL to and into the cells synthesizing porphyrins in the tissues. The present data seem to favour the latter mechanism. Folic acid may have a role as an adjuvant in photodynamic therapy with systemically administered ALA and its derivatives.

Adenocarcinoma↗
PubMed1997

Observations on the prevention of cleft palate in dogs by folic acid and potential relevance to humans.

Folic acid has been shown to prevent neural tube defects in humans, but its effects on other defects is unknown. In a consistent breeding programme of Boston terrier dogs started in 1974, folic acid supplementation (5 mg/day) was introduced in 1981. The frequency of cleft palate fell from 9/51 (17.6%) without folic acid to 8/191 (4.2%) after its introduction, giving a reduction of 76% (95% confidence limits 42%-90%, p = 0.003).

Journal Article↗
PubMed1999

Photodegradation of folic acid in aqueous solution.

A study of the photodegradation of folic acid by ultraviolet radiation in aqueous solution has been made. Folic acid is photolysed by an apparent first-order kinetics and the log k-pH profile shows a gradual decrease in rate in the pH range 2.0-10.0. The profile indicates the appearance of three steps which reflect the participation of different ionic species of folic acid (pKa(1) 2.3, pKa(2) 8.3) in the photolysis reaction. The rate of photodegradation varies from 0.1550 x 10(-3) min(-1) (pH 10.0) to 5.04 x 10(-3) min(-1) (pH 2.5) in the pH range studied. The photolysis of folic acid shows that it is degraded to pterine-6-carboxylic acid and p-amino-benzoyl-L-glutamic acid. A maximum yield of these products is obtained at 3-8 h, depending upon the pH. An HPLC method has been used for the assay of folic acid and its degradation products.

Chromatography, High Pressure Liquid↗
PubMed2006

Awareness and use of folic acid among women in the lower Mississippi Delta.

CONTEXT: National and state efforts to increase folic acid awareness and use may not be reaching large segments of the population. PURPOSE: This study examines folic acid awareness and use among women of childbearing age in a representative, economically at-risk rural sample and identifies factors that influence awareness and use. METHODS: A cross-sectional random digit dialing telephone survey was completed with a representative sample of 646 women aged 14-45 years in 36 counties of the lower Mississippi Delta. Folic acid awareness and supplement use were estimated by percentages weighted to reflect the 36-county population. Pregnancy intentions and the ability to become pregnant were used to predict awareness and use among a subsample of sexually active women. FINDINGS: Compared to national samples, Delta women were less likely to have heard of folic acid (75% vs 64%) or to take a regular (5-7 days/wk) folic acid supplement (34% vs 22%). The proportion of women who took regular folic acid supplements was very low among some subgroups: African Americans (14%), those 14-19 years of age (12%), and those with low incomes (13%) and low educational levels (14%). Of the women who reported being sexually active, the ability to become pregnant more than doubled their likelihood of regular supplement use. CONCLUSIONS: The national folic acid campaign has not reached many women in the rural Mississippi Delta. A new mode of folic acid education is needed that is focused on low-income and young women and women not planning pregnancies. In the Delta and similar geographic regions, health care providers, black church leaders, and youth group leaders could be valuable advocates for folic acid.

Adolescent↗
PubMed2003

Secondary prevention with folic acid: effects on clinical outcomes.

OBJECTIVES: We sought to conduct a randomized trial with folic acid 0.5 mg/day in a patient population with stable coronary artery disease (CAD). BACKGROUND: Folic acid has favorable effects on vascular endothelium and lowers plasma homocysteine levels. In addition, homocysteine appears to be an independent risk factor for atherosclerotic disease. However, the value of folic acid in secondary prevention had seldom been tested. METHODS: In this open-label study, 593 patients were included; 300 were randomized to folic acid and 293 served as controls. Mean follow-up time was 24 months. At baseline all patients had been on statin therapy for a mean of 3.2 years. RESULTS: In patients treated with folic acid, plasma homocysteine levels decreased by 18%, from 12.0 +/- 4.8 to 9.4 +/- 3.5 micromol/l, whereas these levels remained unaffected in the control group (p < 0.001 between groups). The primary end point (all-cause mortality and a composite of vascular events) was encountered in 31 (10.3%) patients in the folic acid group and in 28 (9.6%) patients in the control group (relative risk 1.05; 95% confidence interval: 0.63 to 1.75). In a multifactorial survival model with adjustments for clinical factors, the most predictive laboratory parameters were, in order of significance, levels of creatinine clearance, plasma fibrinogen, and homocysteine. CONCLUSIONS: Within two years, folic acid does not seem to reduce clinical end points in patients with stable coronary artery disease (CAD) while on statin treatment. Homocysteine might therefore merely be a modifiable marker of disease. Thus, low-dose folic acid supplementation should be treated with reservation, until more trial outcomes become available.

Aged↗
PubMed1990

Folic acid transport in organ-cultured mucosa of human intestine. Evidence for distinct carriers.

The transport of folic acid was investigated in organ-cultured endoscopic biopsy specimens of intestinal mucosa from normal subjects. In the proximal small intestine at pH 5.5 and 6.5, [3H]folic acid accumulated to concentrations 2.64- and 2.17-fold higher than those of the medium, respectively, but at pH 7.5 the concentration was same as that of the medium. Saturability of initial rates of uptake was demonstrable with respect to luminal concentrations of [H+] and folic acid. Two proton-dependent transport mechanisms were evident: (a) a carrier with a low affinity for H+ and a low capacity for folic acid, and (b) a high-affinity, high-capacity carrier (Km, 635 and 54.6 nmol/L [H+]; Vmax, 0.066 and 2.583 pmol folic acid/microL intracellular water per 10 minutes, respectively). Kinetic studies of folic acid uptake at pH 5.5 and 7.5 revealed a difference in Km for folic acid (15.76 and 34.38 mumol/L, respectively) with no change in Vmax. In the colon, folic acid did not accumulate against a concentration gradient, and the initial rate of uptake was not affected by luminal pH. The accumulation of folic acid in colonic mucosa was significantly higher at pH 5.5 than at 7.5 and showed significant regional variation, with optimal uptake in the sigmoid colon. Methotrexate inhibited folic acid uptake competitively both in the proximal small intestine and in the cecum (inhibition constant 6.9 and 54 mumol/L, respectively, at pH 5.5). These data indicate the presence of a proton-dependent, active transport of folic acid in the proximal small intestine at pH 5.0-6.5. At pH 7.5 and in the mucosa of the colon, uptake of folic acid proceeds by facilitated diffusion through a low-affinity carrier.

Biological Transport, Active↗
PubMed2005

An intervention study to increase knowledge and use of folic acid among relatives in neural tube defect-affected families in Washington, D.C.

BACKGROUND: Little is known about the level of knowledge and use of folic acid among near relatives in U.S. families of a child with spina bifida. We hypothesized that relatives would be more knowledgeable than the general population and more likely to take folic acid. Further, we hypothesized that relatives would be more motivated by an intervention to increase their use of folic acid. METHODS: We conducted an intervention study among females in families attending a hospital spina bifida clinic in Washington, DC. RESULTS: The 231 subjects consisted of the affected individuals, mothers, sisters, and aunts. The average age was 34 years. At baseline, most (87.4%) reported that they had heard of folic acid; 37.6% were currently taking multivitamins with folic acid and 6.9% were taking folic acid tablets. The intervention significantly increased both knowledge (to 99%) and intake of folic acid from 41.9 to 48.5%. Folic acid intake increased significantly among African-American women and women with less education, women who were older, married, with children, and nonsmokers. CONCLUSIONS: This intervention was successful in increasing folic acid intake among female relatives in spina bifida-affected families. By the end of the study, almost all women had heard of folic acid and folic acid use had increased by 16%. Among these women at higher than expected risk for having an affected child, this rate of intake, while more than the general population, still falls short of optimum. Fortification of food with folic acid may be the only way to ensure increased folic acid intake.

Adolescent↗
PubMed2006

Comparison of folic acid uptake characteristics by human placental choriocarcinoma cells at acidic and physiological pH.

The aim of this work was to characterize the placental uptake of folic acid from the maternal circulation. Using 2 human trophoblast cell lines (BeWo and JAR), we verified that uptake of 3H-folic acid was pH-dependent, increasing significantly with decreasing extracellular pH. In BeWo cells, uptake of 3H-folic acid at pH 5.5 was (i) Na+-independent; (ii) inhibited by folic acid, 5-methyltetrahydrofolate (5-MTHF), and methotrexate (MTX); (iii) inhibited by the anion transport inhibitors 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) and 4-acetamido-4'-isothiocyano-2,2'-disulfonic acid stilbene (SITS); (iv) inhibited by the proton ionophore carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP); (v) not inhibited by blockers of receptor-mediated endocytosis (cytochalasin D and monensin); (vi) trans-inhibited by MTX and folic acid; and (vii) not affected by an anti-reduced folate transporter-1 (RFC) antibody. At pH 7.5, uptake of 3H-folic acid was (i) Na+-independent; (ii) inhibited by folic acid and MTX, but not by 5-MTHF; (iii) inhibited by SITS, but not by DIDS; (iv) not affected by FCCP; (v) inhibited by monensin (but not by cytochalasin D); (vi) trans-inhibited by folic acid (but not by MTX); and (vii) inhibited by an anti-RFC antibody. In conclusion, in BeWo cells, both RFC and receptor-mediated endocytosis seem to be involved in 3H-folic acid uptake at pH 7.5, whereas at pH 5.5, RFC and (or) a low pH-operating transporter distinct from RFC are involved.

Biological Transport↗
PubMed2001

Short-term folic acid supplementation induces variable and paradoxical changes in plasma homocyst(e)ine concentrations.

Folic acid is presently the mainstay of treatment for most subjects with elevated plasma homocyst(e)ine concentrations [Plasma or serum homocyst(e)ine, or total homocysteine, refers to the sum of the sulfhydryl amino acid homocysteine and the homocysteinyl moieties of the disulfides homocystine and homocystein-cysteine, whether free or bound to plasma proteins.] Changes in homocyst(e)ine in response to folic acid supplementation are characterized by considerable interindividual variation. The purpose of this study was to identify factors that contribute to heterogeneity in short-term responses to folic acid supplementation. The effects of folic acid supplementation (1 or 2 mg per day) for 3 wk on plasma homocyst(e)ine concentrations were assessed in 304 men and women. Overall, folic acid supplementation increased mean plasma folate 31.5 +/- 98.0 nmol/L and decreased mean plasma homocyst(e)ine concentrations 1.2 +/- 2.4 micromol/L. There was evidence of substantial interindividual variation in the homocyst(e)ine response from -18.5 to +7.1 micromol/L, including an increase in homocyst(e)ine in 20% of subjects (mean increase 1.5 +/- 1.4 micromol/L). Basal homocyst(e)ine, age, male gender, cigarette smoking, use of multivitamins, methylene tetrahydrofolate reductase, and cystathionine beta-synthase polymorphisms accounted for 47.6% of the interindividual variability in the change in homocyst(e)ine after folic acid supplementation, but about 50% of variability in response to folic acid was not explained by the variables we studied.

Aged↗
PubMed2001

Folic acid utilisation related to sulfa drug resistance in Saccharomyces cerevisiae.

Saccharomyces cerevisiae mutants deficient in folate synthesis have been constructed and employed to study the utilisation of exogenous folates in yeast. One mutant specifically lacked dihydropteroate synthase while the second lacked dihydrofolate synthase. Exogenous folinic acid restored optimal growth to both strains. Folic acid did not generally rescue growth but spontaneous isolates capable of utilising folic acid were selected. The folic acid synthesis pathway in the folate utilising isolates was restored via transformation with FOL1 or FOL3 expression plasmids and transformants were tested for resistance to sulfamethoxazole (SMX). The presence of elevated levels of folic acid led to greatly reduced SMX sensitivity regardless of whether strains were folate utilisers or not.

Anti-Infective Agents↗
PubMed2001

Concomitant supplemental vitamin A enhances the response to weekly supplemental iron and folic acid in anemic teenagers in urban Bangladesh.

BACKGROUND: Iron deficiency is the most common micronutrient deficiency and affects >2 billion persons worldwide, leading to anemia in >40% of women of reproductive age in the developing world. OBJECTIVE: The objective was to determine whether weekly supplementation with iron and folate would reduce the frequency of anemia in teenage women in urban Bangladesh before they became pregnant. DESIGN: Participants with a hemoglobin concentration of 80-120 g/L were entered into a randomized, double-blind, placebo-controlled trial and received supplements of placebo, vitamin A, iron + folic acid, or iron + folic acid + vitamin A weekly for 12 wk. The supplements contained 2.42 mg vitamin A (retinol) as retinyl palmitate, 120 mg elemental Fe as ferrous sulfate, and 3.5 mg folic acid. RESULTS: Hemoglobin concentrations increased significantly more after supplementation with iron + folic acid or iron + folic acid + vitamin A than after either the placebo or vitamin A alone. There was a significantly greater increase in hemoglobin after iron + folic acid + vitamin A than after iron + folic acid, but the additional effect disappeared after adjustment for baseline hemoglobin, serum vitamin A, and ferritin and the number of supplements taken. Those with the lowest baseline hemoglobin had the greatest increase in hemoglobin. Compared with the placebo, iron + folic acid + vitamin A reduced anemia by 92%, iron deficiency by 90%, and vitamin A deficiency by 76%. CONCLUSION: There may be significant health benefits from a program that enhances the nutritional status of iron, folate, and vitamin A in poor urban young women before they become pregnant.

Adolescent↗
PubMed1993

Vitamin B12, folic acid and haematological status in elderly Thais.

Serum vitamin B12, folic acid and haematological data from 147 elderly people (55 males and 92 females) who visited the special clinic for the elderly at Rajvithi Hospital, Bangkok between July and November 1989 were investigated. The individuals studied came from a health-conscious group of the middle socio-economic class in Bangkok. All of them were fairly well except for minor ailments and typical diseases of elderly people such as hypertension, mild to moderate degree coronary heart diseases and non-insulin dependent diabetes mellitus. There was a statistically significant difference in haemoglobin concentrations between males and females. According to the standard haemoglobin cut-off point values of 13 g/dl for males and 12 g/dl for females, anaemia was detected in 22 (15%) of the 147 subjects. The percentage of folic acid deficiency was found to be 20.6 per cent (30 of the 147 cases). Vitamin B12 insufficiency was found in only 6.9 per cent (10 of the 147 cases). No statistically significant correlation between haemoglobin, folic acid and vitamin B12 was found. However, when the data were grouped according to different intervals of increasing haemoglobin concentrations, for females there was a tendency for serum vitamin B12 to decrease, and serum folic acid to increase in both males and females. The results of this study suggest that folate deficiency may play a role in the occurrence of anaemia in elderly people, and therefore, dietary counselling and supplementation of folic acid are recommended.

Aged↗
PubMed2003

The prevention of congenital anomalies with periconceptional folic acid supplementation.

Large randomized trials have demonstrated the critical role of folic acid supplementation in the prevention of neural tube defects. Since 1992, a number of national and international professional societies have released guidelines recommending folic acid supplementation of at least 0.4 mg/day for all women of childbearing age or women planning pregnancies, and 4 mg/day for women with a previous infant with a neural tube defect. Furthermore, a reduction in the incidence of congenital cardiac and urologic anomalies has been demonstrated in some studies following periconceptional folic acid supplementation. There is growing evidence of a possible role of folic acid supplementation in the prevention of other congenital anomalies, including cardiac defects. Since 1998, mandatory fortification of certain foods with folate has been associated with at least a 54% reduction in the incidence of open neural tube defects, yet rates of periconceptional folic acid use remain suboptimal, especially in minority women. Innovative strategies in educating women, health-care providers, and pharmacists on the benefits of folic acid supplementation need to be explored. Mandatory folate fortification of foods needs to be defined and monitored.

Congenital Abnormalities↗
PubMed2000

Homocysteine metabolism and effects of folic acid supplementation in patients affected with spina bifida.

Folic acid supplementation around conception decreases the risk of having offspring with a neural tube defect. However, the aetiology is often still unknown. This study investigated whether spina bifida patients have lower blood folate and higher fasting and post-methionine-load plasma total homocysteine (tHcy) concentrations than control patients. Moreover, the effects of supplementation with 500 microg folic acid/d on folate and tHcy concentrations were determined. Spina bifida patients (n = 12) and disabled control patients (n = 15) received 4 weeks of placebo treatment followed by 4 weeks of intervention with 500 microg folic acid/d. Blood was collected at the start and after 4 and 8 weeks. A methionine-loading test was performed at the start and the end of the study. At baseline, no significant differences occurred between spina bifida and control patients. Folic acid supplementation significantly increased plasma and red blood cell folate concentrations in both groups. Folic acid decreased fasting tHcy concentrations in control patients by 1.6+/-0.5 micromol/l (p<0.01) and in spina bifida patients by 2.2 +/- 1.3 micromol/l (p = 0.10). This study does not show a derangement in homocysteine metabolism in spina bifida compared to control patients. Moreover, folic acid supplementation seems at least as effective in spina bifida patients as in controls.

Administration, Oral↗
PubMed2006

Low folic acid status and its association with anaemia in urban adolescent girls and women of childbearing age in Sri Lanka.

Folic acid deficiency is implicated in the aetiology of nutritional anaemia and adverse pregnancy outcomes for the fetus. Data on folic acid status among adolescent girls and non-pregnant, non-lactating young women are limited. We assessed folic acid status in a random sample of 552 subjects (277 adolescent girls aged 15-18.9 years and 275 women aged 19-30 years) living in Colombo, Sri Lanka. The association of low folic acid status with anaemia was evaluated. Socio-economic, food intake and anthropometric data were obtained. Hb, serum folic acid, vitamin B12 and ferritin and plasma homocysteine concentrations were measured. Forty-three per cent of subjects studied had low serum folic acid concentrations (<3 ng/ml) and 47 % had low Fe stores (serum ferritin <20 microg/l). Overall prevalence of anaemia was 12.9 %, and 43.9 % of anaemic subjects had both low folic acid status and depleted Fe stores (serum ferritin <12 microg/l). Both low folate status and depleted Fe stores were significantly associated with anaemia (odds ratio = 2.32; 95 % CI 1.34, 4.01 and odds ratio = 5.98; 95 % CI 3.36, 10.63, respectively). Serum folic acid concentration was associated (r = 0.108, P = 0.015) with folate intake as indicated by a computed folate index. Folate index was associated inversely with household size and positively with economic status and education level. In this study population low folic acid status, besides depleted Fe stores, was associated with anaemia. The high prevalence of low folic acid status observed highlights the need for nutrition education to improve intakes of folate, Fe and other micronutrients among adolescent girls and young women.

Adolescent↗
PubMed1977

[Folic acid levels in patients with compensated renal failure and during long-term haemodialysis (author's transl)].

Folic acid concentration in plasma and erythrocytes and vitamin B12 concentration in plasma were determined by radioassay in 56 patients with chronic renal failure. Compensated retention was present in 31, while 25 were haemodialysed at regular intervals, 14 at home, and 11 in hospital. One patient had megaloblastic anaemia. Mean folic acid concentration in plasma for the whole group was 4.60 microgram/l (normal 8.30 +/- 2.57 microgram/l), in RBC 385 microgram/l (normal 459 +/- 143 microgram/l. Vitamin B12 levels were normal. These was no significant difference in folic acid levels betwwen patients on home or on hospital dialysis. During dialysis there was a fall in folic acid concentration in plasma which was proportional to the intial levels. After a four-week replacement pause folic acid concentration in RBC had not decreased in those patients on long-term dialysis who had previously received folic acid. The decreased folic-acid concentration in plasma of patients in compensated chronic renal failure is not due to the renal failure. Folic acid concentration in RBC is decisive in the assessment of folic acid deficiency.

Adult↗
PubMed1997

Unpredictable intra-individual variations in serum homocysteine levels on folic acid supplementation.

OBJECTIVE: To determine if changes in serum homocysteine values during folic acid supplementation can identify objectively healthy subjects with subclinical folate deficiency. DESIGN: Blood drawn and processed in a regimented fashion from fasting subjects. Serum homocysteine values determined by gas chromatography-mass spectrometry twice before and on days 5 and 8 of daily folic acid supplementation. SETTING: Outpatient University Hospital Clinical Research Center, Denver, Colorado. SUBJECTS: Subjectively healthy adults with normal hematologic and biochemical screening tests. INTERVENTION: Folic acid 1 mg daily for eight consecutive days. RESULTS: Homocysteine values of the group fell significantly during folic acid supplementation. Values pre supplementation were 7.8 +/- 1.8 and 7.4 +/- 2.4 mumol/L while values on days 5 and 8 of supplementation were 6.5 +/- 2.2 and 6.3 +/- 2.2 mumol/L. However, the homocysteine values of any given individual varied up to 60% (rises up to 7 mumol/L and falls of 5 mumol/L) during folic acid supplementation despite the controlled circumstances of blood handling, and an assay coefficient of variation of 8%. CONCLUSIONS: Although group values of serum homocysteine fall during folic acid supplementation, intraindividual variation is so great that subjects with subclinical folate deficiency can not be identified using this study design. Furthermore, these data suggest than an individuals homocysteine values vary enough that single values must be interpreted with caution.

Adolescent↗
PubMed1961

Studies on the folic acid activity of human serum.

A method for the measurement of serum folic acid activity is described, which is a modification of previous methods. The material in serum with activity for L. casei is made up of a stable and a labile component. The amount of stable component in normal subjects and patients with megaloblastic anaemia is similar. The amount of labile component varies. In patients with folic acid deficiency none is present; in normal subjects it constitutes between 65 and 94% of the total serum L. casei activity. The labile component appears to be an index of folic acid metabolism, and the assay of total serum L. casei activity is therefore a valuable method for differentiating patients requiring treatment with folic acid from normal subjects and patients with primary vitamin B(12) deficiency. Normal subjects had serum folic acid levels from 5.9 to 21.0 mmug./ml. (mean 9.9 mmug./ml. +/- 0.3 mmug./ml. S.E.). In patients with megaloblastic anaemia requiring treatment with folic acid, other than megaloblastic anaemia of pregnancy, the levels were less than 4.0 mmug./ml. Patients with uncomplicated pernicious anaemia had levels from 6.0 to 27.0 mmug./ml. (mean 16.6 mmug./ml. +/- 1.1 mmug./ml. S.E.). The mean level in this group was higher than in normal subjects, and the highest levels of all were found in patients with subacute combined degeneration of the cord with minimal anaemia (range 14.4 to 36.8 mmug./ml.; mean 24.8 mmug./ml. +/- 2.4 mmug./ml. S.E.). The L. casei activity of the labile component is lost during autoclaving or storage at -20 degrees C. This loss can be prevented during autoclaving by using adequate amounts of ascorbic acid in the phosphate buffer used to dilute the serum for assay and by adding ascorbic acid to serum that is to be stored. Moreover, the activity lost during the storage of serum not protected by ascorbic acid could be restored, for periods up to three months, by adding ascorbic acid to this serum before assay.

Anemia↗