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PubMed1998

A mutated murine reduced folate carrier (RFC1) with increased affinity for folic acid, decreased affinity for methotrexate, and an obligatory anion requirement for transport function.

In an ongoing study of structure-function relationships of the murine reduced folate carrier 1 (RFC1), a glutamate to lysine mutation at amino acid 45 was identified in a methotrexate (MTX)-resistant L1210 clonal variant in which MTX and 5-formyltetrahydrofolate (5-CHO-THF) influx was markedly decreased. The characteristics of the mutated carrier, RFC1-E45K, were studied by cDNA transfection into the murine MTXrA line in which endogenous carrier is not functional. Folic acid influx doubled in the transfectant MTXrA-E45K as compared with L1210 or MTXrA cells; in contrast, MTX and 5-CHO-THF influx was only 14 and 27% that of L1210 cells, respectively. 5-CHO-THF influx in MTXrA-E45K cells was characterized by a 12- and 3.6-fold decrease in influx Vmax and Kt respectively, relative to L1210 cells. The folic acid influx Ki in L1210 cells was more than 50-fold greater than that of MTX based upon inhibition of 5-CHO-THF influx. In comparison, the mutated carrier had comparable affinities for folic acid and MTX in MTXrA-E45K cells due to a 7-fold decrease in the folic acid influx Ki and 7-fold increase in the MTX influx Ki. Transport via native RFC1 is inhibited by a variety of anions in L1210 cells associated with an increase in influx Kt. However, influx of 5-CHO-THF in MTXrA-E45K cells in a HEPES buffer (9 mM chloride) was decreased by 70% due to a 3-fold fall in the Vmax. In the complete absence of chloride (K+-HEPES-sucrose buffer) 5-CHO-THF influx was only 10% that in HBS buffer. 5-CHO-THF influx was restored by addition of chloride, fluoride, or nitrate but not by sulfate, phosphate, or ATP which were all inhibitory over a broad range of concentrations. The data suggest that substitution of a positive for a negative amino acid at position 45 results in the loss of RFC1 mobility in the absence of small inorganic anions that bind to, and neutralize the positive charge on, the lysine residue. Inhibition by higher charged anions may be due to interactions at another carrier site present in both the mutated and wild type carrier. This and other studies suggest that amino acids in the first predicted transmembrane domain play an important role in determining the spectrum of affinities for, and mobility of, RFC1 and is a cluster region for mutations when cells are placed under selective pressure with antifolates that utilize RFC1 as the major route of entry into mammalian cells.

Amino Acid Substitution↗
PubMed1992

Drug interactions in intestinal transport of folic acid and methotrexate. Further evidence for the heterogeneity of folate transport in the human small intestine.

The effect of sulfasalazine and olsalazine on the transport of [3H]folic acid and of [3H]methotrexate (MTX) was investigated in organ-cultured endoscopic biopsy specimens of small intestinal mucosa from normal subjects. Biopsy specimens obtained from patients undergoing routine diagnostic upper gastrointestinal endoscopy were organ-cultured at pH 5.5 and the effect of these two drugs on the initial rate of uptake of the two folates was determined. Both drugs inhibited the transport of [3H]folic acid with similar Ki values (1.38 and 1.32 mM for sulfasalazine and olsalazine, respectively). However, the uptake of [3H]MTX was only partially inhibited by sulfasalazine and was unaffected by olsalazine. Sulfasalazine inhibited 26.2% of the total flux of MTX, in close agreement with the fraction of MTX flux that has been shown previously to be inhibited by folic acid. These data corroborate previous findings of heterogeneity of transport of MTX in the mucosa of the human small intestine.

Aminosalicylic Acids↗
PubMed2005

Effects of folic acid fortification on twin gestation rates.

OBJECTIVE: Previous studies have reported an increase in twinning of as much as 40% associated with folic acid-containing supplements, and folic acid fortification of enriched cereal grains was authorized in 1996. The purpose of this study was to investigate whether twinning rates have increased since that time. METHODS: We used United States birth and fetal death records to calculate twin gestation rates from 1990 through 2000. To eliminate the influence of fertility treatments, our analysis was limited to nulliparous women aged 16-19. We compared time trends in twin gestation rates before and after folic acid fortification in 1996. RESULTS: A total of 25,065 twin and 3,362,245 singleton pregnancies were included. Twin gestation rates were stable from January 1990 through December 1996, at 7.2 per 1,000, and then began a steady increase, averaging 2.4% (95% confidence interval 0.1-4.2%, P = .006) per year, which continued through 2000 and reached 8.2 per 1,000. This translates to 2 additional twin pregnancies per 10,000 gestations per year. Twin rates continued to increase well beyond 1998, when the maximal fortification effect on folate status had been reached. CONCLUSION: Although twin gestation rates in women not using fertility treatments increased after food fortification with folic acid, they rose by much less than the 40% rate previously reported; the observed pattern of increase in twin gestation rates is not consistent with a folic acid fortification effect. LEVEL OF EVIDENCE: II-2.

Adolescent↗
PubMedDate not supplied

Primary prevention of neural-tube defects and some other major congenital abnormalities: recommendations for the appropriate use of folic acid during pregnancy.

Neural-tube defects (NTDs) are common and serious congenital abnormalities of the central nervous system. Although some cases of NTDs are induced by hyperhomocysteinaemia, resulting from genetic polymorphism of a thermolabile enzyme, in the majority of cases the cause is unknown. Diet supplementation with a folic acid-containing multivitamin or high dose of folic acid alone in the periconception period reduced the recurrence of NTDs by 83 to 91% and 71%, respectively. Two Hungarian intervention studies demonstrated a high efficacy for periconception multivitamin supplementation (containing a physiological dose: 0.8mg of folic acid) in the primary prevention of the first occurrence of an NTD (approximately 92% reduction in the incidence of NTDs). However, a high dose of folic acid (approximately 6mg) alone during the periconception period was less efficient. Periconception folic acid-containing multivitamin supplementation reduces the occurrence of urinary tract and cardiovascular congenital abnormalities, and congenital limb deficiencies. The occurrence of orofacial cleftings may also be reduced by a high dose of folic acid. This preventive effect may be the result of other mechanisms of action (e.g. compensation of impaired mitosis caused by a folate deficiency). There are 3 options for ensuring appropriate multivitamin/folic acid consumption for women of childbearing age. First, providing a folate- and other vitamin-rich diet, which unfortunately may not be appropriate for this purpose. Second, and perhaps the best choice, the unique opportunity for multivitamin/folic acid supplementation during the periconception period. However, a major proportion of pregnancies are unplanned and, even in planned pregnancies, this type of primary prevention has not been widely used. Furthermore, it would require changes to the previous recommendations since a multivitamin containing a physiological dose of folic acid (0.5 to 0.8mg) seems to be more effective in reducing the occurrence of the first NTD and other congenital abnormalities than folic acid alone. Periconception multivitamin supplementation may also reduce the occurrence of recurrent NTDs. Thirdly, food (e.g. flour, bread) may be fortified with folic acid or 3 B vitamins (folic acid, B 12 and B6). This provides a practical means to ensure all women, especially those from lower socioeconomic backgrounds and/or with a low level of education who are more likely to have unplanned pregnancies, have an adequate folic acid intake.

Adult↗
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↗
PubMed2003

Identification of photoproducts of folic acid and its degradation pathways in aqueous solution.

The UV irradiated aqueous solutions of folic acid at pH 2-10 degrade to give pterin-6-carboxylic acid and p-aminobenzoyl-L-glutamic acid under aerobic conditions. These photoproducts have been identified by TLC, HPLC and Spectrophotometric techniques. A reaction scheme for the photodegradation pathways of folic acid leading to the formation of the photoproducts in acid and alkaline media has been proposed which involves the participation of an enamine intermediate.

Chromatography, High Pressure Liquid↗
PubMed2005

Folic acid reverses hyper-responsiveness of LPS-induced chemokine secretion from monocytes in patients with hyperhomocysteinemia.

Our previous study demonstrated that homocysteine (Hcy) mediated the expression and secretion of MCP-1 and IL-8 in human monocytes. In the present study, we investigated whether the responsiveness of isolated monocytes to lipopolysaccharide (LPS)-induced chemokine secretion was enhanced in patients with hyperhomocysteinemia (HHcy), and if so, whether this enhanced response could be inhibited by folic acid treatment. We studied 38 control subjects and 40 patients with HHcy. The results showed that MCP-1 secretion from isolated monocytes in response to low-dose LPS in patients with HHcy was significantly higher than that in controls. After patients with HHcy underwent low-dose folic acid treatment (0.8 mg/d) for 6 months, plasma Hcy levels were decreased and the hyper-responsiveness of MCP-1 and IL-8 secreted by isolated monocytes was significantly reversed. Furthermore, folic acid treatment at high concentrations (5 microM) significantly reduced the elevated levels of reactive oxygen species, NADPH oxidase activity and chemokines in response to Hcy in cultured human monocytes. HHcy may contribute to atherogenesis through enhancing the responsiveness of monocytes to inflammatory stimuli and promoting leukocyte recruitment into atherosclerotic plaque. In addition to lowering the plasma levels of Hcy, low-dose folic acid treatment exerts beneficial effects on patients with HHcy by inhibiting pro-inflammatory responses such as chemokine secretion from human monocytes.

Arteriosclerosis↗
PubMed2004

The hematological status, plasma vitamin B12 and folic acid levels, and intestinal pathology in rats infected with Giardia lamblia.

The purpose of our study was to investigate the hematological status, vitamin B12 and folic acid absorption and intestinal pathology after Giardia lamblia infection in a rat model. Adult Wistar rats were assigned randomly to receive human giardia cysts orally in the amount of 5 x 10(5) or 1.0 x 10(6) cysts, or none in the controls. The results showed that all the rats injected with giardia cysts became infected. The cyst output in the infected rats varied considerably. In rats infected with 5.0 x 10(5) giardia cysts, the incubation period until cyst output was 10 days compared with 4 days in rats infected with the higher amount of 1.0 x 106 giardia cysts. The highest peaks for cysts output in these 2 groups were on days 4-33, which decreased gradually to days 40-58. The hematocrit and hemoglobin levels in the infected rats were statistically significantly lower than in the controls on days 16, 22, 33, and 37 post-infection (p < 0.05). A reverse relationship between giardia cyst output and hemoglobin concentration was found in the infected rats (p = 0.05). There were no significant differences in plasma vitamin B12 and folic acid levels between the infected rats and the control rats. No pathological changes were found in the small intestine of infected rats. These findings suggest that giardiasis did not affect the absorption of plasma vitamin B12 and folic acid but caused anemia in a rat model.

Animals↗
PubMed2005

Changes in the birth prevalence of selected birth defects after grain fortification with folic acid in the United States: findings from a multi-state population-based study.

BACKGROUND: Observational studies and clinical trials have suggested that periconceptional use of folic acid can reduce the risk of birth defects other than neural tube defects (NTDs). Using data reported by states to the National Birth Defects Prevention Network, we examined whether folic acid fortification might have decreased the prevalence of other specific birth defects. METHODS: For each of 16 birth defect categories selected for study, birth prevalence for two time periods was calculated with data submitted from a number of states in 1995-1996 ("pre-fortification") and 1999-2000 ("post-fortification"). Changes in birth prevalence between the two time periods were assessed by calculating prevalence ratios and 95% confidence intervals for each defect, and compared by maternal race/ethnicity and availability of prenatally diagnosed cases. RESULTS: We confirmed previously reported reductions in the birth prevalence of NTDs. In addition, we found modest, yet statistically significant, decreases in the birth prevalence for transposition of the great arteries(12%), cleft palate only (12%), pyloric stenosis (5%), upper limb reduction defects (11%), and omphalocele (21%). More substantial subgroup decreases were observed for renal agenesis among programs that conduct prenatal surveillance (28%), for common truncus among Hispanics (45%), and for upper limb reduction defects among Hispanics (44%). There were modest yet significant increases in the prevalence of obstructive genitourinary defects (12%) and Down syndrome (7%), but not among programs conducting prenatal surveillance for these defects. CONCLUSIONS: These results suggest some modest benefit from the folic acid fortification on the prevalence of a number of non-NTD birth defects.

Congenital Abnormalities↗
PubMed2006

Homocysteine lowering with folic acid and B vitamins in vascular disease.

BACKGROUND: In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Folic acid and vitamins B6 and B12 lower homocysteine levels. We assessed whether supplementation reduced the risk of major cardiovascular events in patients with vascular disease. METHODS: We randomly assigned 5522 patients 55 years of age or older who had vascular disease or diabetes to daily treatment either with the combination of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 or with placebo for an average of five years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, and stroke. RESULTS: Mean plasma homocysteine levels decreased by 2.4 micromol per liter (0.3 mg per liter) in the active-treatment group and increased by 0.8 micromol per liter (0.1 mg per liter) in the placebo group. Primary outcome events occurred in 519 patients (18.8 percent) assigned to active therapy and 547 (19.8 percent) assigned to placebo (relative risk, 0.95; 95 percent confidence interval, 0.84 to 1.07; P=0.41). As compared with placebo, active treatment did not significantly decrease the risk of death from cardiovascular causes (relative risk, 0.96; 95 percent confidence interval, 0.81 to 1.13), myocardial infarction (relative risk, 0.98; 95 percent confidence interval, 0.85 to 1.14), or any of the secondary outcomes. Fewer patients assigned to active treatment than to placebo had a stroke (relative risk, 0.75; 95 percent confidence interval, 0.59 to 0.97). More patients in the active-treatment group were hospitalized for unstable angina (relative risk, 1.24; 95 percent confidence interval, 1.04 to 1.49). CONCLUSIONS: Supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease. (ClinicalTrials.gov number, NCT00106886; Current Controlled Trials number, ISRCTN14017017.).

Aged↗
PubMed1996

Synthesis and biological activity of folic acid and methotrexate analogues containing L-threo-(2S,4S)-4-fluoroglutamic acid and DL-3,3-difluoroglutamic acid.

The stereospecific syntheses of L-threo-gamma-fluoromethotrexate (1t) and L-threo-gamma-fluorofolic acid (3t) are reported. Compounds 1t and 3t have no substrate activity with folylpoly-gamma-glutamate synthetase isolated from CCRF-CEM human leukemia cells, and compound 1t inhibits human dihydrofolate reductase at similar levels as methotrexate. The synthesis of DL-3,3-difluoroglutamic acid (6) and its incorporation into DL-beta,beta-difluorofolic acid (4) are also reported. Compound 4 acts as a better substrate for human CCRF-CEM folylpoly-gamma-glutamate synthetase than folic acid (V/K = ca. 7-fold greater). Thus, replacement of the glutamate moiety of methotrexate and folic acid with 4-fluoroglutamic acid and 3,3-difluoroglutamic acid results in folates and antifolates with altered polyglutamylation activity.

Animals↗
PubMed1992

Folic acid and neural tube defect: can't we come to closure?

In a series of nonrandomized and randomized intervention trials and case-control and cohort studies, women using multivitamins or folic acid supplements during the first 6 weeks of pregnancy experienced a three- to fourfold reduction in neural tube defects among their offspring. Viewed collectively, these data provide strong evidence that an important subset of US women do not receive sufficient folic acid to minimize their risk of a defective pregnancy. Further, the amounts of folic acid contained in multivitamins (usually 200-400 micrograms per day) appear adequate to greatly reduce, and probably eliminate, the excess risk.

Female↗
PubMed2005

[Oral iron and folic acid supplements in a preoperative autologous blood collection program: a randomized study].

BACKGROUND AND OBJECTIVE: We evaluated the capacity of oral iron with or without oral folic acid administration to improve the accomplishment of our scheduled preoperative autologous blood collection program in patients with baseline hemoglobin > 115 g/l. PATIENTS AND METHOD: Patients were enrolled in a randomized trial. The control group received no vitamin supplements. The iron group received 105 mg of elemental iron daily p.o. The and iron+folate group received 105 mg of elemental iron daily and 5 mg of folic acid daily p.o. RESULTS: Eighty-six percent of patients in the control group, 86% of patients in the iron group and 87% of patients in the iron+folate group accomplished our preoperative autologous blood collection program. CONCLUSION: In our study, neither oral iron nor folic acid supplements enhanced the accomplishment of our preoperative autologous blood collection program in patients with baseline hemoglobin > 115 g/l.

Aged↗
PubMed2004

Folic acid fortification of wheat flour: Chile.

Neural tube defects (open spina bifida, anencephaly, and encephalocele) represent the first congenital malformations to be preventable through public health measures such as supplementation and/or food fortification with folic acid. In Chile, starting in January 2000, the Chilean Ministry of Health legislated to add folic acid to wheat flour (2.2 mg/kg) to reduce the risk of NTDs. This policy resulted in an estimated mean additional supply of 427 microg/d in significant increases in serum folate and red cell folate of 3.8 and 2.4-fold, respectively, in women of fertile age, one year after fortification. The impact on the rate of NTDs is presently being studied in all births, both live births and still births, with birth weight >500 g in the city of Santiago. Preliminary results show a reduction of 40% in the rates on NTDs from the pre-fortification period (1999-2000) to post-fortification period (2001-June 2002). Fortification of wheat flour with folic acid in Chile is effective in preventing NTDs in Chile.

Bread↗
PubMed1986

Folic acid as an adjunct in the treatment of children with the autism fragile-X syndrome (AFRAX).

Four boys with the combination of infantile autism and the fragile-X syndrome were given oral folic acid and placebo, according to a double-blind crossover design. One boy's behaviour appeared to improve on folic acid, but another boy did not seem to be affected at all. For the remaining two boys the results were equivocal. Further study of folic acid in the treatment of autistic boys with the fragile-X syndrome is warranted.

Adolescent↗
PubMed2005

Folic acid and pantothenic acid protection against valproic acid-induced neural tube defects in CD-1 mice.

In utero exposure to valproic acid (VPA) during pregnancy is associated with an increased risk of neural tube defects (NTDs). Although the mechanism by which VPA mediates these effects is unknown, VPA-initiated changes in embryonic protein levels have been implicated. The objectives of this study were to investigate the effect of in utero VPA exposure on embryonic protein levels of p53, NF-kappaB, Pim-1, c-Myb, Bax, and Bcl-2 in the CD-1 mouse. We also evaluated the protective effects of folic acid and pantothenic acid on VPA-induced NTDs and VPA-induced embryonic protein changes in this model. Pregnant CD-1 mice were administered a teratogenic dose of VPA prior to neural tube closure and embryonic protein levels were analyzed. In our study, VPA (400 mg/kg)-induced NTDs (24%) and VPA-exposed embryos with an NTD showed a 2-fold increase in p53, and 4-fold decreases in NF-kappaB, Pim-1, and c-Myb protein levels compared to their phenotypically normal littermates (P<0.05). Additionally, VPA increased the ratio of embryonic Bax/Bcl-2 protein levels (P<0.05). Pretreatment of pregnant dams with either folic acid or pantothenic acid prior to VPA significantly protected against VPA-induced NTDs (P<0.05). Folic acid also reduced VPA-induced alterations in p53, NF-kappaB, Pim-1, c-Myb, and Bax/Bcl-2 protein levels, while pantothenic acid prevented VPA-induced alterations in NF-kappaB, Pim-1, and c-Myb. We hypothesize that folic acid and pantothenic acid protect CD-1 embryos from VPA-induced NTDs by independent, but not mutually exclusive mechanisms, both of which may be mediated by the prevention of VPA-induced alterations in proteins involved in neurulation.

Animals↗
PubMed2002

Hyperhomocysteinaemia and cardiovascular risk in female ovariectomized rats: role of folic acid and hormone replacement therapy.

Hyperhomocysteinaemia is an independent risk factor for arteriosclerosis, recurrent thromboembolic complications and osteoporosis. After menopause, a high level of total homocysteine seems to be secondary to the altered hormonal status. Hormone replacement therapy (HRT) limits the development of coronary artery disease through a variety of mechanisms. One such mechanism is through affecting homocysteine metabolism. Folate and vitamin B12 deficiencies are considered to be major risks for hyperhomocysteinaemia. This study, therefore, was undertaken to examine whether lowering homocysteine with HRT or folic acid in ovariectomized rats could attenuate cardiovascular complications. Sixty sexually mature female Wistar rats were ovariectomized. Three weeks later, they were treated with estradiol (15 microg kg(-1), every two weeks, i.m.) or folic acid (90 microg daily, orally), either alone or in a combined form for four weeks. In addition, groups of ovariectomized rats (positive control) and healthy rats (negative control) were given cottonseed oil. Blood samples were then collected for serum and plasma separation. Serum total homocysteine, folate, estradiol, plasma nitric oxide (NO), lipid profile, and susceptibility of non-high-density-lipoprotein cholesterol (non HDLC) content to oxidation were determined. In ovariectomized rats, hyperhomocysteinaemia was established and associated with significant increments of both atherogenic indexes (total cholesterol/HDLC, low-density-lipoprotein cholesterol (LDLC)/HDLC) and susceptibility of their non HDLC to oxidation. However, plasma NO, serum folate, and estradiol levels significantly decreased. HRT and folic acid significantly reduced total homocysteine and susceptibility of non HDLC to oxidation and increased plasma NO content. Moreover, a significant negative correlation was found between total homocysteine versus folate and estradiol (r = -0.5, P < 0.01; r = -0.25, P < 0.05, respectively). Meanwhile, a positive correlation with the susceptibility of lipoprotein to oxidation was observed (r = 0.85, P < 0.001). In conclusion, a low folate level is found to be associated with elevated total homocysteine. Folic acid supplementation, either individually or in a combined form with HRT, has a beneficial effect in low estrogen status subsequent to ovariectomy.

Animals↗