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Folic acid was found to stimulate and its structural analog methotrexate was found to inhibit the reproduction of an oncogenic RNA-containing virus in tissue culture.
N-acetyl-p-aminobenzoylglutamate is a major urinary metabolite of folic acid. It is formed by acetylation of p-aminobenzoylglutamate following cleavage of the C9-N10 bond of folic acid. Using recombinant human type 1 (NAT1) and type 2 (NAT2) arylamine N-acetyltransferase, we have shown that p-aminobenzoylglutamate is a specific NAT1 substrate. At an acetyl-CoA concentration of 50 microM, the Km for p-aminobenzoylglutamate (pABG) acetylation by recombinant NAT1 was 130 +/- 13 microM. For the human pro-monocytic cell-line U937, the apparent Km was slightly higher (333 +/- 17 microM). Inhibitor studies supported NAT1-dependent acetylation of pABG by U937 cell cytosols. These studies are the first to identify a potential endogenous substrate for human NAT1 and suggest that this enzyme may be important in the cellular clearance of pABG.
The bone marrow status of 31 consecutive pregnant women who had been on supplemental oral iron and folic acid since early pregnancy at the University of Benin Teaching Hospital was assessed later in pregnancy to test the efficacy of oral iron and folic acid in preventing iron deficiency and/or megaloblastic anaemia in our community. Only those pregnant patients with haemoglobin genotype AA or AS took part in the study. Nobody was excluded except those with CC or SC. 96.77% (30 out of 31 patients) had iron deficiency with no stainable iron in the bone marrow. 35.4% (11 out of 31 patients) had megaloblastic changes in the bone marrow. 32.2% (10 out of 31 patients) had a combined iron deficiency and megaloblastic anaemia while only one out of 31 patients (3.23%) had megaloblastic anaemia without concurrent iron deficiency. 60.4% (20 out of 31 patients) had iron deficiency alone without concomitant megaloblastic changes in marrow. The bone marrow in all the patients were normal in other respects except with regards to iron-deficiency and/or megaloblastic status. The significance of this high incidence of iron-deficiency and/or megaloblastic anaemia in patients already on routine pre-natal drugs is discussed.
As part of an effort to improve the safety of plant foods, a need exists to more clearly delineate the mechanisms of toxicities of glycoalkaloids, which may be present in Solanum plant species such as potatoes, tomatoes and eggplants. Alpha-chaconine is a major glycoalkaloid present in potatoes. To assess the possible influence of structure of pteridine derivatives on toxicity of potato glycoalkaloids, a previous study that demonstrated the protective effects of folic acid against the Solanum glycoalkaloid alpha-chaconine-induced toxicity on Xenopus laevis frog embryo cell membranes was extended to two folate analogues--a synthetic compound widely used as a therapeutic agent methotrexate, and naturally occurring L-monapterin. Adverse effects on embryos were evaluated by observing changes in membrane potentials with an electrochromic dye, di-4-ANEPPS, as a fluorescent probe for the integrity of the membranes. Methotrexate decreased alpha-chaconine-induced polarization, as did folic acid. This decrease may result from an alteration of membrane conformations that prevents the binding of the glycoalkaloid to the membrane receptor sites, and/or from effects on folic acid metabolism. In contrast, L-monapterin did not significantly reduce the alpha-chaconine-induced toxicity. The possible significance of these results to food safety is discussed.
Recent evidence demonstrates that hyperhomocyst(e)inaemia is a novel risk factor for cardiovascular diseases. In patients with chronic hyperhomocyst(e)inaemia, endothelial function is impaired. However, whether hyperhomocyst(e)inaemia per se is a cause or an epiphenomenon of endothelial dysfunction remains unknown. In this study, we examined the effects of methionine-induced acute hyperhomocyst(e)inaemia on human endothelial function. In healthy volunteers we administered methionine (0.1 g/kg body weight, per os), a substrate of homocyst(e)ine, with or without folic acid (20 mg, per os) and examined flow-mediated vasodilatation of the brachial artery by high-resolution ultrasonography as a non-invasive measure of endothelial function. We also measured plasma levels of homocyst(e)ine before and 3, 8 and 24 h after methionine loading. Methionine administration increased plasma levels of homocyst(e)ine by four times the basal level at 8 h (P<0.0001, ANOVA). The plasma levels returned to baseline at 24 h. Flow-mediated vasodilatation was significantly decreased to half of the baseline value at 8 h and returned to baseline at 24 h (P<0.0001, ANOVA), whereas endothelium-independent vasodilatation by glyceryl trinitrate was not affected by the methionine loading. Co-administration of folic acid did not attenuate methionine-induced hyperhomocyst(e)inaemia but completely prevented endothelial dysfunction. Our results suggest that in humans a methionine-rich diet may acutely impair endothelial function, which can be prevented by folic acid supplementation.
The relationship of natural and artificial feeding to serum and red cell folate levels, as a means of evaluating nutritional intake of this vitamin, was studied. First a cross-sectional study was undertaken in which a group of 112 infants still being breast-fed at 4, 6, and 9 months of age had significantly higher folate concentrations than another group of 102 infants who had been weaned before 2 months. At 6 months of age the prevalence of folic acid deficiency (red cell folate less than 160 micrograms/l of erythrocytes) was 0% in the first group and 15.4% in the second (P less than 0.02), and at 9 months the respective proportions were 3.6 and 28.9% (P less than 0.01). In a second study, 50 nursing infants were followed longitudinally during their first 15 months of life, and up to 9 months of age a direct correlation was observed between the folate concentrations and the duration of breast-feeding. In order to prevent a deficiency of this vitamin, it is recommended that infants be exclusively breast-fed at least through the age of 6 months or, failing this, that they be fed infant formula enriched with folic acid.
Homocysteine is associated with atherothrombotic disease, which may be mediated through associations of homocysteine levels with blood pressure, endothelial function, or arterial stiffness. In a placebo-controlled, randomized clinical trial, we measured blood pressure, brachial artery endothelium-dependent vasodilation, and common carotid artery stiffness in 158 clinically healthy siblings of patients with premature atherothrombotic disease at baseline and after 1 and 2 years of homocysteine-lowering treatment with folic acid (5 mg) plus pyridoxine (250 mg). Intention-to-treat analyses limited to participants (n=130) who underwent at least 1 measurement after the baseline visit showed that compared with placebo, treatment with folic acid plus pyridoxine was associated with a 3.7-mm Hg (95% CI -6.8 to -0.6 mm Hg) lower systolic and a 1.9-mm Hg (95% CI -3.7 to -0.02 mm Hg) lower diastolic blood pressure over the 2-year trial period. Together with the decreased occurrence of abnormal exercise electrocardiography tests reported previously, our results support the hypothesis that homocysteine-lowering treatment with folic acid plus pyridoxine has beneficial vascular effects. Because no effects could be demonstrated on brachial artery endothelium-dependent vasodilation or on common carotid artery stiffness, the present study does not support the hypothesis that the cardiovascular effects of homocysteine are mediated through these factors, at least in clinically healthy individuals.
Thirteen patients with significant hemorrhage, severe thrombocytopenia, and megaloblastic bone marrows are described. Unusual features of this problem included its acute onset, frequent absence of the typical peripheral blood changes of megaloblastic anemia, normal serum B12 levels, and serum folates which were often not clearly abnormal. Most patients were critically ill and common clinical features included reduced dietary intake, renal failure, renal dialysis, the postoperative state, and sepsis. These clinical features, the laboratory findings, and a platelet increase in most patients after folate therapy lead to the conclusion that this problem is probably due to acute folic acid deficiency. Possible explanations for the atypical laboratory findings include the acuteness of onset, recent blood transfusion therapy, and impaired folate utilization. This problem may be relatively common. Because of its potential clinical importance, rapid onset, and attendent diagnostic difficulties, prophylactic folic acid is recommended in the clinical setting described.
Folic acid applied topically in solution to the rat cuneate nucleus reduced presynaptic inhibition produced by peripheral stimulation. This resembles the action of picrotoxin in the same animals and it is possible that these two convulsants are acting in a similar manner by blockade of the receptors for the presynaptic inhibitory transmitter.
Homocysteinemia is associated with juvenile arteriosclerosis, recurrent thromboembolic complications and osteoporosis. Plasma homocysteine, measured as homocysteine-cysteine mixed disulfide (MDS), has in other than homocysteinemics been reported to be higher in patients with coronary heart or cerebrovascular disease than in controls, and higher in men than in premenopausal women. Here, in groups of normal men and normal premenopausal and postmenopausal women, we measured plasma MDS in the fasting state and four hours after a methionine load (100 mg/kg body weight), before and after four weeks of folic acid therapy at 5 mg daily. In their fasting plasma, postmenopausal women (n = 5) had significantly (P less than 0.05) higher MDS concentrations than premenopausal women (n = 5) and younger men (n = 5). After the methionine load MDS concentrations in postmenopausal women rose markedly, reaching levels significantly higher than those in younger men (P less than 0.05), and with no overlap with values in premenopausal women (P less than 0.01), or in older men (n = 5, P less than 0.01). Folic acid therapy resulted in substantial reductions (n = 15, P less than 0.01) of MDS concentrations both before the methionine load (-31%) and after (-28%), though subjects had initially had normal concentrations of serum and erythrocyte folates. We speculate that moderate homocysteinemia might contribute to postmenopausal arteriosclerosis and osteoporosis. Should this prove to be the case, folic acid might be a useful prophylactic.
Forty-two patients with the fragile-X syndrome have been treated with oral folic acid, 0.5 mg/kg/d. An improvement of the behavior was observed in the majority of the cases, and evolution of the IQ showed a favorable tendency at the border of statistical significance. On the contrary, the addition to the treatment regime of methionine or of carnitine (carriers of methyl radicals) had unfavorable effects. In view of the few preliminary convergent observation recorded in literature, a continued trial of folic acid treatment seems justified. Simultaneously, however, research is indicated on monocarbon metabolism, probably affected in these patients.
OBJECTIVE: To determine whether hyperhomocysteinemia (HH) exacerbates other cardiovascular risk factors and markers of coagulation and hemostasis in patients with type 2 diabetes mellitus (DM) and whether treatment of HH with vitamins will alter these risk factors. METHODS: We measured several cardiovascular risk factors and markers of coagulation and hemostasis in patients with type 2 DM with and without HH. We also treated patients with type 2 DM and coexistent HH with high doses of folic acid and pyridoxine to determine whether this treatment would lower plasma total homocysteine concentrations as well as correct other associated cardiovascular risk factors in this population. RESULTS: Plasma levels of plasminogen activator inhibitor type 1 and fibrinogen were significantly higher in all patients with DM in comparison with control subjects (P<0.01), whether they had HH or not. No significant difference was noted between the two groups of patients with DM. The presence of hypertension and microalbuminuria did not lead to a higher plasma total homocysteine. After treatment with folic acid, 15 mg daily, and pyridoxine, 600 mg daily, fasting (basal) plasma total homocysteine declined significantly in patients with DM from 12.3 +/- 2.9 micromol/L to 9.1 +/- 1.1 micromol/L (P<0.01). The peak post-methionine load plasma total homocysteine in the patients with DM decreased from 39.9 +/- 11.4 micromol/L to 30.4 +/- 6.5 micromol/L (P<0.05). Neither fasting nor peak plasma total homocysteine changed in normal subjects. None of the cardiovascular risk factors measured changed significantly with the vitamin treatment. CONCLUSION: The coexistence of type 2 DM and HH does not lead to an exacerbation of abnormalities in the measured variables of coagulation and hemostasis. Treatment with high doses of folic acid and pyridoxine lowers the plasma total homocysteine significantly but does not improve any of the associated cardiovascular risk factors that we measured. Long-term clinical trials should be conducted to determine whether high-dose vitamin treatment will diminish the increased morbidity and mortality associated with cardiovascular disease in patients with type 2 DM.
PURPOSE: This phase II clinical study evaluated the efficacy of pemetrexed for the treatment of malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Patients with a histologically proven diagnosis of MPM, chemotherapy-naive measurable lesions, and adequate organ function received pemetrexed (500 mg/m2) intravenously over 10 minutes every 3 weeks. After a protocol change, most patients also received folic acid and vitamin B12 supplementation to improve safety. RESULTS: A total of 64 patients were enrolled. Nine (14.1%) of the 64 patients had a partial response. The Kaplan-Meier estimate for median overall survival was 10.7 months. Forty-three patients received vitamin supplementation for all courses of therapy, and 21 patients did not. Seven of the nine responders were vitamin supplemented. The median overall survival was 13.0 months for supplemented patients and 8.0 months for nonsupplemented patients. Vitamin-supplemented patients completed more cycles of therapy than nonsupplemented patients (median, six v two cycles, respectively). Grade 3/4 neutropenia (23.4%) and grade 3/4 leukopenia (18.8%) were the most common laboratory toxicities. Fatigue and febrile neutropenia were the most commonly reported nonlaboratory events (grade 3, 6.3%; grade 4, 0.0% each). The incidence of these toxicities was generally lower in the supplemented patients. CONCLUSION: Single-agent pemetrexed for MPM resulted in a moderate response rate (14.1%) and median overall survival of 10.7 months. Patients supplemented with folic acid and vitamin B12 tolerated treatment better (less toxicity and more cycles of treatment) and had a 5-month greater median overall survival than nonsupplemented patients. These results indicate that patients with MPM could benefit from single-agent pemetrexed treatment combined with vitamin supplementation.
Shin et al. (Biochim Biophys Acta 444: 794-801, 1976) described the subcellular location of [3H]folic acid after injection into rats. The microsomal fraction of the liver contained relatively large amounts of tracer initially but lower amounts at later times. Because of the heterogeneous nature of the microsomal fraction of the liver we re-examined the nature of the folate binding fraction. The location of injected [3H]folic acid resembled that of the microsomes derived from the plasma membrane, where ultracentrifugal analysis was conducted in the presence and absence of cesium ions. The location of the folate did not resemble that of microsomes derived from the endoplasmic reticulum (ER). One of the marker enzymes of the ER was the vitamin K-dependent carboxylase. A simple method for reducing vitamin K is described.
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An ionization chamber method was used in vivo to demonstrate a delayed oxidation of [14C] formaldehyde and [14C] formate to 14CO2 in folic acid-deficient rats as compared to control rats or folic-acid-deficient rats treated by folic acid. Results obtained showed that oxidation of these two molecules required the presence of folic acid.
Cited2 (also Mrg1/p35srj) is a member of a new conserved gene family that is expressed during mouse development and in adult tissues. In order to investigate the function of Cited2 during mouse embryogenesis, we introduced a null mutation into the Cited2 locus. Cited2(-/-) mutants died at late gestation and exhibited heart defects and exencephaly, arising from defective closure of the midbrain (MB) and hindbrain. Initiation of neural tube closure at the forebrain-midbrain (FB-MB) boundary, an essential step for closure of the cranial neural tube, was impaired in the Cited2(-/-) mutants. Gene marker analysis using in situ hybridization revealed that the patterning of the anterior neural plate and head mesenchyme was little affected or normal in the Cited2(-/-) embryos. However, Cited2 was required for the survival of neuroepithelial cells and its absence led to massive apoptosis in dorsal neuroectoderm around the FB-MB boundary and in a restricted transverse domain in the hindbrain. Treatment with folic acid significantly reduced the exencephalic phenotype in the Cited2(-/-) embryos both in vivo and in vitro. However, assessment of folate metabolism revealed no defect in the Cited2(-/-) mutants, and the elevated apoptosis observed in the neuroepithelium of the Cited2(-/-) mutants was apparently not decreased by folic acid supplementation. To our knowledge, the Cited2 mouse represents the first genetic model in which folic acid can prevent a defect in neural tube closure by a mechanism other than the neutralization of a defect in folate homeostasis.