10-Formyl-dihydrofolic acid is bioactive in human leukemia cells.
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The bioactivity of 10-formyl-7,8-dihydrofolic acid and 10-formyl-folic acid was determined in human leukemia (CCRF-CEM) cells grown in a folate-depleted medium containing methotrexate. Excess 10-formyl-7,8-dihydrofolic acid, (but not 10-formyl folic acid) supported the growth of these cells, but it was less potent than5-formyl-5,6,7,8-tetrahydrofolic acid (a control). 10-formyl-7, 8-dihydrofolic acid (not 10-formyl folic acid) was active as substrate for aminoimidazole carboxamide ribotide transformylase and dihydrofolate reductase. This is the first experimental evidence that 10-formyl-7,8-dihydrofolic acid is a bioactive folate in mammalian cells. These experiments and several other lines of evidence in the literature suggest that 10-formyl-folic acid must be metabolized to bioactive folate by enteric bacteria before it can be utilized by the vertebrate host. (+info)
Racial differences in prevalence of cobalamin and folate deficiencies in disabled elderly women.
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BACKGROUND: Many previous investigations of cobalamin and folate status were performed in white populations. OBJECTIVE: Our objective was to determine whether there are racial differences in the prevalence of cobalamin and folate deficiency. DESIGN: The study was a cross-sectional comparison of baseline serum cobalamin, folate, methylmalonic acid (MMA), total homocysteine (tHcy), and creatinine concentrations, complete blood count, and vitamin supplementation in 550 white and 212 African American subjects from a cohort of physically disabled older women. RESULTS: The mean (+/-SD) serum MMA concentration was significantly higher in whites than in African Americans: 284 +/- 229 compared with 218 +/- 158 nmol/L (P = 0.0001). tHcy concentration was higher in African Americans than in whites: 12.4 +/- 7.0 compared with 10.9 +/- 4.6 micromol/L (P = 0.001). Serum cobalamin was lower in whites (P = 0.0002). Cobalamin deficiency (serum cobalamin <258 pmol/L and MMA >271 nmol/L) was more frequent in the white women (19% compared with 8%; P < 0.0003). Folate deficiency (serum folate <11.4 nmol/L, tHcy >13.9 micromol/L, and MMA <271 nmol/L) was more prevalent in African Americans than in whites (5% compared with 2%; P = 0.01). Multivitamin use was associated with lower tHcy but not with MMA concentrations. Regression models showed that age >85 y, African American race, serum creatinine >90 micromol/L, and high MMA concentration were all significantly correlated with higher tHcy. Creatinine > 90 micromol/L, white race, and folate concentration were positively associated with MMA concentration. CONCLUSIONS: Cobalamin deficiency with elevated serum MMA concentration is more prevalent in elderly white than in African American women and elevated serum tHcy and folate deficiency are more prevalent in elderly African American than in white women. (+info)
Folic acid binding protein in acute myeloid leukaemia.
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Folic acid binding protein was estimated in the serum of 94 control subjects and a normal range was established. Raised levels were found in folate deficiency and chronic myeloid leukaemia. Considerably raised levels were found in untreated acute myeloid leukaemia, most often in cases with a marked monocytic element. (+info)
Similarities in the epidemiology of neural tube defects and coronary heart disease: is homocysteine the missing link?
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It is hypothesised that a single aetiological pathway could explain both the strong ecological association between the birth prevalence of neural tube defects (NTD) and coronary heart disease (CHD) mortality and the potential efficacy of dietary measures, especially increased folic acid intake, in their prevention. The epidemiological similarities between NTD and CHD are strong and consistent suggesting that the relation is real rather than artefactual. It is suggested that this epidemiological association reflects a shared aetiology arising from the role of disturbed homocysteine metabolism in the pathogenesis of both conditions. Current public health measures designed to increase the intake of periconceptional folic acid in women, reinforced by a broadening of this policy to target both sexes throughout life, will (if successful) result in a reduction in both the birth prevalence of NTD and the incidence of CHD, although not necessarily contemporaneously. If disordered homocysteine metabolism is the cause of both NTD and CHD, this has implications for future research and preventive strategies for these serious and often lethal diseases. (+info)
Folate and carcinogenesis: an integrated scheme.
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Collectively, the evidence from epidemiologic, animal and human studies strongly suggests that folate status modulates the risk of developing cancers in selected tissues, the most notable of which is the colorectum. Folate depletion appears to enhance carcinogenesis whereas folate supplementation above what is presently considered to be the basal requirement appears to convey a protective effect. The means by which this modulation of cancer risk is mediated is not known with certainty, but there are several plausible mechanisms which have been described. Folate plays a major role in the formation of S-adenosylmethionine, the universal methyl donor, as well as in the formation of purine and thymidine synthesis for DNA and RNA. Therefore, most mechanistic studies performed to date have focused on alterations in DNA methylation, disruption of DNA integrity and disruption of DNA repair, all of which have been observed with folate depletion. These aberrations in DNA are believed to enhance carcinogenesis by altering the expression of critical tumor suppressor genes and proto-oncogenes. Recently, the role of a common polymorphism of the methylenetetrahydrofolate reductase gene has been highlighted as well. This review presents those mechanisms which are the most likely candidates to explain folate's effects and it proposes an integrated scheme to explain how these mechanisms might interact. (+info)
Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine study.
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BACKGROUND: Total homocysteine (tHcy) measured in serum or plasma is a marker of folate status and a risk factor for cardiovascular disease. OBJECTIVE: Our objective was to investigate associations between tHcy and complications and adverse outcomes of pregnancy. DESIGN: Plasma tHcy values measured in 1992-1993 in 5883 women aged 40-42 y were compared with outcomes and complications of 14492 pregnancies in the same women that were reported to the Medical Birth Registry of Norway from 1967 to 1996. RESULTS: When we compared the upper with the lower quartile of plasma tHcy, the adjusted risk for preeclampsia was 32% higher [odds ratio (OR): 1. 32; 95% CI: 0.98, 1.77; P for trend = 0.02], that for prematurity was 38% higher (OR: 1.38; 95% CI: 1.09, 1.75; P for trend = 0.005), and that for very low birth weight was 101% higher (OR: 2.01; 95% CI: 1.23, 3.27; P for trend = 0.003). These associations were stronger during the years closest to the tHcy determination (1980-1996), when there was also a significant relation between tHcy concentration and stillbirth (OR: 2.03; 95% CI: 0.98, 4.21; P for trend = 0.02). Neural tube defects and clubfoot had significant associations with plasma tHcy. Placental abruption had no relation with tHcy quartile, but the adjusted OR when tHcy concentrations >15 micromol/L were compared with lower values was 3.13 (95% CI: 1.63, 6. 03; P = 0.001). CONCLUSION: Elevated tHcy concentration is associated with common pregnancy complications and adverse pregnancy outcomes. (+info)
Folic acid deficiency and cancer: mechanisms of DNA instability.
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Folic acid deficiency in humans has been linked with megaloblastic anaemia, neural tube defects in the neonate, and heart disease. Folate has also been implicated in the development of cancer, especially cancer of the colorectum. There appear to be two principal mechanisms through which low folate status may increase the risk of malignancy. Folate deficiency, by reducing intracellular S-adenosylmethionine (SAM), can alter cytosine methylation in DNA, leading to inappropriate activation of proto-oncogenes and induction of malignant transformation. Alternatively, folic acid is crucial for normal DNA synthesis and repair. Folate deficiency may cause an imbalance in DNA precursors, uracil misincorporation into DNA, and chromosome breakage. This chapter briefly describes the epidemiological data supporting the involvement of folic acid in the aetiology of cancer. It also assesses the evidence from cellular, animal and human studies that folic acid can modulate DNA by such mechanisms. (+info)
Brain function in the elderly: role of vitamin B12 and folate.
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Vitamin B12 (cobalamin) deficiency associated neuropathy, originally called subacute combined degeneration, is particularly common in the elderly. The potential danger today is that with supplementation with folic acid of dietary staples such as flour, that the incidence of this disease could rise as folic acid, as opposed to natural folate (N5CH3HFGlu1), enters the cell and the metabolic cycle by a cobalamin independent pathway. This chapter briefly describes the clinical presentation of the disease, which unless treated will induce permanent CNS damage. The biochemical basis of the interrelationship between folate and cobalamin is the maintenance of two functions, nucleic acid synthesis and the methylation reactions. The latter is particularly important in the brain and relies especially on maintaining the concentration of S-adenosylmethionine (SAM) which, in turn, maintains the methylation reactions whose inhibition is considered to cause cobalamin deficiency associated neuropathy. SAM mediated methylation reactions are inhibited by its product S-adenosylhomocysteine (SAH). This occurs when cobalamin is deficient and, as a result, methionine synthase is inhibited causing a rise of both homocysteine and SAH. Other potential pathogenic processes related to the toxic effects of homocysteine are direct damage to the vascular endothelium and inhibition of N-methyl-D-aspartate receptors. (+info)