Absorption Transport And Metabolism Of Dietary Folates

Because man is unable to manufacture folate, he depends on a variety of exogenous sources for the vitamin. In addition to the rich sources mentioned earlier, moderate sources such as bread, potatoes, and dairy products are consumed in large amounts and thus contribute a significant proportion to our total folate requirement. If one takes into account all folyl oligo-y-glutamyl forms of the various one-carbon and unsubstituted oxidation states of the vitamin, folate metabolism becomes complex....

Recommended Dietary Allowances For Folate And Vitamin B12 Based On Genomic Stability

There is now increasing interest to redefine recommended dietary allowances (RDAs) of minerals and vitamins not only to prevent diseases of extreme deficiency but also to prevent developmental abnormalities and degenerative diseases of old age as well as optimizing cognition (75). Prevention of chromosome breakage and aneuploidy is an important parameter for the definition of new RDAs for micronutrients (9) such as folic acid and vitamin B12 because increased rates of DNA damage have been shown...

Clinical And Animal Studies Reinterpretation In Light Of Molecular Data

Studies of clinical populations and animals have indicated that iron deficiency alters folate-dependent one-carbon metabolism. Specifically, iron deficiency can influence all of the biochemical indicators listed in Fig. 2. However, marked discrepancies exist within the literature, primarily resulting from different patient populations, indicators of folate status or metabolism, experimental protocols, as well as insufficient measurements and lack of experimental controls (70). These...

Info

Many investigators evaluated the effect of folate nutriture on fetal growth. As shown in Table 1, several groups of researchers have reported that folic acid supplementation resulted in the increase in birth weight of infants born to women with inadequate dietary folate intake during pregnancy (12-16). On the other hand, two Australian groups did not observe such a positive effect of folic acid supplementation on birth weight, probably the result of adequate folate nutriture of the subjects...

Folate Deficiency And Chromosome Instability

Chromosomal Aberrations and Micronuclei Folate and or B12 deficiency in humans has been long associated with chromosomal instability and multiple chromosomal aberrations. Early cytogenetic studies of folate- or B12-deficient human lymphocytes or marrow cells revealed multiple chromosomal breaks and gaps, decondensed chromosomes, premature centromeric division, and centromeric spreading (31,32). Chronic folate deficiency is manifested in a futile cycle of uracil misincorporation during DNA...

Folate Nutriture And Pregnancy Outcome

Folate Deficiency and Pregnancy Complications Folate deficiency is believed to be one of the most common nutrient deficiencies worldwide and is common during pregnancy, possibly the result of increased demand for fetal growth and poor dietary folate intake in certain countries. Folate may be one of the most widely studied vitamins in relation to pregnancy outcome. It is well known that plasma and red cell folate concentrations decline throughout pregnancy, although the exact mechanism is...

Folate Deficiency And Cancer

The biochemical manifestations of a folate deficiency can be seen in a decreased supply of S-adenosylmethionine and then in loss of methylation of CpG islands as well as a decrease in dTMP and a rise in the dUMP pool, which has been shown to result in misincorporation of deoxyuridine (du) into DNA. Recently, Ames and colleagues showed the significant extent of misincorporation of dU into DNA in folate-deficient patients (9) and, like others (10), speculated on the consequences. The protective...

References

Lucock, M. (2000) Folic acid nutritional biochemistry, molecular biology, and role in disease processes. Mol. Genet. Metab. 71, 121-138. 2. Fowler, B. (2001) The folate cycle and disease in humans. Kidney Int. 59, S221-S229. 3. Goyette, P., Sumner, J. S., Milos, R., Duncan, A. M. V., Rosenblatt, D. S., Matthews, R. G., et al. (1994) Human methylenetetrahydrofolate reductase isolation of cDNA, mapping and mutation identification. Nature Genet. 7, 195-200. 4. Goyette, P., Pai, A., and Milos, R....

Preface

Neural tube defects (NTDs) are a complex developmental trait in which several genes, interacting with environmental factors, create the phenotype. In the United States, the rate of NTDs has been reported to range from 4 to 10 per 10,000 live births. Currently, in the United States, the two most common types of NTDs, anencephaly and spina bifida, which occurs in varying degrees of severity, affect approximately 4000 pregnancies per annum, resulting in the birth of 2500 to 3000 children...

Specifics Of Potocytosis As Described In Ma104 Cells

Was developed in near-confluent cells growing in physiological (1-10 nM reduced folate) rather than 2-5 M folic acid found in most standard tissue culture medium. 2. The receptor was in a 1 1 distribution between the external (acid labile AL ) and internal, but membrane bound (acid resistant AR ) pools and the pools exchanged about once an hour (Fig. 1). 3. Receptor-mediated uptake accounted for > 90 of total cytoplasmic 5-methyl 3H tetrahydrofolate when assessed under physiological...

Changes In Cell Birth And Migration

Cell birth and migration in the hippocampus and septum initially involve progenitor cells residing in the neuroepithelial layer adjacent to these brain regions. In the developing hippocampus, thymidine-labeling studies established the existence of three distinct developmental domains of neurogenesis in the ventricular neuroepithelium One region provides cells for the development of Ammon's horn (i.e., pyramidal cells) a second region provides cells for the development of the dentate gyrus...

Homocysteine And

Homocysteine is a sulfur-containing amino acid, formed at demethylation of the essential amino acid methionine. Three B vitamins are involved in homocysteine metabolism the biological active form of vitamin B6 as a co-factor for the enzyme cystathionine P synthase, vitamin B12 as a cofactor for methionine synthase, and 5-methyltetrahydrofolate (methyl-THF) as a substrate. The formation of methyltetrahydrofolate is catalyzed by methylene tetrahydrofolate reductase (MTHFR), a vitamin B2-dependent...

Unexplained Pregnancy Loss

With the start of the homocysteine research in relation to NTD and the genetic mutations found, it was logical to also explore this fascinating field in early embryonic development. Hibbard (3) was the first to suggest a possible relationship between miscarriage and folate deficiency. An increased FIGLU excretion was found after histidine loading in 32 of women with an isolated unexplained abortion and in 60.5 of women with two or more recurrent events. Mild hyperhomocysteinemia was suggested...

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NTD, 144 Deferoxamine, 247-248 Deoxynucleotide triphosphate (dNTP), 43-45 Developmental toxicants, 183-192, folate metabolism, 184-186 folate perturbation, 188-192 Dietary folates, absorption, 265-268 biosynthetic pathways, 268 metabolism, 265-268 transport, 265-268 Dihydrofolate reductase, 149, 184 DNA, integration prevention, 79 DNA metabolism, biochemistry, 43-46 molecular genetics, 43-46 DNA methylation, 44-45, 72, folate, 78 folate deficiency, 57 patterns, 47-48 pericentromeric...

Ntd And Nutrition

Numerous reports have suggested that nutritional deficiencies in general would cause adverse birth outcomes. As an example, a Dutch midwife found an increase in NTD in 1722 and 1732, 2 yr that were linked with poor crops. She also noted that the children with NTD came from the poorest homes in urban areas (1). A similar observation was made in the children who were exposed in utero to severe food shortage during the Second World War in Holland. In addition to a significant decrease in birth...

A J

Folate and choline metabolism are highly interrelated. Choline, via its oxidation product betaine, can donate a methyl-group to homocysteine, forming methionine. In parallel, methyltetrahydrofolate is an alternative donor of a methyl-group to homocysteine. Choline can also be formed de novo from methyl-groups (derived from S-adenoslymethionine) and phosphatidylethanolamine. (17) human amniotic fluid choline concentration is 10-fold greater than that present in maternal blood (Zeisel,...

Folate Metabolism In Zinc Or Copperdeficient Rats

In order to evaluate the effect of zinc deficiency on folate metabolism, we produced zinc-deficient male rats by feeding a low-zinc diet for 6 wk (98,99). As shown in Table 8, various parameters relating to folate metabolism were measured and compared with two control groups (pair-fed or ad libitum-fed zinc-sufficient groups). Hepatic methionine synthase activities were increased in zinc-deficient rats compared to the controls. This increase resulted in a decreased 5-methyltetrahydrofolate in...

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P-aminobenzoic acid, 184 Paroxysmal nocturnal hemoglobinuria (PNH), 129 Patch mice, undulated mice, 9-10 PAX3 gene mutations, patch mice, 9-10 Pericentromeric heterochromatin, DNA methylation, 48-50 Peripheral blood neutrophils, 248 Pernicious anemia, chromosome aberrations, 76 Phenylketonuria screening, 168 Phenytoin, 188-189 Phorbol myristic acid (PMA), 123, 126-128 Phosphatidylcholine, 210 Placental abruptio, 219, 312-317, fetal growth retardation, 312-313 folic acid, 314 maternal...

Compounds That May Alter Folate Levels Metabolism

Several compounds have been reported to alter plasma serum folic acid levels, but there are no strong data to suggest that these compounds are developmental toxicants in humans. Because pregnancy increases the demand for folic acid, women having marginally adequate folate intake may be especially susceptible to adverse effects of these compounds. The diuretic drug triamterene and the organic solvent 2-methoxyethanol are included in this category, but they were previously reviewed (36) and will...

Choline And Apoptosis

Choline deficiency also resulted in an increase in apoptosis in a specific region of the hippocampus, namely the dentate gyrus. We observed an inverse correlation between apoptosis rates in the brains of rat fetuses and dietary intake of choline by their mothers (65). Others have reported apoptosis in the hippocampus and cortex of rats during the perinatal period (66,67) we were the first to report an effect of maternal nutrition. Apoptosis is usually inducible when cells are dividing and then...

Putative Mechanisms Involving Folate Metabolism That May Explain The Above Disorders

As explained in some detail earlier, folate nutritional status and common allelic variants of Hcy remethylation cycle enzymes, particularly C677T MTHFR, are implicated in several disorders. The mechanistic link between C677T MTHFR (and possibly other SNPs) and these disease processes may involve the following mechanisms. The cytosine base of 5'-CG-3' DNA sequences is methylated to yield a 5-methylcytosine residue, representing a biologically important covalent modification that modulates the...

Biochemical Mechanisms For Ironfolate Interactions

Iron Metabolism Influences Folate Status Regulation of intracellular folate concentrations is complex and is influenced by dietary folate intake, intestinal and cellular transport systems, polyglutamylation of the cofactor, and folate turnover, including folate catabolism (19,24,38). Folate catabolism is defined as the oxidative and irreversible scission of the p-aminobenzoyl(poly)glutamate moiety of the cofactor from the quinazoline ring system, a reaction that destroys folate as a metabolic...

In Vivo And Clinical Correlates Oncological Tangents

During the tenure of and even prior to the basic experiments of folate receptor function, we have studied the effects of antifolate therapy on folate stores in mice, rats, monkeys, and humans. This data have been reported over the past decade (72-74). In brief, repetitive, low-dose methotrexate results in a folate deficiency in the liver, red cells, and, of interest for this symposium, the brain. In particular, 1 yr of a typical methotrexate dose and schedule for treatment of children with...

Studies Of Folate Receptoramediated Folate Uptake

The model of potocytosis (Fig. 1) was developed using a near-confluent culture of MA104 cells, a monkey kidney cell line growing in physiological folate (i.e., folic acid free medium containing 2-10 nM reduced folate). Drugs or conditions that affect the process are listed under each step in Fig. 1. In addition, N-ethylmaleimide stops receptor cycling and the nonsteroidal antiinflammatory agent indomethacin also alters folate receptor distribution and interferes with accumulation of folic acid....

Genenutrient Interactions In The Maternal Risk Of Down Syndrome Link To Abnormal Folate Metabolism

Multifactorial gene-environment interactions that compromise maternal folate status may promote chromosomal meiotic nondisjunction and risk of Down syndrome. The 677C T polymorphism of the MTHFR gene causes an alanine to valine substitution that decreases enzyme activity by 35 with the heterozygous (C T) genotype and 70 with the homozygous (T T) genotype (101). The reduction in enzyme activity associated with the MTHFR polymorphism raises the dietary requirement for folic acid to maintain...

Environmental And Genetic Factors That Determine The Bioavailability Of Folic Acid And Vitamin B12

Alcoholism is associated with significantly reduced levels of tissue folate, vitamin B12, and vitamin B6 in humans at intakes greater than 3.0 g kg d, there was a doubling in the level of DNA hypomethylation of lymphocytes (57). The reduced folate level in alcoholics may be the result of reduced absorption or suboptimal dietary intake. However, if results in the rat model reflect the situation in humans, then there is a good probability that the microbial metabolism of alcohol can result in...

The Folate Receptor 1 Gene

The human folate receptor 1 gene (FOLR1 alternative titles and symbols folate-binding protein, FBP folate receptor, FOLR folate receptor-a, hFR ovarian-cancer-associated antigen Mov18, CaMov18) is located at chromosome 11q13.3 - q13.5 (76,77). The FOLR1 gene (GenBank accession number U20391) encompasses 6.8 kb and consists of 7 exons (78). The entire coding region is 771 bp long (GenBank accession number J05013) (79) and is encoded by exons 4-7 (78). Two complementary DNA isoforms exist showing...

Homocysteine And Early Miscarriage

Clinical Background of Early Miscarriage The term miscarriage is used to emphasize the spontaneous interruption of pregnancy. For clinical and scientific reasons, it is important to avoid the international confusion on the duration of pregnancy when the term abortion is used because the range of pregnancy duration can be as wide as from 0 to 28 wk. Another reason for this distinction is that the causes for embryonic loss are quite different from those of fetal loss. We therefore tried to...

Severe Mthfr Deficiency

Severe MTHFR deficiency, with less than 20 of control enzyme activity, is the most common inborn error of folate metabolism (8). These patients have dramatic elevations of plasma homocysteine with homocystinuria, and low or low-normal levels of plasma methionine. This relatively rare condition can have devastating consequences. Some patients die in the first year of life others have variable clinical features, including developmental delay, motor and gait disturbances, seizures, and psychiatric...

Placental Abruption

Placental Abruption Great Risk for Mother and Child In obstetrics, various clinical syndromes are accompanied with disturbances of blood coagulation. Placental abruption is a classic example for such disease. Placental abruption is an obstetric syndrome with great risks for mother and child (82,83). The placenta separates from the uterine wall during pregnancy by retroplacental bleeding and blood clotting. Histology points to a rupture of the spiral artery or arteries. When the placenta is...

Cart1 Knockout

Gene targeting has been used to generate mice with a null mutation in Cartl, a homeobox-containing gene that encodes the transcription factor, cartilage homeoprotein 1 (16,17). Homozygous Cartl mutant mice develop cranial NTD and die shortly after birth. The penetrance is influenced by genetic background with a maximum NTD incidence of 100 on a 129 SvEv strain background (17). Cranial NTD result from failure of closure at the prospective forebrain midbrain boundary, so called Closure 2. Failure...

The Methionine Synthase Reductase Gene

The human methionine synthase reductase gene (MTRR) is located on chromosome 5p15.2 - p15.3 (36). The MTRR gene (GenBank accession numbers AF121202 - AF121213) encompasses approx 34 kb and comprises 15 exons, varying in size from 43 to 1.213 bp, and 14 introns, with sizes ranging from 108 bp to 5 kb (57). The entire coding region has a length of 2.094 bp (GenBank accession numbers AF025794 and AF121214), encoding a protein with a predicted molecular mass of 77.7 kDa. A predominant mRNA of 3.6...