Folic Acid scientific update |
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Eur J Nutr. 2007 May 3;
Kloosterman J, Fransen HP, de Stoppelaar J, Verhagen H, Rompelberg C.
National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA, Bilthoven, The Netherlands.
Safe addition of vitamins and minerals to foods: setting maximum levels for fortification in the Netherlands.
BACKGROUND: In 2004, the European Court of Justice decided that the prohibition of fortification with vitamin A, vitamin D, folic acid, selenium, copper, and
zinc in the Netherlands conflicts with the principle of free movement of goods in the European Union. This decision led to a change in the Dutch policy,
resulting in a more flexible handling of requests for exemption from this prohibition to fortify. Therefore, an investigation was proposed in which it would
be determined whether a general exemption could be granted for food fortification with a certain maximum safe amount per micronutrient. AIM OF THE STUDY: To
develop a risk assessment model to estimate maximum safe fortification levels (MSFLs) of vitamins and minerals to foods on the Dutch market, and to evaluate
these levels to derive allowed fortification levels (AFLs), which can be used for a general exemption. METHODS: We developed a risk assessment model to
estimate MSFLs of vitamins and minerals to foods on the basis of existing models. We used European tolerable upper intake levels in combination with national
food consumption data to estimate MSFLs for fortification of foods for several age groups. Upon extensive stakeholder dialogue, the risk manager considered
these estimated MSFLs and the final AFLs for a general exemption were set. RESULTS: For folic acid, vitamin A, and vitamin D, the MSFLs were calculated in
the risk-assessment model. Children up to 6-years old were the group most sensitive to folic acid fortification, and they had an MSFL of 0 microg/100 kcal,
but following a risk management evaluation, this was upgraded to an AFL of 100 microg/100 kcal. The MSFL for vitamin D was 3.0 microg/100 kcal (children 4-10
years old), and the risk manager increased this to an AFL of 4.5 microg/100 kcal. Children up to 10 years old, men, and postmenopausal women were the groups
most sensitive to vitamin A fortification (MSFL = 0 microg/100 kcal). Because these groups represent a large part of the population and because of the
seriously harmful effects of excessive vitamin A, the risk manager did not allow a general exemption. CONCLUSIONS: The combination of a risk assessment model
and risk manager evaluation led to the setting of AFLs for general exemption of fortification with folic acid and vitamin D. This model is also applicable
for other micronutrients, for which an UL is derived, and in other countries.
Am J Clin Nutr. 2007 May;85(5):1392-400.
Krauss-Etschmann S, Shadid R, Campoy C, Hoster E, Demmelmair H, Jimenez M, Gil A, Rivero M, Veszpremi B, Decsi T, Koletzko BV.
Clinical Cooperation Group Pediatric Immune Regulation and Pediatrics, University of Pecs, Pecs, Hungary.
Effects of fish-oil and folate supplementation of pregnant women on maternal and fetal plasma concentrations of docosahexaenoic acid and eicosapentaenoic acid: a European randomized multicenter trial.
Background: Pregnant women usually meet their increased energy needs but do not always meet their increased micronutrient requirements. The supply of both
folic acid and docosahexaenoic acid (DHA) has been related to positive pregnancy and infant outcomes. Objective: We aimed to assess whether fish-oil (FO)
supplementation with or without folate from gestation week 22 to birth improves maternal and fetal n-3 long-chain polyunsaturated fatty acid (n-3 LC-PUFA)
status. Design: We conducted a multicenter (Germany, Hungary, and Spain), randomized, double-blind, 2 x 2 factorial, placebo-controlled trial. From gestation
week 22 until delivery, 311 pregnant women received daily a preparation with FO [0.5 g DHA and 0.15 g eicosapentaenoic acid (EPA)], 400 mug
methyltetrahydrofolic acid (MTHF), FO with MTHF, or placebo. Outcome measures included maternal and cord plasma DHA and EPA contents at gestation weeks 20
and 30 and at delivery, indicators of pregnancy outcome, and fetal development. Results: FO significantly (P < 0.001) increased maternal DHA and EPA (% by
wt), as shown by 3-factor repeated-measures ANOVA (ie, MTHF, FO, and time) with adjustment for maternal baseline DHA and EPA. In addition, FO significantly
(P < 0.001) increased cord blood DHA (% by wt; 2-factor ANOVA). MTHF was significantly (P = 0.046) associated with increased maternal DHA (% by wt). There
was no FO x MTHF interaction for the time course of DHA or EPA (P = 0.927 and 0.893). Pregnancy outcomes and fetal development did not differ significantly
among the intervention groups. Conclusions: FO supplementation from gestation week 22 until delivery improves fetal n-3 LC-PUFA status and attenuates
depletion of maternal stores. MTHF may further enhance maternal n-3 LC-PUFA proportions.
J Agric Food Chem. 2007 May 12;
Koehler P, Hartmann G, Wieser H, Rychlik M.
Deutsche Forschungsanstalt fur Lebensmittelchemie, Hans-Dieter-Belitz-Institut fur Mehl- und Eiweibetaforschung, and Lehrstuhl fur Lebensmittelchemie der Technischen Universitat Munchen, Lichtenbergstrasse 4, D-85748 Garching, Germany.
Changes of Folates, Dietary Fiber, and Proteins in Wheat As Affected by Germination.
Wheat kernels of the cultivar 'Tommi' were germinated for up to 168 h at 15, 20, 25, or 30 degrees C. Samples were taken at different stages of germination
and were analyzed for the quantitative protein composition using an extraction/HPLC method, for folate vitamers using a stable isotope dilution assay, and
for soluble, insoluble, and total dietary fiber using a gravimetric method. Gluten proteins were substantially degraded during germination. During the first
stages of germination the degradation of glutenins was predominant, whereas longer germination times were required to degrade gliadins. The optimal
temperature for gliadin degradation was 20 degrees C, and that for glutenin degradation was 25 degrees C. omega5- and omega1,2-gliadins were less sensitive
to proteolytic degradation than alpha- and gamma-gliadins, and LMW subunits of glutenin were less sensitive than HMW subunits. During germination a time- and
temperature-dependent increase of total folate occurred. A maximum 3.6-fold concentration was obtained after 102 h of germination at 20 and 25 degrees C
including 5-methyltetrafolate as the major vitamer. The concentration of dietary fiber remained constant or decreased during the first 96 h of germination.
Prolonged germination times of up to 168 h led to a substantial increase of total dietary fiber and to a strong increase of the soluble dietary fiber by a
factor of 3, whereas the insoluble fiber decreased by 50%. Keywords: Wheat; germination; gluten proteins; dietary fiber; folic acid.
Pol J Vet Sci. 2006;9(3):185-90.
Debski B, Bertrandt J, Klos A, Gralak M.
Department Physiological Sciences, Veterinary Medicine Faculty, Warsaw Agricultural
Influence of folic acid, vitamin B2 and B6 supplementation on feed intake, body and organs
Growing rats fed for 3 months a low-protein (LP) diet (4.5% of energy from protein), possessed
about 29% lower body weight than animals consuming adequate-protein diet (20% energy from
protein). The LP diet feeding caused an increase in daily feed intake followed by a decrease
in feed conversion efficiency. The enrichment of LP diet with folic acid, vitamin B2 and B6 (3
times above the level applied in the control diet) did not have any impact on rats BW and
supplementation with these vitamins minimize the effect of LP diet on feed intake. The use of
examined vitamins had a tendency to diminish an increase in feed conversion ratio caused by
the LP nutrition. This effect was significant when all vitamins were added together. Rats fed
the LP diet had higher relative weights of lungs, heart, liver and testis. Vitamins enriching
the LP diet were observed to decrease a relative weight of lungs (folic acid, vitamin B6 and
vitamin mixture), and liver (vitamin B6 and vitamin mixture). A tendency of increasing
relative testis weight was also revealed in rats given the LP diet enriched with vitamins. The
lower content of hepatic polyunsaturated fatty acids (FA) and a tendency for monounsaturated
FA content to be higher were found in rats fed the LP diet. The LP diet enrichment with folic
acid caused that these changes were more pronounced and statistically significant.
Semin Thromb Hemost. 2006 Oct;32(7):716-23.
Cattaneo M.
Hematology and Thrombosis Unit, Hospital San Paolo, University of Milan, Milan, Italy.
Hyperhomocysteinemia and venous thromboembolism.
Homocysteine (Hcy) is a sulfhydryl amino acid derived from the metabolic conversion of
methionine, which is dependent on vitamins (folic acid, B (12) and B (6)) as cofactors or
cosubstrates. Severe hyperhomocysteinemia (homocystinuria), due to inherited metabolic defects
of Hcy metabolism, is associated with very high risk of venous thromboembolism (VTE);
treatment with vitamins is associated with dramatic decrease of VTE risk. Several case-control
and prospective studies showed that also mild/moderate hyperhomocysteinemia (which is caused
by the interaction of environmental factors with mild genetic abnormalities of Hcy metabolism)
is associated with heightened risk of VTE; however, it is uncertain whether treatment with
vitamins also decreases the VTE risk in these patients.
Cancer Epidemiol Biomarkers Prev. 2004 Jul;13(7):1244-9.
Basten GP, Hill MH, Duthie SJ, Powers HJ.
Human Nutrition Unit, University of Sheffield, Coleridge House, Northern General Hospital, United Kingdom.
Effect of folic Acid supplementation on the folate status of buccal mucosa and lymphocytes.
Folate deficiency may be associated with an increased risk of cancer at certain sites. There is a need to measure folate status and putative biomarkers of cancer risk in the same target tissue, or in surrogate tissues. A study was carried out to develop a method for the rapid measurement of folate in human buccal mucosa and lymphocytes and to evaluate the responsiveness of this measurement in both tissues to folic acid supplementation in healthy subjects, relative to conventional markers of folate status. Three hundred and twenty-three adults, ages between 20 and 60 years, were screened for RBC folate concentrations. Sixty-five subjects with red cell folate between 200 and 650 nmol/L participated in a randomized, double blind, placebo-controlled, folic acid (1.2 mg) intervention trial, lasting 12 weeks. As anticipated, a significant baseline correlation (r = 0.36, P < 0.01) was observed between red cell folate and plasma 5-methyltetrahydrofolate (5-MeTHF). Lymphocyte total folate was significantly associated with plasma 5-MeTHF (r = 0.28, P < 0.05) and plasma total homocysteine concentration (r = -0.34, P < 0.05). Buccal mucosa total folate showed no correlation with either red cell folate or 5-MeTHF, but was significantly associated with lymphocyte total folate (r = 0.35, P < 0.01). Supplementation elicited a significant increase in lymphocyte total folate (P < 0.01), and this was strongly associated with the increase in RBC total folate (P < 0.01) and plasma 5-MeTHF (P < 0.01). Buccal mucosa total folate was not influenced by folate supplementation. Methods have been developed for the rapid measurement of lymphocyte and buccal mucosal total folate. Lymphocyte folate is sensitive to folate intake and is reflected by plasma 5-MeTHF.
Br J Biomed Sci. 2004;61(2):84-7.
Megahed MA, Taher IM.
Department of Biochemistry, Medical Research Institute, Alexandria, Egypt.
Folate and homocysteine levels in pregnancy.
This study aims to determine serum folate and plasma homocysteine levels in healthy pregnant women following a live birth and compare them with healthy non-pregnant women. Fifty healthy gravid multiparous women are included in the study and 25 normal non-pregnant female subjects act as controls (group I). The pregnant women are divided into two groups according to interpregnancy interval: group II (six months or less); group III (18-24 months). Venous blood samples are analysed for red blood cell folate and homocysteine, vitamin B12, serum folate and albumin, and serum aminotransferases (ALT and AST). There was a significant decrease in red cell folate and serum folate in group II compared to the control group (P<0.001). Serum vitamin B12 showed no significant difference. Plasma homocysteine and serum albumin showed significant decreases in both groups II and III compared to the control group. (P<0.001) There was significant positive correlation between homocysteine and serum albumin in the three studied groups. (r=0.42, P<0.001; r=0.45, P<0.001; r=0.51, P<0.001, respectively). There was significant negative correlation between red cell folate and homocysteine in the three studied groups. (r=-0.48, P<0.001; r=-0.53, P<0.001; r=-0.49, P<0.001, respectively). Two cases in group II showed signs of intrauterine growth retardation. The results suggest that pregnant females with short interpregnancy intervals are more likely to develop folate deficiency. Educational strategies are required to increase folate awareness among women to promote the benefits of folic acid supplementation. Mandatory folate fortification of foods should be defined and monitored.
Z Kardiol. 2004 Jun;93(6):439-53.
Stanger O, Herrmann W, Pietrzik K, Fowler B, Geisel J, Dierkes J, Weger M.
Universitatsklinik fur Herzchirurgie, Private Medizinische Universitat (PMU), Landeskliniken Salzburg, Mullner Hauptstrasse 48, 5020, Salzburg, Austria.
Clinical use and rational management of homocysteine, folic acid, and B vitamins in cardiovascular and thrombotic diseases.
About half of all deaths are due to cardiovascular disease and its complications. The economic burden on society and the healthcare system from cardiovascular disability, complications, and treatments is huge and becoming larger in the rapidly aging populations of developed countries. As conventional risk factors fail to account for part of the cases, homocysteine, a "new" risk factor, is being viewed with mounting interest.Homocysteine is a sulfur-containing intermediate product in the normal metabolism of methionine, an essential amino acid. Folic acid, vitamin B(12), and vitamin B(6) deficiency and reduced enzyme activities inhibit the breakdown of homocysteine, thus increasing the intracellular homocysteine concentration. Numerous retrospective and prospective studies have consistently found an independent relationship between mild hyperhomocysteinemia and cardiovascular disease or all-cause mortality. Starting at a plasma homocysteine concentration of approximately 10 micromol/l, the risk increase follows a linear dose-response relationship with no specific threshold level. Hyperhomocysteinemia as an independent risk factor for cardiovascular disease is thought to be responsible for about 10 percent of total risk. Elevated plasma homocysteine levels (> 12 micromol/l; moderate hyperhomocysteinemia) are considered cytotoxic and are found in 5 to 10 percent of the general population and in up to 40 percent of patients with vascular disease. Additional risk factors (smoking, arterial hypertension, diabetes, and hyperlipidemia) may additively or, by interacting with homocysteine, synergistically (and hence overproportionally) increase overall risk. Hyperhomocysteinemia is associated with alterations in vascular morphology, loss of endothelial antithrombotic function, and induction of a procoagulant environment. Most known forms of damage or injury are due to homocysteine-mediated oxidative stresses. Especially when acting as direct or indirect antagonists of cofactors and enzyme activities, numerous agents, drugs, diseases, and life style factors have an impact on homocysteine metabolism. Folic acid deficiency is considered the most common cause of hyperhomocysteinemia. An adequate intake of at least 400 microg of folate per day is difficult to maintain even with a balanced diet, and high-risk groups often find it impossible to meet these folate requirements. Based on the available evidence, there is an increasing call for the diagnosis and treatment of elevated homocysteine levels in high-risk individuals in general and patients with manifest vascular disease in particular. Subjects of both populations should first have a baseline homocysteine assay. Except where manifestations are already present, intervention, if any, should be guided by the severity of hyperhomocysteinemia. Consistent with other working parties and consensus groups, we recommend a target plasma homocysteine level of < 10 micromol/l. Based on various calculation models, reduction of elevated plasma homocysteine concentrations may theoretically prevent up to 25 percent of cardiovascular events. Supplementation is inexpensive, potentially effective, and devoid of adverse effects and, therefore, has an exceptionally favorable benefit/risk ratio. The results of ongoing randomized controlled intervention trials must be available before screening for and treatment of hyperhomocysteinemia can be recommended for the apparently healthy general population.
Cancer Detect Prev. 2005;29(1):46-53. Epub 2004 Nov 11.
Kane MA.
Division of Medical Oncology, University of Colorado Health Sciences Center and the Denver Veterans Affairs Medical Center, Denver VA Medical Center (111F), 1055 Clermont Street, Denver, CO 80220, USA.
The role of folates in squamous cell carcinoma of the head and neck.
The primary objective of this review is to explore the hypothesis that folate insufficiency may be important in the pathogenesis of squamous cell carcinomas of the head and neck (SCCHN) and that folate repletion may be an effective component of chemoprevention. The main results are that folate insufficiency disrupts DNA global and specific gene methylation patterns such that the activity of certain tumor suppressor genes such as p16 and possibly p53 may be lost. Folate pool imbalance and impaired repair mechanisms may contribute to DNA instability and strand breaks. Sensitive methods exist for identification of individuals with folate insufficiency in contrast to the relatively insensitive conventional serum or red cell folate assays with broad "normal" ranges. The impact of folate supplementation can thus be quantified. Folate imbalance may result from alterations in folate cellular uptake by the reduced folate carrier (RFC) and/or the folate receptor (FR) and polymorphisms in enzymes important in folate retention such as folylpolyglutamate synthetase and in folate modification such as methylene tetrahydrofolate reductase (MTHFR). Known predisposing factors for SCCHN such as alcohol and tobacco carcinogens may influence folate balance. Folate supplementation may reduce primary or secondary risk of cancer. Formal studies of folate sufficiency in persons at risk for or diagnosed and treated for SCCHN are needed to define the role of folate supplementation in the prevention of these cancers.
Folic Acid description...
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Drug category:Antioxidants and Vitamines
 Folic Acid scientific update
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