Absorption and Tissue Distribution of Folate Forms in Rats: Indications for Specific Folate Form Supplementation during Pregnancy

Food fortification and folic acid supplementation during pregnancy have been implemented as strategies to prevent fetal malformations during pregnancy. However, with the emergence of conditions where folate metabolism and transport are disrupted, such as folate receptor alpha autoantibody (FRαAb)-induced folate deficiency, it is critical to find a folate form that is effective and safe for pharmacologic dosing for prolonged periods. Therefore, in this study, we explored the absorption and tissue distribution of folic acid (PGA), 5-methyl-tetrahydrofolate (MTHF), l-folinic acid (levofolinate), and d,l-folinic acid (Leucovorin) in adult rats. During absorption, all forms are converted to MTHF while some unconverted folate form is transported into the blood, especially PGA. The study confirms the rapid distribution of absorbed folate to the placenta and fetus. FRαAb administered, also accumulates rapidly in the placenta and blocks folate transport to the fetus and high folate concentrations are needed to circumvent or overcome the blocking of FRα. In the presence of FRαAb, both Leucovorin and levofolinate are absorbed and distributed to tissues better than the other forms. However, only 50% of the leucovorin is metabolically active whereas levofolinate is fully active and generates higher tetrahydrofolate (THF). Because levofolinate can readily incorporate into the folate cycle without needing methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) in the first pass and is relatively stable, it should be the folate form of choice during pregnancy, other disorders where large daily doses of folate are needed, and food fortification.

[1]  R. Obeid,et al.  Pharmacokinetics of Sodium and Calcium Salts of (6S)-5-Methyltetrahydrofolic Acid Compared to Folic Acid and Indirect Comparison of the Two Salts , 2020, Nutrients.

[2]  N. Greene,et al.  Deficient or Excess Folic Acid Supply During Pregnancy Alter Cortical Neurodevelopment in Mouse Offspring , 2020, Cerebral cortex.

[3]  R. Rozen,et al.  Moderate Folic Acid Supplementation in Pregnant Mice Results in Behavioral Alterations in Offspring with Sex-Specific Changes in Methyl Metabolism , 2020, Nutrients.

[4]  V. Ramaekers,et al.  Improving Outcome in Infantile Autism with Folate Receptor Autoimmunity and Nutritional Derangements: A Self-Controlled Trial , 2019, Autism research and treatment.

[5]  R. Berry Lack of historical evidence to support folic acid exacerbation of the neuropathy caused by vitamin B12 deficiency. , 2019, The American journal of clinical nutrition.

[6]  J. Revuelta,et al.  Formation of folates by microorganisms: towards the biotechnological production of this vitamin , 2018, Applied Microbiology and Biotechnology.

[7]  W. Brown,et al.  Folate receptor autoantibodies are prevalent in children diagnosed with autism spectrum disorder, their normal siblings and parents , 2018, Autism research : official journal of the International Society for Autism Research.

[8]  R. Frye,et al.  Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial , 2016, Molecular Psychiatry.

[9]  M. Desoto,et al.  Is High Folic Acid Intake a Risk Factor for Autism?—A Review , 2017, Brain sciences.

[10]  J. M. Sequeira,et al.  Prevention of behavioral deficits in rats exposed to folate receptor antibodies: implication in autism , 2017, Molecular Psychiatry.

[11]  R. Frye,et al.  Folate metabolism abnormalities in autism: potential biomarkers. , 2017, Biomarkers in medicine.

[12]  V. Ramaekers,et al.  The basis for folinic acid treatment in neuro-psychiatric disorders. , 2016, Biochimie.

[13]  J. M. Sequeira,et al.  The metabolic basis for developmental disorders due to defective folate transport. , 2016, Biochimie.

[14]  J. M. Sequeira,et al.  Exposure to Folate Receptor Alpha Antibodies during Gestation and Weaning Leads to Severe Behavioral Deficits in Rats: A Pilot Study , 2016, PloS one.

[15]  R. Frye,et al.  Blocking and Binding Folate Receptor Alpha Autoantibodies Identify Novel Autism Spectrum Disorder Subgroups , 2016, Front. Neurosci..

[16]  J. M. Sequeira,et al.  The role of folate receptor autoantibodies in preterm birth. , 2015, Nutrition.

[17]  M. Fenech,et al.  Biomarkers of Nutrition for Development-Folate Review. , 2015, The Journal of nutrition.

[18]  P. Bergold,et al.  Folate deficiency in rat pups during weaning causes learning and memory deficits , 2014, British Journal of Nutrition.

[19]  Subit Barua,et al.  Folic acid supplementation in pregnancy and implications in health and disease , 2014, Journal of Biomedical Science.

[20]  I. Goldman,et al.  The intestinal absorption of folates. , 2014, Annual review of physiology.

[21]  S. Krupenko,et al.  Molecular mechanisms underlying the potentially adverse effects of folate , 2013, Clinical chemistry and laboratory medicine.

[22]  V. Ramaekers,et al.  Role of folate receptor autoantibodies in infantile autism , 2013, Molecular Psychiatry.

[23]  V. Ramaekers,et al.  The diagnostic utility of folate receptor autoantibodies in blood , 2013, Clinical chemistry and laboratory medicine.

[24]  S. J. James,et al.  Cerebral folate receptor autoantibodies in autism spectrum disorder , 2012, Molecular Psychiatry.

[25]  J. Gärtner,et al.  Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency. , 2012, Brain : a journal of neurology.

[26]  G. Koren,et al.  Circulating Unmetabolized Folic Acid: Relationship to Folate Status and Effect of Supplementation , 2012, Obstetrics and gynecology international.

[27]  J. Greenberg,et al.  Folic Acid supplementation and pregnancy: more than just neural tube defect prevention. , 2011, Reviews in obstetrics & gynecology.

[28]  B. Koletzko,et al.  Perinatal folate supply: relevance in health outcome parameters. , 2010, Maternal & child nutrition.

[29]  Tracy A Wolff,et al.  Folic Acid Supplementation for the Prevention of Neural Tube Defects: An Update of the Evidence for the U.S. Preventive Services Task Force , 2009, Annals of Internal Medicine.

[30]  J. M. Sequeira,et al.  Association between blocking folate receptor autoantibodies and subfertility. , 2009, Fertility and sterility.

[31]  L. Matherly,et al.  Membrane transporters and folate homeostasis: intestinal absorption and transport into systemic compartments and tissues , 2009, Expert Reviews in Molecular Medicine.

[32]  J. Daval,et al.  Impact of folate and homocysteine metabolism on human reproductive health. , 2007, Human reproduction update.

[33]  K. Balamurugan,et al.  Role of reduced folate carrier in intestinal folate uptake. , 2006, American journal of physiology. Cell physiology.

[34]  Nenad Blau,et al.  Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. , 2005, The New England journal of medicine.

[35]  J. M. Sequeira,et al.  Autoantibodies against folate receptors in women with a pregnancy complicated by a neural-tube defect. , 2004, The New England journal of medicine.

[36]  D. Goldman,et al.  Membrane transport of folates. , 2003, Vitamins and hormones.

[37]  E. Reynolds Benefits and risks of folic acid to the nervous system , 2002, Journal of neurology, neurosurgery, and psychiatry.

[38]  Joshua W. Miller,et al.  Folate deficiency beyond megaloblastic anemia: hyperhomocysteinemia and other manifestations of dysfunctional folate status. , 1999, Seminars in hematology.

[39]  G. Varela-Moreiras,et al.  Long-term folate deficiency alters folate content and distribution differentially in rat tissues. , 1992, The Journal of nutrition.

[40]  R. Hillman,et al.  Kinetics of the normal folate enterohepatic cycle. , 1979, The Journal of clinical investigation.

[41]  A. V. Hoffbrand,et al.  Synthesis of folate polyglutamates in human cells. , 1976, Clinical science and molecular medicine.

[42]  S. Rothenberg,et al.  The determination of erythrocyte folate concentration using a two-phase ligand-binding radioassay. , 1974, Blood.

[43]  D. Freedman,et al.  The absorption of the diastereoisomers of 5-methyltetrahydropteroylglutamate in man: a carrier-mediated process. , 1973, Clinical science and molecular medicine.

[44]  J. Bertino,et al.  Intestinal folate absorption. II. Conversion and retention of pteroylmonoglutamate by jejunum. , 1973, The Journal of clinical investigation.

[45]  J. Selhub,et al.  Uptake and reduction of radioactive folate by everted sacs of rat small intestine. , 1973, European journal of biochemistry.

[46]  S. Rothenberg,et al.  A radioassay for serum folate: use of a two-phase sequential-incubation, ligand-binding system. , 1972, The New England journal of medicine.

[47]  B. Cooper,et al.  Intestinal Conversion of Folinic Acid to 5‐Methyltetrahydrofolate in Man , 1972, British journal of haematology.

[48]  M. Wintrobe [The megaloblastic anemias]. , 1960, Il Policlinico. Sezione pratica.

[49]  C. Butterworth,et al.  A study of folate absorption and metabolism in man utilizing carbon-14--labeled polyglutamates synthesized by the solid phase method. , 1969, The Journal of clinical investigation.

[50]  D. Mollin,et al.  Absorption of crystalline folic acid in man. , 1968, Lancet.