[en] Metabolic breakdown of valproate (VPA), carbamazepine (CBZ) and phenytoin (PHT) by the cytochrome P450 pathway generates toxic drug intermediates and reactive oxygen species (ROS). This mechanism has been suspected to play a role in the pathogenesis of secondary cerebral folate deficiency (CFD). Using KB-cell cultures, highly expressing the folate receptor 1 (FOLR1), the effect of antiepileptic drugs (AEDs) and reactive oxygen species (ROS) on the FOLR1 dependent 5-methyltetrahydrofolate (MTHF) uptake was studied. MTHF uptake is time and concentration dependent and shows saturation kinetics. At physiological MTHF concentrations the high-affinity FOLR1 represents the predominant mechanism for cellular incorporation, while at high MTHF concentrations other transport mechanisms participate in folate uptake. Exposure to PHT for more than 8h led to a higher MTHF uptake and decreased cell count, whereas MTHF uptake remained unaltered by VPA and CBZ. However, exposure to superoxide and hydrogen peroxide radicals significantly decreased cellular MTHF uptake. By specific elimination and downregulation of FOLR1 using phosphatidyl-inositol-specific phospholipase C (PIPLC) and siRNA silencing, it was shown that ROS not only inhibited FOLR1 mediated MTHF uptake but also affected all other mechanisms of membrane-mediated MTHF uptake. Generation of ROS with the use of AED might therefore provide an additional explanation for the disturbed folate transfer across the blood-CSF barrier in patients with CFD.
Disciplines :
Neurology
Author, co-author :
Opladen, Thomas
Blau, Nenad
RAMAEKERS, Vincent ; Centre Hospitalier Universitaire de Liège - CHU > Pédiatrie
Language :
English
Title :
Effect of antiepileptic drugs and reactive oxygen species on folate receptor 1 (FOLR1)-dependent 5-methyltetrahydrofolate transport.
Publication date :
2010
Journal title :
Molecular Genetics and Metabolism
ISSN :
1096-7192
eISSN :
1096-7206
Publisher :
Academic Press
Volume :
101
Issue :
1
Pages :
48-54
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
research grant from medical faculty at University Aachen, Dr Emil-Alexander Huebner foundation, Swiss national science foundation grant 3100A0-1199852/1
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Bibliography
Blom H.J., Shaw G.M., den Heijer M., Finnell R.H. Neural tube defects and folate: case far from closed. Nat. Rev. Neurosci. 2006, 7:724-731.
Zhao R., Seither R., Brigle K.E., Sharina I.G., Wang P.J., Goldman I.D. Impact of overexpression of the reduced folate carrier (RFC1), an anion exchanger, on concentrative transport in murine L1210 leukemia cells. J. Biol. Chem. 1997, 272:21207-21212.
Anderson R.G., Kamen B.A., Rothberg K.G., Lacey S.W. Potocytosis: sequestration and transport of small molecules by caveolae. Science 1992, 255:410-411.
Fan J., Vitols K.S., Huennekens F.M. Multiple folate transport systems in L1210 cells. Adv. Enzyme Regul. 1992, 32:3-15.
Selhub J. Folate binding proteins. Mechanism for placental and intestinal uptake. Lactation and Infant Growth 1994, 141-149. Springer, Berlin. L. Allen, J. King, B. Lönnerdal (Eds.).
Qiu A., Jansen M., Sakaris A., Min S.H., Chattopadhyay S., Tsai E., Sandoval C., Zhao R., Akabas M.H., Goldman I.D. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 2006, 127:917-928.
Holm J., Hansen S.I., Hoier-Madsen M., Bostad L. High-affinity folate binding in human choroid plexus. Characterization of radioligand binding, immunoreactivity, molecular heterogeneity and hydrophobic domain of the binding protein. Biochem. J. 1991, 280:267-271.
Wu D., Pardridge W.M. Blood-brain barrier transport of reduced folic acid. Pharm. Res. 1999, 16:415-419.
Korevaar W.C., Geyer M.A., Knapp S., Hsu L.L., Mandell A.J. Regional distribution of 5-methyltetrahydrofolic acid in brain. Nat. New Biol. 1973, 245:244-245.
Spector R., Lorenzo A.V. Folate transport by the choroid plexus in vitro. Science 1975, 187:540-542.
Opladen T., Ramaekers V., Heimann G., Blau N. Analysis of 5-methyltetrahydrofolate in serum of healthy children. Mol. Genet. Metab. 2006, 87:61-65.
Ramaekers V.T., Hausler M., Opladen T., Heimann G., Blau N. Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution. Neuropediatrics 2002, 33:301-308.
Ramaekers V.T., Rothenberg S.P., Sequeira J.M., Opladen T., Blau N., Quadros E.V., Selhub J. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome [see comment]. N. Engl. J. Med. 2005, 352:1985-1991.
Cario H., Bode H., Debatin K.M., Opladen T., Schwarz K. Congenital null mutations of the folr1 gene: a progressive neurologic disease and its treatment. Neurology 2009, 73:2127-2129.
Steinfeld R., Grapp M., Kraetzner R., Dreha-Kulaczewski S., Helms G., Dechent P., Wevers R., Grosso S., Gartner J. Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am. J. Hum. Genet. 2009, 85:354-363.
Skovby F. Disorders of sulfur amino acids. Physician' Guide to the Laboratory Diagnosis of Metabolic Disease 2005, 243-260. Springer, Heidelberg. N. Blau, M. Duran, M. Blaskovics, K.M. Gibson (Eds.).
Ponzone A., Spada M., Ferraris S., Dianzani I., De Sanctis L. Dihydropteridine reductase deficiency in man: from biology to treatment. Med. Res. Rev. 2004, 24:127-150.
Ramaekers V.T., Steen-Ingemann H., Holm J., Opladen T., Senderek J., Häusler M., Heimann G., Fowler B., Maiwald R., Blau N. Reduced folate transport to the brain in Rett syndrome. Neurology 2003, 61:506-514.
Blau N., Bonafé L., Krägeloh-Mann I., Thöny B., Kierat L., Häusler M., Ramaekers V.T. Cerebrospinal fluid pterins and folates in Aicardi-Goutières syndrome: a new phenotype. Neurology 2003, 61:642-648.
Hasselmann O., Blau N., Ramaekers V.T., Quadros E.V., Sequeira J., Weissert M. Cerebral folate deficiency and CNS inflammatory markers in Alpers disease. Mol. Genet. Metab. 2010, 99:58-61.
Pineda M., Ormazabal A., Lopez-Gallardo E., Nascimento A., Solano A., Herrero M.D., Vilaseca M.A., Briones P., Ibanez L., Montoya J., Artuch R. Cerebral folate deficiency and leukoencephalopathy caused by a mitochondrial DNA deletion. Ann. Neurol. 2006, 59:394-398.
Geller J., Kronn D., Jayabose S., Sandoval C. Hereditary folate malabsorption: family report and review of the literature. Medicine (Baltimore) 2002, 81:51-68.
Rothenberg S.P., da Costa M.P., Sequeira J.M., Cracco J., Roberts J.L., Weedon J., Quadros E.V. Autoantibodies against folate receptors in women with a pregnancy complicated by a neural-tube defect [see comment]. N. Engl. J. Med. 2004, 350:134-142.
Mullers-Kuppers M. Embryopathy during pregnancy caused by taking anticonvulsants. Acta Paedopsychiatr. 1963, 30:401-405.
Speidel B.D., Meadow S.R. Maternal epilepsy and abnormalities of the fetus and the newborn. Lancet 1972, 2:839-843.
Anonymous, Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group [see comment], Lancet 338 (1991) 131-137.
Rosenberg I.H., Godwin H.A., Streiff R.R., Castle W.B. Impairment of intestinal deconjugation of dietary folate. A possible explanation of megaloblastic anaemia associated with phenytoin therapy. Lancet 1968, 2:530-532.
Suh J.R., Herbig A.K., Stover P.J. New perspectives on folate catabolism. Annu. Rev. Nutr. 2001, 21:255-282.
Antony A.C., Kane M.A., Krishnan S.R., Kincade R.S., Verma R.S. Folate (pteroylglutamate) uptake in human red blood cells, erythroid precursors and KB cells at high extracellular folate concentrations. Evidence against a role for specific folate-binding and transport proteins. Biochem. J. 1989, 260:401-411.
Tamura T., Aiso K., Johnston K.E., Black L., Faught E. Homocysteine, folate, vitamin B-12 and vitamin B-6 in patients receiving antiepileptic drug monotherapy. Epilepsy Res. 2000, 40:7-15.
Ariel M., Eilam Y., Jablonska M., Grossowicz N. Effect of phenytoin on folic acid uptake in isolated intestinal epithelial cells. J. Pharmacol. Exp. Ther. 1982, 223:224-226.
Slesinger P.A., Singer H.S. Effects of anticonvulsants on cell growth and enzymatic and receptor binding activity in a neuroblastoma×glioma hybrid cell culture. Epilepsia 1987, 28:214-221.
Reinhardt C.A. Neurodevelopmental toxicity in vitro: primary cell culture models for screening and risk assessment. Reprod. Toxicol. 1993, 7(Suppl. 1):165-170.
Regan C.M., Gorman A.M., Larsson O.M., Maguire C., Martin M.L., Schousboe A., Williams D.C. In vitro screening for anticonvulsant-induced teratogenesis in neural primary cultures and cell lines. Int. J. Dev. Neurosci. 1990, 8:143-150.
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