[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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