Although direct kinetic transport data were not explored here, the binding curves presented are a representation of the possibility of folate transport that occurs when a folate receptor binds its substrate. The addition of VPA to a closed system of substrate and receptor modified binding such that the maximal binding effect could never be achieved.
The data described herein illustrate that VPA, acting alone, has a basal level of binding to the folate receptor, and therefore, serves to bind to either an allosteric site or directly to the folate receptor binding pocket. We suggest that upon oral dosing, VPA could bind to folate receptors as VPA is being absorbed in the epithelial cells of the intestine, a known region of folate receptor expression and function Sega and Low, This binding by VPA is hypothesized to produce folate deficient conditions in the pregnant mother, reducing the transfer of folates to the developing embryo, which could potentially contribute to the range of congenital and developmental defects, such as NTDs, seen in embryos developing in a low folate environment.
Modifications to these high affinity folate receptors may even directly decrease the amount of folates, even folic acid, that are being passed through the placenta to the developing embryo. Folate deficient conditions, such as those that could result from VPA exposure, have been shown to increase the risk for selected congenital defects Smithells et al. This hypothesized folate deficient environment resulting from VPA exposure has been previously described Alonso-Aperte and Varela-Moreiras, ; Whitsel et al.
Reports showing that concurrent doses of VPA and FA under experimental conditions operate to decrease damage to the developing embryo support the notion that VPA is a noncompetitive inhibitor Umur et al. In fact, some physicians recommend the concurrent dosing of women of childbearing age who take VPA to also supplement with FA, in hopes to decrease their risk of having an NTD affected pregnancy Ornoy, The Kd determined here for FA is orders of magnitude smaller than that of VPA, such that when the two compounds are administered in parallel, FA will bind more efficiently to the receptors and outcompete any other substrate available.
Of interest, VPA is usually given to humans in divided dosages so that the patients maintain a stable concentration in their blood. Although the experiments presented here were preformed at superphysiologic concentrations of VPA, over time the effects of the VPA treatment may be seen through the reduction of total possible folates that may bind to their high affinity receptors. After a prolonged exposure to the folate receptors, these constant quantities of VPA may be able to bind to the folate receptors and block the binding and transport of some fraction of the FA provided to the patient in hopes of preventing NTDs and other birth defects.
The data presented in this report provide a basis for a novel mechanism of VPA teratogenicity. The decreased levels of folates observed in VPA treated individuals may be a direct result of inhibition of the folate receptors by the small molecule valproic acid.
If this inhibition is great enough, congenital malformations and NTDs manifest. Blocking the folate receptors from functioning to their normal capacity would be expected to increase risk for NTDs, as when these receptors are knocked out in mice, NTD phenotypes are observed Blom et al. Further investigation will be conducted using folate transport knock-out mouse models. The existence of both the Proton Coupled Folate Receptor knock-out mouse and the Reduced Folate Carrier conditional mouse would allow for tissue specific studies i.
The study presented here will serve as the starting point of an investigation into the mechanism underlying some of the adverse effects associated with one of the most commonly prescribed drugs for epilepsy, a condition that accounts for 0.
National Center for Biotechnology Information , U. Author manuscript; available in PMC Apr Richard H. Author information Copyright and License information Disclaimer. Austin, TX Copyright notice. See other articles in PMC that cite the published article.
Abstract Background Valproic acid VPA is a commonly prescribed drug for those affected by epilepsy and bipolar disorders. Methods We herein approach this question experimentally, using enzyme-linked immunosorbent assay assays and cell culture modeling, to demonstrate that VPA serves as a noncompetitive inhibitor of the high affinity folate receptors.
Results Binding affinities experimentally determined through enzyme-linked immunosorbent assay assays indicate that VPA serves as a noncompetitive substrate that can lessen the ability of the three primary folate forms to bind to the high affinity folate receptors.
Conclusion If these data translate to the overall transport and subsequent bioavailability of folates, noncompetitive inhibition of the folate receptors by VPA may serve to lower the bioavailable folates in VPA treated mothers. Keywords: valproic acid, folate, vitamin transport, birth defects, teratogens.
Introduction The Centers for Disease Control and Prevention estimates that epilepsy currently affects 2. Materials and Methods To determine the different binding affinities of the folates to the receptors, an enzyme-linked immunosorbent assay ELISA assay was performed. Open in a separate window. Discussion The displacement curves of folate substrates versus VPA to the high-affinity folate receptors presented in this report demonstrate that VPA serves as an exogenous noncompetitive binding molecule to the high affinity folate receptors.
Drugs-nutrient interactions: a potential problem during adolescence. Eur J Clin Nutr. This increased risk is comparable to the recurrence risk for neural tube defects and warrants informed counselling and access to prenatal diagnosis.
There is no substantial evidence that valproic acid use increases the risk for other specific major malformations above the increased risk due to maternal epilepsy. Valproic acid may cause a characteristic pattern of minor facial malformations.
Further definition and confirmation are required, and the magnitude of the risk needs to be determined. There are inadequate data to assess the magnitude, if any, of the risks for postnatal growth abnormalities and developmental disabilities associated with the use of valproic acid during pregnancy.
Birth-defect monitoring programs and international collaboration among the staffs of monitoring programs played a major role in determining that valproic acid is a human teratogen.
Full text links Read article at publisher's site DOI : References Articles referenced by this article 49 Valproic acid and fetal abnormality. Valproic acid and congenital malformations. A case report. Valproic acid and spina bifida. Valproic acid embryopathy? Teratogenic potential of valproic acid. Drug therapy: Valproic acid.
Teratogenic effects of valproic acid and diphenylhydantoin on mouse embryos in culture. Possible teratogenic effect of valproic acid. Teratogenicity of valproic acid. Transmission of valproic acid Depakene across the placenta: half-life of the drug in mother and baby. Show 10 more references 10 of Smart citations by scite. The number of the statements may be higher than the number of citations provided by EuropePMC if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles.
Explore citation contexts and check if this article has been supported or disputed. Bioinformatics and system biology approaches to identify the diseasome and comorbidities complexities of SARS-CoV-2 infection with the digestive tract disorders. Valproate and spina bifida in the Netherlands. Absts Eur Teratol Soc. Lindhout D, Schmidt D. In-utero exposure to valproate and neural tube defects.
Effect of supplementation with folinic acid, vitamin B6, and vitamin B12 on valproic acid-induced teratogenesis in mice. Fundam Appl Toxicol. Methionine reduces the valproic acid-induced spina bifida rate in mice without altering valproic acid kinetics.
J Nutr. Finkelstein JD. Methionine metabolism in mammals. J Nutr Biochem. Coelho, Klein. Methionine and neural tube closure in cultured rat embryos: morphological and biochemical analyses. Copp AJ. Prevention of neural tube defects: vitamins, enzymes and genes.
Curr Opin Neurol. Folate-homocysteine interrelations: potential new markers of folate status. Mol Genet Metab. Homocysteine metabolism in pregnancies complicated by neural tube defects. Nutrition ;—5. Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid. Proc Natl Acad Sci. Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects.
QJ Med. J Cell Biochem. Al-Gazali L. Abnormal folate metabolism and genetic polymorphism of the folate pathway in a child with down syndrome and neural tube defect. Am J Med Genet. Ashfield Watt PA. Pullin L, Catherine H, et al. Am J Clin Nutr. The effects of valporic acid, vitamin E and folic acid on ribs of rat fetuses in the prenatal period.
Ann Anat. Increased oxidative stress in epileptic children treated with valproic acid. Epilepsy Res. Effects of valproate, carbamazepine, and levetiracetam on the antioxidant and oxidant systems in epileptic patients and their clinical importance. Clin Neuropharmacol. RSC Adv. Prior exposure to indolecarbinol decreases the incidence of specific cyclophosphamide-induced developmental defects in mice. Valproate induced effects on development in the rat are partially prevented by folinic acid and S-adenosylmethionine.
Eur J Anat. Maternal administration of superoxide dismutase and catalase in phenytoin teratogenicity. Free Radic Biol Med. Tweets by medcraveonline. At human therapeutic doses, immunofluorescence revealed that type II collagen was reduced, while type I collagen increased. In addition, the alcian blue-staining matrices i. Moreover, the Golgi apparatus had swelling in the trans-face cisternae suggesting that proteoglycan synthesis may be altered.
0コメント