Valproic Acid Increases Conservative Homologous Recombination Frequency and Reactive Oxygen Species Formation: A Potential Mechanism for Valproic Acid-Induced Neural Tube Defects

Abstract

Valproic acid, a commonly used antiepileptic agent, is associated with a 1 to 2% incidence of neural tube defects when taken during pregnancy; however, the molecular mechanism by which this occurs has not been elucidated. Previous research suggests that valproic acid exposure leads to an increase in reactive oxygen species (ROS). DNA damage due to ROS can result in DNA double-strand breaks, which can be repaired through homologous recombination (HR), a process that is not error-free and can result in detrimental genetic changes. Because the developing embryo requires tight regulation of gene expression to develop properly, we propose that the loss or dysfunction of genes involved in embryonic development through aberrant HR may ultimately cause neural tube defects. To determine whether valproic acid induces HR, Chinese hamster ovary 3-6 cells, containing a neomycin direct repeat recombination substrate, were exposed to valproic acid for 4 or 24 h. A significant increase in HR after exposure to valproic acid (5 and 10 mM) for 24 h was observed, which seems to occur through a conservative HR mechanism. We also demonstrated that exposure to valproic acid (5 and 10 mM) significantly increased intracellular ROS levels, which were attenuated by preincubation with polyethylene glycol-conjugated (PEG)-catalase. A significant change in the ratio of 8-hydroxy-2Ј-deoxyguanosine/2Ј-de-oxyguanosine, a measure of DNA oxidation, was not observed after valproic acid exposure; however, preincubation with PEG-catalase significantly blocked the increase in HR. These data demonstrate that valproic acid increases HR frequency and provides a possible mechanism for valproic acid-induced neural tube defects.

Pharmacological safety during pregnancy: the principles of teratogenesis and teratogenicity of drugs

“…Некоторые лекарственные средства известны в качестве агентов окислительно-вос-становительного цикла и подвержены одноэлектронным восстановительным реакциям с образованием АФК, что, как считается, может служить основой их тератогенного эффекта [43][44][45]. Примером таких препаратов являются талидомид, фенитоин, вальпроевая кислота, антиаритми-ческие средства III класса, препараты железа и различные химиотерапевтические средства [43,46,47]. Из-за несо-вершенства системы антиоксидантной защиты развитие эмбриона особенно чувствительно к высоким уровням АФК, в частности на ранней стадии органогенеза, хотя ферменты плаценты играют роль в защите будущего ребенка от окислительного стресса [46,48].…”

“…Примером таких препаратов являются талидомид, фенитоин, вальпроевая кислота, антиаритми-ческие средства III класса, препараты железа и различные химиотерапевтические средства [43,46,47]. Из-за несо-вершенства системы антиоксидантной защиты развитие эмбриона особенно чувствительно к высоким уровням АФК, в частности на ранней стадии органогенеза, хотя ферменты плаценты играют роль в защите будущего ребенка от окислительного стресса [46,48].…”

Prophylactic Effects of Melatonin on Sodium Valproate-Induced Neural Tube Defects and Skeletal Malformations in Rat Embryos

“…It has been the drug of choice in the treatment of most forms of primary generalized epilepsies and is also efficient against partial seizures (Rowan et al, 1997). Valproic acid, a commonly used antiepileptic agent, is associated with a 1-2% incidence of neural tube defects when taken during pregnancy; however, the molecular mechanism by which this occurs has not been elucidated (Defoort and Winn, 2006). As many as 10% of the 12000 infants that are exposed to anti-epileptic drugs during pregnancy every year show malformations (Finnell, 1991;Lindhout and Omtzigt, 1992).…”

Efeito da fortificação alimentar com ácido fólico na prevalência de defeitos do tubo neural

“…1,3 The most studied genes involved in this malformation are associated with the folic acid metabolism, 3 particularly one mutation of the 5,10 metylenetetrahydrofolate reductase gene. 1,3 The following are among maternal risk factors for this anomaly: diabetes mellitus, 7 use of valproic acid during pregnancy, 5 maternal obesity, 18 hyperthermia, 14 and folic acid defi ciency. 4 Studies report the importance of folic acid to prevent NTDs, despite its functioning being little understood yet.…”