Sister chromatid exchanges in adult epilepsy patients on valproate monotherapy

Schaumann, Blanka A.; Winge, Vernon B.; Garry, Vincent F.

doi:10.1016/0920-1211(89)90048-x

Cited by 11 publications

(7 citation statements)

References 8 publications

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“…A significant increase in sister chromatid exchanges was observed in peripheral lymphocytes from epileptic children treated with valproic acid (Hu et al, 1990). However, another study demonstrated that valproic acid treatment did not induce sister chromatid exchanges in peripheral lymphocytes in adult male patients (Schaumann et al, 1989). Further evidence indicates that valproic acid may contribute to genomic instability, because a growing body of evidence demonstrates that valproic acid alters chromatin structure because it can function as a histone deacetylase inhibitor, leading to the acetylation of histone tails (Marchion et al, 2005).…”

Section: Discussionmentioning

confidence: 96%

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

Defoort¹,

Kim²,

Winn³

2005

Mol Pharmacol

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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.

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Section: Discussionmentioning

confidence: 96%

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

Defoort¹,

Kim²,

Winn³

2005

Mol Pharmacol

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“…[6] It is also reported that it lacks mutagenic potential within the therapeutic dose range when administered chronically to adult male patients with epilepsy. [7]…”

Section: Introductionmentioning

confidence: 99%

Reproductive toxicity of sodium valproate in male rats

Bairy¹,

Paul²,

Rao³

2010

Indian J Pharmacol

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Objectives:To assess the effects of sodium valproate on rat sperm morphology, sperm count, motility, and histopathological changes in testis.Materials and Methods:Male Wistar rats (12 week old) were treated with sodium valpraote and sacrificed at the end of 2nd, 4th, 5th, 7th, 10th and 15th week after the last exposure to sodium valproate. Epididymal sperm count, sperm motility, sperm morphology, and histopathology of testes were analyzed.Results:Sperm count and sperm motility were decreased significantly by sodium valproate. The percentage of abnormal sperms increased in a dose-dependent manner. A histopathological study revealed that sodium valproate had caused sloughing of epithelial cells in testes.Conclusion:Sodium valproate causes reversible change in sperm motility, sperm count, morphology, and cytoarchitecture of testes.

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“…Kulkarni et al (1984) reported a significant increase in SCE of epileptic patients treated PHT and/or PB as compared with controls. According to Schaumann et al (1985aSchaumann et al ( , 1989, there was no significant increase of SCE in patients with CBZ or YPA monotherapy.…”

Section: Resultsmentioning

confidence: 99%

Effects of antiepileptic drugs and organic brain damage on SCE frequency in cerebral palsies.

Yamamoto¹,

Kohnosu²,

Nakagawara

et al. 1990

Tohoku J. Exp. Med.

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In order to assess the genotoxic effects of antiepileptic drugs (AEDs), analysis of sister chromatid exchanges (SCEs) was performed in lymphocytes of three groups of males ; epileptics with AED therapy, non-epileptics without AED therapy and healthy controls. The epileptics and non-epileptics were cases of severe cerebral palsies due to perinatal asphyxia. Possible confounding factors of SCE frequencies, such as age, smoking habit, drug usage other than AED, recent history of viral infection, etc. were controlled. The frequency of SCE per cell was 4.63+0.71 (mean±s.n.) in epileptics, 4.70+0.89 in non-epileptics and 3.84+0.56 in healthy controls. SCEs in both epileptics and non-epileptics were significantly higher (p <0.05) than those in controls. There was no significant difference of SCE frequency between epileptics and non-epileptics. These results suggested that no mutagenic effect of AED could be demonstrated as revealed by SCEs, and organic brain damage per se might influence the baseline SCE frequency. The possible explanations for such observations are discussed.sister chromatid exchange (SCE); antiepileptic drug ; cerebral palsy ; brain damage Patients with severe organic brain damage are frequently complicated by intractable epilepsy, and long term therapy with two or more antiepileptic drugs (AEDs) is usually necessary. Therefore, these patients may be particularly subject to various adverse effects of AEDs. Among them, genotoxicity of AEDs presents one of the most important medical problems.Sister chromatid exchange (SCE) involves a symmetrical exchange between two chromatids of one chromosome. Since the original report of Perry and Evans (1975), SCE has been recognized as a sensitive indicator of DNA damage and repair and widely used not only as a useful in vitro test to assess the mutagenic

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Sister chromatid exchanges in adult epilepsy patients on valproate monotherapy

Cited by 11 publications

References 8 publications

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

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

Reproductive toxicity of sodium valproate in male rats

Effects of antiepileptic drugs and organic brain damage on SCE frequency in cerebral palsies.

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