GENOTOXIC AND MUTAGENIC STUDIES OF THE ANTIEPILEPTIC DRUG LEVETIRACETAM IN PREGNANT RATS AND THEIR FETUSES
Keywords:Mutagenicity, Nil, HRAS gene mutation, Comet assay, Levetiracetam
Objective: Levetiracetam (LEV) is an anti-epileptic drug, initially approved as an adjunct therapy in adult patients with partial-onset seizures, and used as monotherapy treatment during pregnancy. However, very few, if none, investigations have been focused on LEV neurotoxicity or hepatotoxicity at the molecular level. This study aimed to evaluate the genotoxic and mutagenic potential of LEV, in liver and brain tissues of treated pregnant rats and their fetuses during pregnancy.
Methods: LEV was administered to pregnant female albino rats at doses 300 or 600 mg/kg b. w, from gestation days 5-18. Comet assay, DNA fragmentation were performed for detection of DNA damage. Single-stranded conformation polymorphism (SSCP) followed by DNA sequencing were accomplished for detecting possible mutagenicity.
Results: Administration of the two tested doses of LEV resulted in a significant increase of DNA damage as detected by alkaline Comet assay, and an appearance of both apoptotic laddered and smeared DNA in the tissues tested. Moreover, a significant incidence of mutations in exon 2 and 3 of Harvey rat sarcoma viral oncogene (HRAS) gene, were detected in fetal liver and brain tissues respectively, using single-stranded conformation polymorphism (SSCP) and were conï¬rmed by DNA sequencing.
Conclusion: Maternal and fetal DNA damage induced by LEV was evidenced in our study, even at the commonly used therapeutic dose (300 mg/kg), and thus these side effects should be considered when using LEV for long-term during pregnancy.
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