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Increased susceptibility to phenytoin teratogenicity: excessive generation of reactive oxygen species or impaired antioxidant defense?
Basic Clin Pharmacol Toxicol. 2006 Oct; 99(4):305-11.BC

Abstract

Phenytoin is a human and animal teratogen. Accumulating evidence suggests that the teratogenicity is associated with a potential of phenytoin to cause embryonic cardiac arrhythmia and resultant generation of toxic reactive oxygen species via hypoxia-reoxygenation mechanisms. The A/J mouse is more susceptible to phenytoin teratogenicity than other mouse strains. The aim of this study was to investigate whether A/J mice have other antioxidant enzyme activities than C57BL/6J and CD-1 mice. Also, strain differences in phenytoin effects on embryonic heart rate and rhythm were determined. Another objective was to determine whether a spin trapping agent with capacity to capture reactive oxygen species alter the developmental toxicity of phenytoin. Treatment with this agent resulted in a marked decrease in phenytoin teratogenicity, which supports the idea that reactive oxygen species are important mediators for the teratogenic action of phenytoin. The A/J mice embryos were most susceptible to the adverse cardiac effects of phenytoin and had the highest activity of superoxide dismutase and glutathione peroxidase, while the activity of catalase was the same in embryos of the three different strains. The high activities of antioxidant enzymes in the A/J stain indicate that the sensitivity to develop malformations is caused by excessive arrhythmia-related generation of reactive oxygen species rather than impaired antioxidant defense.

Authors+Show Affiliations

Division of Toxicology, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. Faranak.Azarbayjani@medcellbiol.uu.seNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17040216

Citation

Azarbayjani, Faranak, et al. "Increased Susceptibility to Phenytoin Teratogenicity: Excessive Generation of Reactive Oxygen Species or Impaired Antioxidant Defense?" Basic & Clinical Pharmacology & Toxicology, vol. 99, no. 4, 2006, pp. 305-11.
Azarbayjani F, Borg LA, Danielsson BR. Increased susceptibility to phenytoin teratogenicity: excessive generation of reactive oxygen species or impaired antioxidant defense? Basic Clin Pharmacol Toxicol. 2006;99(4):305-11.
Azarbayjani, F., Borg, L. A., & Danielsson, B. R. (2006). Increased susceptibility to phenytoin teratogenicity: excessive generation of reactive oxygen species or impaired antioxidant defense? Basic & Clinical Pharmacology & Toxicology, 99(4), 305-11.
Azarbayjani F, Borg LA, Danielsson BR. Increased Susceptibility to Phenytoin Teratogenicity: Excessive Generation of Reactive Oxygen Species or Impaired Antioxidant Defense. Basic Clin Pharmacol Toxicol. 2006;99(4):305-11. PubMed PMID: 17040216.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Increased susceptibility to phenytoin teratogenicity: excessive generation of reactive oxygen species or impaired antioxidant defense? AU - Azarbayjani,Faranak, AU - Borg,L A Håkan, AU - Danielsson,Bengt R, PY - 2006/10/17/pubmed PY - 2007/2/16/medline PY - 2006/10/17/entrez SP - 305 EP - 11 JF - Basic & clinical pharmacology & toxicology JO - Basic Clin. Pharmacol. Toxicol. VL - 99 IS - 4 N2 - Phenytoin is a human and animal teratogen. Accumulating evidence suggests that the teratogenicity is associated with a potential of phenytoin to cause embryonic cardiac arrhythmia and resultant generation of toxic reactive oxygen species via hypoxia-reoxygenation mechanisms. The A/J mouse is more susceptible to phenytoin teratogenicity than other mouse strains. The aim of this study was to investigate whether A/J mice have other antioxidant enzyme activities than C57BL/6J and CD-1 mice. Also, strain differences in phenytoin effects on embryonic heart rate and rhythm were determined. Another objective was to determine whether a spin trapping agent with capacity to capture reactive oxygen species alter the developmental toxicity of phenytoin. Treatment with this agent resulted in a marked decrease in phenytoin teratogenicity, which supports the idea that reactive oxygen species are important mediators for the teratogenic action of phenytoin. The A/J mice embryos were most susceptible to the adverse cardiac effects of phenytoin and had the highest activity of superoxide dismutase and glutathione peroxidase, while the activity of catalase was the same in embryos of the three different strains. The high activities of antioxidant enzymes in the A/J stain indicate that the sensitivity to develop malformations is caused by excessive arrhythmia-related generation of reactive oxygen species rather than impaired antioxidant defense. SN - 1742-7835 UR - https://www.unboundmedicine.com/medline/citation/17040216/Increased_susceptibility_to_phenytoin_teratogenicity:_excessive_generation_of_reactive_oxygen_species_or_impaired_antioxidant_defense L2 - https://doi.org/10.1111/j.1742-7843.2006.pto_416.x DB - PRIME DP - Unbound Medicine ER -