Antioxidant and GSH-related enzyme response to a single teratogenic exposure to the anticonvulsant phenytoin: temporospatial evaluation.
BACKGROUND
It has been proposed that the anticonvulsant drug phenytoin (PHT) requires bioactivation to reactive intermediate(s) to achieve its recognized teratogenic potential and that embryonal detoxification power may play a fundamental role in the teratogenic response. On this basis, we sought to investigate the potential effects of a teratogenic exposure to PHT on the activities of antioxidant and GSH-related detoxifying enzymes in gestational murine tissues.


METHODS
Pregnant Swiss mice were injected intraperitoneally with 0 (vehicle) or 65 mg/kg of PHT on gestation day (GD) 12 (plug day = GD 1). Biochemical determinations, including activities of glutathione transferase, glutathione peroxidase, glutathione reductase, glyoxalase I, glyoxalase II, catalase, and superoxide dismutase, were carried out on maternal and embryonic/fetal livers and in placentas on GD 14 and 19.


RESULTS
The major findings of this study show that (1) organogenesis-stage conceptal tissues have detectable levels of all the tested enzymes; (2) most of the embryonic liver and placental enzymes investigated undergo a significant induction within 48 hr (GD 14) after PHT administration; and (3) in the same tissues a down-regulation of enzyme activities is noted near term (GD 19).


CONCLUSIONS
Overall, these findings show that teratogenic exposure to PHT is associated with a modulation of reactive-intermediates-scavenging enzyme activities, and provide further support for role of generation of reactive intermediates in PHT-induced teratogenesis.
Dipartimento di Biologia di Base ed Applicata, Facoltà di Scienze Università degli Studi di L'Aquila, Coppito I-67100 L'Aquila, Italy. cellular@univaq.it
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Amicarelli
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Tiboni
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Colafarina
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Bonfigli
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Iammarrone
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Miranda
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Di Ilio
D000034:Abortion, Veterinary / Q000139:chemically induced; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D000975:Antioxidants / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D002972:Cleft Palate / Q000139:chemically induced; D003600:Cytosol / Q000201:enzymology; D015536:Down-Regulation; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007791:Lactoylglutathione Lyase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000201:enzymology; D051379:Mice; D010672:Phenytoin / Q000633:toxicity*; D010920:Placenta / Q000187:drug effects / Q000201:enzymology; D011247:Pregnancy; D013482:Superoxide Dismutase / Q000378:metabolism; D013723:Teratogens; D013869:Thiolester Hydrolases / Q000378:metabolism; D013997:Time Factors; D000099301:Hydroxyacylglutathione Hydrolase
D000927:Anticonvulsants; D000975:Antioxidants; D002374:Catalase; D005978:Glutathione; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005982:Glutathione Transferase; D007791:Lactoylglutathione Lyase; D010672:Phenytoin; D013482:Superoxide Dismutase; D013723:Teratogens; D013869:Thiolester Hydrolases; D000099301:Hydroxyacylglutathione Hydrolase