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 (PH T) requires bioactivation to reactive intermediate(s) to achieve its recogn ized teratogenic potential and that embryonal detoxification power may play a fundamental role in the teratogenic response. On this basis, we sought t o investigate the potential effects of a teratogenic exposure to PHT on the activities of antioxidant and GSH-related detoxifying enzymes in gestation al murine tissues. Methods: Pregnant Swiss mice were injected intraperitoneally with 0 (vehicl e) or 65 mg/kg of PHT on gestation day (GD) 12 (plug day = GD 1). Biochemic al determinations, including activities of glutathione transferase, glutath ione peroxidase, glutathione reductase, glyoxalase I, glyoxalase II, catala se, and superoxide dismutase, were carried out on maternal and embryonic/fe tal 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) mo st of the embryonic fiver and placental enzymes investigated undergo a sign ificant 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 13). 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 PMT-induced teratogenesis. Teratology 62:100-107, 2000. ( C) 2000 Wiley-Liss, Inc.