title: Maternal administration of superoxide dismutase and catalase in phenytoin teratogenicity.
abstract: Embryonic bioactivation and formation of reactive oxygen species (ROS) are implicated in the mechanism of phenytoin teratogenicity. This in vivo study in pregnant CD-1 mice evaluated whether maternal administration of the antioxidative enzymes superoxide dismutase (SOD) and/or catalase conjugated with polyethylene glycol (PEG) could reduce phenytoin teratogenicity. Initial studies showed that pretreatment with PEG-SOD alone (0.5-20 KU/kg i.p. 4 or 8 h before phenytoin) actually increased the teratogenicity of phenytoin (65 mg/kg i.p. on gestational days [GD] 11 and 12, or 12 and 13) (p < .05), and appeared to increase embryonic protein oxidation. Combined pretreatment with PEG-SOD and PEG-catalase (10 KU/kg 8 or 12 h before phenytoin) was not embryo-protective, nor was PEG-catalase alone, although PEG-catalase alone reduced phenytoin-initiated protein oxidation in maternal liver (p < .05). However, time-response studies with PEG-catalase (10 KU/kg) on GDs 11, or 11 and 12, showed maximal 50-100% increases in embryonic activity sustained for 8-24 h after maternal injection (p < .05), and dose-response studies (10-50 KU/kg) at 8 h showed maximal respective 4-fold and 2-fold increases in maternal and embryonic activities with a 50 KU/kg dose (p < .05). In controls, embryonic catalase activity was about 4% of that in maternal liver, although with catalase treatment, enhanced embryonic activity was about 2% of enhanced maternal activity (p < .05). PEG-catalase pretreatment (10-50 KU/kg 8 h before phenytoin) also produced a dose-dependent inhibition of phenytoin teratogenicity, with maximal decreases in fetal cleft palates, resorptions and postpartum lethality at a 50 KU/kg dose (p < .05). This is the first evidence that maternal administration of PEG-catalase can substantially enhance embryonic activity, and that in vivo phenytoin teratogenicity can be modulated by antioxidative enzymes. Both the SOD-mediated enhancement of phenytoin teratogenicity, and the inhibition of phenytoin teratogenicity by catalase, indicate a critical role for ROS in the teratologic mechanism, and the teratologic importance of antioxidative balance.
authors.affiliation: Faculty of Pharmacy, University of Toronto, Ontario, Canada.
authors.forename: L M
authors.initials: LM
authors.lastname: Winn
authors.forename: P G
authors.initials: PG
authors.lastname: Wells
mesh_terms: D000014:Abnormalities, Drug-Induced; D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D002374:Catalase / Q000627:therapeutic use*; D005260:Female; D008431:Maternal-Fetal Exchange; D051379:Mice; D010672:Phenytoin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011247:Pregnancy; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D017382:Reactive Oxygen Species; D011092:Polyethylene Glycols; D010672:Phenytoin; D002374:Catalase; D013482:Superoxide Dismutase; C063471:polyethylene glycol-superoxide dismutase