Maternal administration of superoxide dismutase and catalase in phenytoin teratogenicity.
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.
Winn
L M
LM
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Wells
P G
PG
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*
D000927:Anticonvulsants; D017382:Reactive Oxygen Species; D011092:Polyethylene Glycols; D010672:Phenytoin; D002374:Catalase; D013482:Superoxide Dismutase; C063471:polyethylene glycol-superoxide dismutase