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 ant ioxidative enzymes superoxide dismutase (SOD) and/or catalase conjugated wi th polyethylene glycol (PEG) could reduce phenytoin teratogenicity. Initial studies showed that pretreatment with PEG-SOD alone (0.5-20 KU/kg IP 4 or 8 h before phenytoin) actually increased the teratogenicity of phenytoin (6 5 mg/kg LP on gestational days [GD] 11 and 12, or 12 and 13) (p < .05), and appeared to increase embryonic protein oxidation. Combined pretreatment wi th PEG-SOD and PEG-catalase (10 KU/kg 8 or 12 h before phenytoin) was not e mbryo-protective, nor was PEG-catalase alone, although PEG-catalase alone r educed phenytoin-initiated protein oxidation in maternal liver (p < .05). H owever, time-response studies with PEG-catalase (10 KU/kg) on GDs II, or 11 and 12, showed maximal 50-100% increases in embryonic activity sustained f or 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 m aternal and embryonic activities with a 50 KU/kg dose (p < .05). In control s, embryonic catalase activity was about 4% of that in maternal liver, alth ough with catalase treatment, enhanced embryonic activity was about 2% of e nhanced maternal activity (p < .05). PEG-catalase pretreatment (10-50 KU/kg 8 h before phenytoin) also produced a dose-dependent inhibition of phenyto in teratogenicity, with maximal decreases in fetal cleft palates, resorptio ns and postpartum lethality at a 50 KU/kg dose (p < .05). This is the first evidence that maternal administration of PEG-catalase can substantially en hance embryonic activity, and that in vivo phenytoin teratogenicity can be modulated by antioxidative enzymes. Both the SOD-mediated enhancement of ph enytoin teratogenicity, and the inhibition of phenytoin teratogenicity by c atalase, indicate a critical role for ROS in the teratologic mechanism, and the teratologic importance of antioxidative balance. (C) 1998 Elsevier Sci ence Inc.