PMID- 9895216
OWN - NLM
STAT- MEDLINE
DCOM- 19990331
LR  - 20220409
IS  - 0891-5849 (Print)
IS  - 0891-5849 (Linking)
VI  - 26
IP  - 3-4
DP  - 1999 Feb
TI  - Maternal administration of superoxide dismutase and catalase in phenytoin 
      teratogenicity.
PG  - 266-74
AB  - 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.
FAU - Winn, L M
AU  - Winn LM
AD  - Faculty of Pharmacy, University of Toronto, Ontario, Canada.
FAU - Wells, P G
AU  - Wells PG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Anticonvulsants)
RN  - 0 (Reactive Oxygen Species)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - 6158TKW0C5 (Phenytoin)
RN  - EC 1.11.1.6 (Catalase)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 1.15.1.1 (polyethylene glycol-superoxide dismutase)
SB  - IM
MH  - *Abnormalities, Drug-Induced
MH  - Analysis of Variance
MH  - Animals
MH  - Anticonvulsants/*toxicity
MH  - Catalase/*therapeutic use
MH  - Female
MH  - *Maternal-Fetal Exchange
MH  - Mice
MH  - Phenytoin/antagonists & inhibitors/*toxicity
MH  - Polyethylene Glycols/*therapeutic use
MH  - Pregnancy
MH  - Reactive Oxygen Species/metabolism
MH  - Superoxide Dismutase/*therapeutic use
EDAT- 1999/01/23 00:00
MHDA- 1999/01/23 00:01
CRDT- 1999/01/23 00:00
PHST- 1999/01/23 00:00 [pubmed]
PHST- 1999/01/23 00:01 [medline]
PHST- 1999/01/23 00:00 [entrez]
AID - S0891-5849(98)00193-2 [pii]
AID - 10.1016/s0891-5849(98)00193-2 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 1999 Feb;26(3-4):266-74. doi: 10.1016/s0891-5849(98)00193-2.