Clinical and experimental studies linking oxidative metabolism to phenytoin-induced teratogenesis.
The research presented in this article concerns the proposed mechanism of phenytoin-induced teratogenicity that focuses on oxidative metabolites as sources of reactive species in clinical studies and by testing paradigms in animal models. The clinical aspect involved determining whether at-risk fetuses could be detected prenatally on the basis of low or deficient epoxide hydrolase activity. In 19 pregnancies monitored by amniocentesis, we predicted an adverse outcome in four infants on the basis of low enzyme activity. When examined neonatally, all four infants had the dysmorphic features of the "fetal hydantoin syndrome." In an animal model of phenytoin-induced teratogenesis, the level of fetal exposure to oxidative metabolites was decreased by coadministration of the cytochrome P-450-inhibiting antiepileptic drug stiripentol, which significantly reduced the incidence of phenytoin-induced congenital malformations in two of the three inbred mouse strains, thus providing support for the hypothesis that oxidative metabolites are critical in mediating phenytoin teratogenesis.
Finnell
R H
RH
Program in Genetics and Cell Biology, College of Veterinary Medicine, Washington State University, Pullman.
Buehler
B A
BA
Kerr
B M
BM
Ager
P L
PL
Levy
R H
RH
D000014:Abnormalities, Drug-Induced / Q000378:metabolism*; D000650:Amnion / Q000166:cytology; D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects* / Q000494:pharmacology; D001835:Body Weight; D004148:Dioxolanes / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000378:metabolism*; D005260:Female; D005315:Fetal Diseases / Q000378:metabolism*; D005333:Fetus / Q000033:anatomy & histology / Q000201:enzymology; D006801:Humans; D006827:Hydantoins; D051379:Mice; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000378:metabolism*; D010672:Phenytoin / Q000009:adverse effects* / Q000378:metabolism; D011247:Pregnancy / Q000378:metabolism; D013577:Syndrome
D000927:Anticonvulsants; D004148:Dioxolanes; D006827:Hydantoins; D010672:Phenytoin; D004851:Epoxide Hydrolases; C021092:stiripentol