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.

The heat shock response: potential to screen teratogens.

The embryonic stress hypothesis of teratogenesis suggests that a proportion of all human congenital defects is due to a failure in essential gene transcription along with translational pre-emption by the heat shock response (HSR). We sought to determine the potential usefulness of the murine HSR to screen agents suspected of being human teratogens. The teratogenic potential of a selected group of known teratogenic (hyperthermia, insulin, retinoic acid and valproic acid) or non-teratogenic (cycloheximide, dinitrophenol and tetracycline) agents were administered to pregnant SWV mice at critical periods of neural tube closure. Following exposure to either teratogenic doses or at the highest dose possible that did not induce maternal toxicity for those compounds that were not teratogenic, the induction of heat shock protein (hsp) synthesis and changes in total protein synthesis were determined in lymphocytes isolated from murine spleens. The varied results obtained in these studies cast doubt on the value of the murine HSR to screen teratogens.