The in vitro bioactivation of phenytoin will be studied by 1) a cytochrome P-450 system and 2) peroxidative metabolism to an arene oxide and subsequent detoxification of the arene oxide by 1) hydrolysis to the dihydrodiol by epoxide hydrolase, 2) glutathione conjugation by GSH transferase(s) and 3) non-enzymic conversion of the arene oxide to 5-(p-hydroxy phenyl)-(p-HPPH) and subsequent glucuronide conjugation with UDP-glucuronic acid using appropriate subcellular fractions from A/J and C57BL/6J mouse fetal tissue. These findings will then be applied to study the effect of phenytoin metabolism by fetal tissue upon the incidence of cleft lip an A/J and C57BL/6J mouse embryo cultures. Scanning electronmicrographs and 3-dimensional computer reconstructions from histological cross-sections will be analyzed.
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