Previous animal research has suggested that the
phenytoin arene
oxide metabolite is teratogenic in acute studies and that the fetal effects were increased after injecting an inhibitor of
microsomal epoxide hydrolase (mEH) (Martz et al., Pharmacol Exp Ther 203:231-239, 1977, Barcellona et al., Teratog Carcinog
Mutagen 7:159-168, 1987). We have studied the effects of chronic oral
phenytoin exposure in utero and the mEH inhibitor
trichloropropene oxide (TCPO) on the prenatal growth and development of an inbred mouse strain with a low incidence of spontaneous oral clefting (C57BL/6J). Chronic daily gastric gavage of
phenytoin produced a plasma level (mean 10.7 micrograms/ml on gestation Day 8) within the range recommended to prevent
epilepsy in humans; this did not produce an increase in oral clefting or
ventricular septal defects in the exposed C57BL/6J pups. It did produce a significant delay in prenatal growth and development, including phalangeal ossification. However, except for percentage resorptions/implantation, there was no synergism between
phenytoin and TCPO in contrast to the finding reported by Martz et al. in Swiss mice. This issue was also assessed in a test of the fetal effect of
phenytoin injected with TCPO, as had been done by Martz et al. There were no oral clefts or
ventricular septal defects or a difference (P > 0.05) in prenatal growth and development in these C57BL/6J pups compared to the chronic gastric
phenytoin plus TCPO group. This suggests either that differences in the genotypes of Swiss and C57BL/6J mice may be a contributing factor or that other teratogenic mechanisms were involved.