A lower
microsomal epoxide hydrolase (mEH) activity has been associated with increased likelihood of
fetal hydantoin syndrome. While
phenytoin anticonvulsive regimens are long-term, there are no data regarding induction of mEH by chronic
phenytoin exposure. Two inbred mouse strains which differ in their susceptibility (A/J > C57BL/6J) to
phenytoin-induced oral clefting were treated with an oral gavage of
phenytoin for 14 consecutive days. The mice were sacrificed on the 15th day, and hepatic microsomes were prepared. mEH activity was determined using
benzo[a]pyrene-4,5-
oxide. The
dihydrodiol product was separated by HPLC and quantified. There was no significant difference (P = 0.15) in the
phenytoin plasma level between the two strains on Day 15. There was no significant difference (P = 0.07) between control and
sham control groups within each strain, so they were combined for further analysis. There was a significant strain difference (P = 0.0001) between the control and
phenytoin-exposed group means, with the C57BL/6J strain having the greater activity before and after
phenytoin exposure. The A/J
phenytoin-exposed group activity was 51% higher (P = 0.01) than the A/J control, while the C57BL/6J
phenytoin-exposed group activity was 78% higher (P = 0.001) than the C57BL/6J control. The greater mEH activity in the
phenytoin-induced clefting resistant strain (C57BL/6J) before and after
phenytoin exposure is consistent with a putative oxidative metabolism mechanism of
phenytoin teratogenecity. Chronic
phenytoin exposure induced mEH activity in both strains, although the strain with the greater
enzyme activity prior to the exposure continued to have the greater activity following induction.