INDUCTION OF MICROSOMAL EPOXIDE HYDROLASE ACTIVITY IN INBRED MICE BY CHRONIC PHENYTOIN EXPOSURE

A lower microsomal epoxide hydrolase (mEH) activity has been associate d with increased likelihood of fetal hydantoin syndrome. While phenyto in anticonvulsive regimens are long-term, there are no data regarding induction of mEH by chronic phenytoin exposure. Two inbred mouse strai ns which differ in their susceptibility (A/J > C57BL/6J) to phenytoin- induced oral clefting were treated with an oral gavage of phenytoin fo r 14 consecutive days. The mice were sacrificed on the 15th day, and h epatic microsomes were prepared. mEH activity was determined using ben zo[a]pyrene-4,5-oxide. The dihydrodiol product was separated by HPLC a nd quantified. There was no significant difference (P = 0.15) in the p henytoin plasma level between the two strains on Day 15. There was no significant difference (P = 0.07) between control and sham control gro ups within each strain, so they were combined for further analysis. Th ere was a significant strain difference (P = 0.0001) between the contr ol and phenytoin-exposed group means, with the C57BL/6J strain having the greater activity before and after phenytoin exposure. The A/J phen ytoin-exposed group activity was 51% higher (P = 0.01) than the A/J co ntrol, while the C57BL/6J phenytoin-exposed group activity was 78% hig her (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 meta bolism mechanism of phenytoin teratogenecity. Chronic phenytoin exposu re induced mEH activity in both strains, although the strain with the greater enzyme activity prior to the exposure continued to have the gr eater activity following induction. (C) 1995 Academic Press, Inc.