Alterations in maternal plasma corticosterone levels following treatment with phenytoin.
The mechanisms of the embryotoxic effects of the anticonvulsant drug, phenytoin (PHT), are unknown. Glucocorticoids and PHT demonstrate similar embryopathic effects and strain sensitivity in that A/J mice are very sensitive to the embryopathic effects of synthetic glucocorticoids and PHT while C57BL/6 (B6) mice are comparatively resistant to both. It is possible that teratogenic consequences of PHT are not a result of drug interaction at the target site but are mediated indirectly by glucocorticoids. In this study, PHT was administered by intraperitoneal injection at 25 (a nonteratogenic dose) or 75 mg/kg body weight (a teratogenic dose) to pregnant A/J mice on Day 10 of gestation. Mice of the B6 strain received the drug at 75 mg/kg on Day 10. Control mice received vehicle (pH 11.0 distilled water). Dams were killed at various times after the injection; plasma samples were obtained, and corticosterone levels were determined by radioimmunoassay. In control animals, maternal plasma corticosterone levels were elevated soon after dosing but gradually declined, except for an apparent circadian rhythm effect seen in samples obtained in the afternoon. Administration of a nonteratogenic dose of PHT to A/J mice caused a temporary increase in plasma corticosterone levels which decreased to the control level between 6 and 24 hr following dosing. Treatment with a teratogenic dose in A/J mice led to plasma levels that remained elevated for the entire 48-hr period examined in this study. In B6 mice, treatment with 75 mg/kg increased plasma corticosterone levels for 24 hr, after which they declined to the control value by 30 hr. The adrenal corticosteroid response of A/J mice to PHT appeared to be much more sensitive than that of B6 mice, and there appeared to be a relationship between plasma levels of PHT and corticosterone. The lengthy increase in plasma corticosterone during organogenesis may be a factor in the increased incidence of cleft lip and palate seen after administration of PHT to A/J mice.
Hansen
D K
DK
Division of Reproductive and Developmental Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079.
Holson
R R
RR
Sullivan
P A
PA
Grafton
T F
TF
D000818:Animals; D003345:Corticosterone / Q000097:blood*; D005260:Female; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D010672:Phenytoin / Q000097:blood / Q000494:pharmacology*; D011247:Pregnancy; D011863:Radioimmunoassay
D010672:Phenytoin; D003345:Corticosterone