The effect of Phenytoin (DPH) on the Conversion of Testosterone(T) to Dihydrotestosterone (DHT) in vitro

Abstract

Diminished or absent virilization of male external genitalia is an occasional feature of the fetal hydantoin syndrome. We have studied the effect of DPH on the conversion of 14C-testosterone to its 5α reduced metabolites in skin of male infants. Neonatal foreskins obtained at circumcision were incubated for two hours with 14C-testosterone in buffer, with glucose, penicillin, and supra-pharmacological concentrations of DPH. Using thin layer chromatography, the incubation mixture was assayed for T and androstenedione plus the 5α reduced metabolites, DHT, androstanedione, androstanediol, and androsterone. Testosterone metabolites formed were expressed as nanomoles/100 mg tissue/hour with and without DPH. There was a significant nonlinear decrease in the amount of both DHT and total 5α reduced metabolites formed with increasing amounts of DPH, with minimal production at 4,400 nanomoles of DPH. This result was comparable to that obtained under identical experimental conditions following addition of progesterone, a known 5α reductase inhibitor. These in vitro results may explain the mechanism of abnormal phenotypic sexual differentiation of the male fetus exposed to DPH in utero.