Abstract
We previously reported the possible role of a reactive metabolite in phenytoin (DPH) teratogenic injury (Ped Res 16:131A, 1982). We now report data obtained to test the hypothesis that cellular thiols (T), including glutathione (GSH, may play a protective role in DPH-induced tissue injury. In vitro DPH covalent binding (CB) to fetal liver and placenta microsomes from AJ mice (a strain highly susceptible to DPH teratogenesis) was 91 and 73 pmols/mg protein, respectively. By contrast, DPH in vitro CB to liver microsomes from a single human male fetus (14 weeks gestation, weight 465 grams, spontaneous abortion) and to microsomes from two term placentas was 707 and 44 pmols/mg protein, respectively. Addition of T (GSH, cysteine) or T generator (methylthiazolidine) decreased DPH in vitro CB by 50%. Quantitative measurement by HPLC with on-line radiochemical detection of DPH metabolites (dihydrodiol, catechol, methoxycatechol, para-hydroxyDPH (p-HPPH), meta-hydroxyDPH) in the microsomal mixtures treated with GSH revealed increased dihydrodiol and p-HPPH.
These data demonstrate that: 1. human fetal liver microsomes activate DPH to a reactive intermediate, 2. the human fetus metabolizes DPH, and 3. cellular T decreases DPH in vitro CB. We conclude that the human fetus has the metabolic machinery to generate a reactive intermediate that may be responsible for DPH teratogenic injury.
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Snodgrass, W., Roy, D. SHUNTING OF PHENYTOIN IN VITRO METABOLIC ACTIVATION BY GLUTATHIONE TO LESS REACTIVE METABOLITES: ANIMAL AND HUMAN FETAL TISSUE. Pediatr Res 21 (Suppl 4), 242 (1987). https://doi.org/10.1203/00006450-198704010-00447
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DOI: https://doi.org/10.1203/00006450-198704010-00447