Teratogenicity, oxidative metabolism

As with carbamazepine, phenytoin also causes idiosyncratic toxic effects, including hematological and connective tissue toxicities, hepatotoxicity, and teratogenicity (89). Although some of these toxicities have been hypothesized to be caused by P450 oxidative metabolism (92,93) or peroxidase-mediated reactions (94,95), mechanisms for these toxic effects in humans are unknown. 

It has been proposed that metabolic activation of diphenylhydantoin may be responsible for the teratogenicity. After the administration of radioactively labeled diphenylhydantoin to pregnant mice, radioactive drug or a metabolite was found to be covalently bound to protein in the embryo. It was shown that both the teratogenicity and embryolethality of diphenylhydantoin could be increased by using an inhibitor of epoxide hydrolase (see chap. 4), trichloropropene oxide. Similarly, the covalent binding of radiolabeled diphenylhydantoin to protein was also increased by this treatment. 

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