Epileptics on chronic phenytoin (PHT, 5,5-diphenylhydantoin) therapy frequently experience a toxic reaction to the drug, PHT-induced gingival overgrowth (GO), in approximately 50% of the population. The lesion is characterized by an increase in the connective tissue substance of the gingivae, which is postulated to occur by stimulation of gingival fibroblasts by PHT and its metabolites. The lesion also predisposes """"""""responders"""""""" to the drug to an increased likelihood of gingival inflammation and infection. The proposed studies will examine pediatric epileptic patients on PHT therapy and attempt to correlate drug metabolism parameters with the incidence and severity of gingival overgrowth. The theory that the presence of enzyme-inducing co-medications increases the incidence of GO will be examined. Gas chromatographic and high-pressure liquid chromatographic (HPLC) methods will be used to assay the number, types, and stereochemistry of PHT metabolites, particularly the phenolic (p-HPPH) and dihydrodiol (DHD) metabolites, as these are derived from potentially toxic arene oxide intermediates. Temporal changes in gingival overgrowth and PHT metabolism will be studied as patients progress in the study. A second portion of the study will examine the cytotoxic or mitogenic effects of p-HPPH and DHD stereoisomers on cultured human gingival fibroblasts in vitro. Metabolism of 14C-PHT by gingival fibroblasts will be examined with the use of HPLC techniques. The gingival fibroblast studies will provide additional information as to how PHT metabolites, generated in situ by fibroblast metabolism of PHT, or absorbed from the blood stream, exert their effects to cause a proliferation similar to that observed in vivo. The pediatric study will provide PHT metabolism data in responders and non-responders and will attempt to correlate differences in susceptibility to the actions of PHT metabolites in vitro. 0f the pediatric study confirms the increased incidence of gingival overgrowth with enzyme-inducing antiepileptic co-medication, recommendations for antiepileptic therapies utilizing PHT could be made such that a lower incidence of GO would result.
