Since 1938, when phenytoin (PHT, Dilantin) entered the market as an antiepileptic drug, it was observed that one of its side effects was gingival overgrowth. Our major objective is to investigate the mechanism of action of PHT in this regard. Clinically, there are indications that PHT mimics the effects of sex steroid hormones. Therefore, we propose to evaluate whether PHT or a PHT analog or any of four PHT metabolites inhibit or stimulate the binding of androgen or estrogen to their respective steroid hormone receptors in target tissues such as uterus, prostate, mammary gland and gingiva. If either stimulation or inhibition is documented, we will then determine the concentration of specific binding sites. Also, we propose to characterize the receptor-PHT complex using sucrose density gradient analysis. Finally, we shall prepare cytosol and nuclei from cultured human gingival fibroblasts derived from normal and PHT-enlarged gingivae, and evaluate the binding of PHT, its analog and metabolites in this in vitro system. Successful completion of these studies will yeild significant new knowledge not only with regard to the pathogenesis of PHT-induced gingival overgrowth and its apparent limitation to pubertal and post-pubertal young persons, but would also provide additional insight into steroid binding in sex target tissues.
