Stimulation and inhibition of fibroblast subpopulations by phenytoin and phenytoin metabolites: pathogenetic role in gingival enlargement

Functional heterogeneity exists among fibroblasts in gingiva. There is remarkable variation in the protein synthetic activities, the proliferative capacities and the drug-response potentials of various subpopulations of such cells. These functional differences may play a role in the pathogenesis of phenytoin-induced gingival enlargement, as subpopulation mixtures are altered by conditions within the connective tissue milieu. This could result from stimulation of a subpopulation(s) characterized by elevated collagen synthesis or, alternatively, from inhibition of a subpopulation(s) characterized by low growth and synthetic potential. Phenytoin and its metabolic breakdown products are present in significant quantity in the gingivae ofphenytointreated patients. Data collected in our laboratory and by other investigators indicate that direct stimulatory or inhibitory action of phenytoin or a metabolite upon gingival fibroblast subpopulations is a factor in the pathogenesis of phenytoin-induced gingival enlargement. Experimental data indicate that rapidly-dividing cell subpopulations are sensitive to phenytoin, while quiescent subpopulations are not.The major metabolite of phenytoin in man is 5-para-hydroxyphenyl-5phenylhydantoin (pHPPH). Addition ofpHPPHto quiescent human gingival fibroblasts did not alter protein synthetic rates, nor was proliferation enhanced, nor were any cells killed by the treatment. However, pHPPH added to rapidly proliferating cells caused significant inhibition of replication in some strains.