Effect of phenytoin medication on the metabolism of epidermal growth factor receptor in cultured gingival fibroblasts

Human gingival fibroblasts derived from 2 patients before and 9 months after the start of phenytoin (PHT) therapy were studied with respect to the effect of epidermal growth factor (EGF) on the incorporation of 3H-thymidine into DNA, binding of EGF to its cell-surface receptor, internalization of EGF-receptor-ligand complexes and, finally, with respect to EGF receptor mRNA levels. In fibroblasts derived from the patient who developed gingival overgrowth during the PHT medication (responder) as well as in the fibroblasts derived from the patient where gingival overgrowth did not develop (non-responder), the affinity of the EGF receptor for EGF was not significantly changed. In the non-responder patient the internalization of EGF receptor ligand was decreased, whereas it was increased in the fibroblasts derived from the responder patient after PHT therapy. The steady-state level of EGF-r mRNA increased significantly (p < 0.001) in the cultured fibroblasts derived from the non-responder but decreased (p < 0.05) in the responder patient following PHT therapy. Ligand affinity cross-linking studies revealed one major component of EGF receptor with a molecular weight of 170 KDa in fibroblasts from the non-responder as well as from the responder. The study indicates that PHT medication results in a down-regulation of EGF receptor metabolism in fibroblasts derived from a responder patient, whereas in the non-responder patient EGF receptor metabolism is up-regulated.