Objectives: Phenytoin (diphenylhydantoin; DPH) is a well-known anti-epileptic drug, and 90% of DPH is metabolized to 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) by CYP2C9, a subtype of cytochrome P450 microsomal enzyme, in human liver. Oral administration of DPH induces gingival overgrowth as a side effect in human, but the mechanism of this phenomenon remains yet unclear. The purpose of this study was to clarify the mechanism of human gingival overgrowth induced by DPH. Methods: We incubated the cultured human gingival fibroblast (HGF) cells for 24 or 48 hours with 0.39 to 50mg/ml of DPH or HPPH, then the number of HGF was measured by MTT method. After incubation of HGF cells for 72 hours with DPH or HPPH, specific activity of type 1 collagen was measured by RIA. And after incubation of HGF cells for 48 hours with DPH or HPPH, specific activity of b-fibroblast growth factor (bFGF) was measured by ELISA. Results: With increasing concentrations of HPPH, the number of HGF increased at 24 and 48 hours, whereas the number of HGF was not significantly changed at any concentrations of DPH. Although specific activity of type 1 collagen was not significantly different between with DPH and with HPPH, specific activity of bFGF was higher with HPPH than with DPH. Conclusion: Our results suggest that HPPH, the major metabolite of DPH in human, induced gingival overgrowth possibly by increasing bFGF activity for the most part in HGF culture cells.

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