Phenytoin metabolism by gingiva from normal humans

Gingival hyperplasia, a complication of cyclosporine A, Ca²⁺ channel blocker and phenytoin therapy, is characterized by inflammation and fibrosis. We propose that it may be initiated by the metabolism of these drugs to reactive metabolites causing cellular injury and thereby inducing gingival hyperplasia. To evaluate this hypothesis we examined phenytoin metabolism and cytochrome P450 (CYP) content of gingival microsomes from 10 patients undergoing periodontal surgery. We found that the microsomes had phenytoin hydroxylase activity as determined by 5-(4'-hydroxy-phenyl)-5-phenylhydantoin (HPPH) formation (range = 12.8 to 276.9 pmol HPPH/min-mg prot; rat liver control = 133.7 ± 11.5 pmol HPPH/min-mg prot). CYP1A1, 1A2, 2C9, 2E1 and 3A4 were present but no CYP2B6 or 2D6. We feel that these data support our hypothesis that the proliferation seen with these drugs may be initiated by the local formation of reactive metabolites which cause cellular injury leading to the inflammatory response and fibroblastic proliferation.