Metabolism of phenytoin by the gingiva of normal humans: The possible role of reactive metabolites of phenytoin in the initiation of gingival hyperplasia

Ling Xiang Zhou, Bruce Pihlstrom, James P. Hardwick, Sang S. Park, Steven A. Wrighton, Jordan L. Holtzman

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Gingival hyperplasia is a well-known complication of therapy with cyclosporine, calcium channel blockers, and phenytoin. It is characterized by the presence of inflammation and a marked fibrotic response. The mechanism of this adverse reaction is unknown. We propose that it may be initiated by the metabolic activation of these drugs to form reactive metabolites. These then cause cellular injury and lead to the gingival hyperplasia. To evaluate this hypothesis we examined phenytoin metabolism and the cytochrome P450 contents of gingival tissues from 10 patients undergoing surgery for various periodontal conditions. We found that microsomes obtained from the gingiva show significant phenytoin hydroxylase activity as determined by the production of 5-(4'-hydroxyphenyl)-5-phenylhydantoin (HPPH) (range, 12.8 pmol HPPH/min · mg microsomal protein to 276.9 pmol HPPH/min · mg microsomal protein; rat control, 133.7 ± 11.5 pmol HPPH/min · mg microsomal protein). We also found that CYP1A1, CYP1A2, CYP2C9, CYP2E1, and CYP3A4 were present in these microsomes. We detected no CYP2B6 or CYP2D6. We believe that these data support our hypothesis that the proliferative inflammation observed with drugs such as phenytoin, nifedipine, and cyclosporine may be initiated by the formation of reactive metabolites and that the formation of these metabolites may be catalyzed by one or more CYPs found in the gingiva. These metabolites may then cause cellular injury and induce a reactive inflammatory response, followed by fibroblastic proliferation. This proliferation leads to the execes collagen deposition observed with gingival hyperplasia.

Original languageEnglish (US)
Pages (from-to)191-198
Number of pages8
JournalClinical pharmacology and therapeutics
Volume60
Issue number2
DOIs
StatePublished - Aug 1 1996
Externally publishedYes

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