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

Title

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

Creator

Zhou L X; Pihlstrom B; Hardwick J P; Park S S; Wrighton S A; Holtzman J L

Publisher

Clinical Pharmacology & Therapeutics

Date

1996
1996-08

Description

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 excess collagen deposition observed with gingival hyperplasia.

Subject

clinical report; cyclosporine-a; cytochrome P450; enlargement; hepatotoxicity; microsomes; monoclonal-antibodies; overgrowth; Pharmacology & Pharmacy; proteins; severity

Format

Journal Article

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Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

191-198

Issue

2

Volume

60

Citation

Zhou L X; Pihlstrom B; Hardwick J P; Park S S; Wrighton S A; Holtzman J L, “Metabolism of phenytoin by the gingiva of normal humans: The possible role of reactive metabolites of phenytoin in the initiation of gingival hyperplasia,” NEOMED Bibliography Database, accessed March 5, 2021, https://neomed.omeka.net/items/show/7657.

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