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Cited by 97Oral and gingival health researchOral Health Pathology and TreatmentOral microbiology and periodontitis research

Mechanism of drug‐induced gingival overgrowth revisited: a unifying hypothesis

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Brown, RS, Arany, PR·2015·Oral Diseases
DOI 10.1111/odi.12264PMC PMC5241888
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Abstract

Drug‐induced gingival overgrowth (DIGO) is a disfiguring side effect of anti‐convulsants, calcineurin inhibitors, and calcium channel blocking agents. A unifying hypothesis has been constructed which begins with cation flux inhibition induced by all three of these drug categories. Decreased cation influx of folic acid active transport within gingival fibroblasts leads to decreased cellular folate uptake, which in turn leads to changes in matrix metalloproteinases metabolism and the failure to activate collagenase. Decreased availability of activated collagenase results in decreased degradation of accumulated connective tissue which presents as DIGO. Studies supporting this hypothesis are discussed.

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  • Cation-dependent active cellular intake of folic acid is impaired by phenytoin, which can result in systemic and localized folate deficiency in gingival tissue.

    “The cation dependent active cellular intake of folic acid is impaired by phenytoin [4]. This can result in a systemic and localized folate deficiency in the gingival tissue.”

    From An Update on the Mechanisms of Phenytoin Induced Gingival Overgrowth (2019) · cites this paper as [4]

    The Introduction’s “Folate cellular uptake” section links phenytoin metabolism to reactive oxygen species that decrease folate uptake and proposes reduced uptake in gingival fibroblasts. It does not establish that phenytoin directly impairs cation-dependent folate intake; it says direct phenytoin exposure could increase uptake. The same section discusses localized deficiency even when serum folate is normal, so it does not support the claimed systemic deficiency. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Phenytoin is known to cause folate deficiencies locally or systemically.

    “Phenytoin is known to cause folate deficiencies locally or systemically.”

    From An Update on the Mechanisms of Phenytoin Induced Gingival Overgrowth (2019) · cites this paper as [4]

    The Introduction’s “Folate cellular uptake” section discusses a proposed local folate deficiency in drug-induced gingival overgrowth and suggests that phenytoin-related processes could reduce folate uptake in gingival fibroblasts. It does not establish that phenytoin is known to cause folate deficiency, and the passages do not support the systemic-deficiency alternative. Page numbers were not available in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Folic acid requirement depends on tissue and is higher in some tissues including gingival tissues, which can result in local folate deficiency despite normal serum folate levels.

    “Folic acid requirement depends on the type of tissue and is higher in some tissues including gingival tissues. This can result in local folate deficiency despite normal serum folate levels [ 4].”

    From An Update on the Mechanisms of Phenytoin Induced Gingival Overgrowth (2019) · cites this paper as [4]

    The Introduction’s “Folate cellular uptake” section says folic acid requirements may differ among tissues and that localized deficiency may occur despite normal serum folate. It does not establish that gingival tissue specifically has a higher requirement; the Discussion notes that studies characterizing folate uptake in gingival fibroblasts are lacking. The claim also states as fact what the paper presents as a possibility. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Phenytoin-induced folate deficiency can cause degenerative changes in gingival epithelium.

    “As a result, phenytoin induced folate deficiency can cause degenerative changes in gingival epithelium.”

    From An Update on the Mechanisms of Phenytoin Induced Gingival Overgrowth (2019) · cites this paper as [4]

    The Introduction proposes that phenytoin can reduce folate uptake in gingival fibroblasts, contributing to impaired breakdown of gingival connective tissue. It does not say that folate deficiency causes degenerative changes in the gingival epithelium. No page number was available for the indexed passage. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Inflammatory mediators play a major role in altering the expression of genes related to gingival overgrowth.

    “Inflammatory mediators play a major role in altering the expression of the genes related to gingival overgrowth [ 4].”

    From An Update on the Mechanisms of Phenytoin Induced Gingival Overgrowth (2019) · cites this paper as [4]

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Authors
Brown, R., & Arany, P.
Affiliations
  • National Institutes of Health (US)
  • NIDCR/NIH Bethesda MD USA
Corresponding author
Brown, RS
Venue
Oral Diseases
Publisher
Wiley
Published
2014-08-07
Volume
21
Issue
1
Pages
e51-61
ISSN
  • 1354-523X (ISSN-L)
  • 1601-0825
DOI
10.1111/odi.12264
PMC
PMC5241888
OpenAlex
W2046826803
Cited by
97
References
0
Citations by year
2026: 7 · 2025: 3 · 2024: 11 · 2023: 8 · 2022: 9 · 2021: 10 · 2020: 16 · 2019: 11 · 2018: 5 · 2017: 8 · 2016: 3 · 2015: 5 · 2014: 1
FWCI
1.14
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Oral Diseases (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Howard (Howard University) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute of Dental and Craniofacial Research (ZIADE000741)
Topics
  • Health Sciences › Health Professions › Pharmacy › Oral and gingival health research
  • Health Sciences › Dentistry › Periodontics › Oral Health Pathology and Treatment
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
Keywords
drug-induced gingival hyperplasia, antiepileptic drugs, calcineurin inhibitors, calcium channel blockers, folate uptake, gingival fibroblasts, matrix metalloproteinases, collagenase activation, connective tissue degradation, unifying hypothesis
MeSH terms
Animals, Anticonvulsants, Calcium Channel Blockers, Gingiva, Humans, Models, Biological, Gingival Overgrowth, Calcineurin Inhibitors

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