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Cited by 18Oral and gingival health researchOral Health Pathology and TreatmentDrug-Induced Adverse Reactions

An Update on the Mechanisms of Phenytoin Induced Gingival Overgrowth

Open access
Farook, Fathima Fazrina, M. Nizam, Mohamed Nuzaim, Alshammari, Abdulsalam·2019·The Open Dentistry Journal
DOI 10.2174/1874210601913010430
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Abstract

Background: Phenytoin induced gingival overgrowth, a side effect with multifactorial aetiology, is characterized by an increase in the volume of extracellular tissues, particularly collagenous components, with varying degrees of inflammation. Objective: The aim of this paper is to review the available literature regarding the pathophysiological mechanisms of phenytoin induced gingival overgrowth. Methods: A thorough literature search of the PubMed/ Embase/ Web of science/ Cochrane central database was conducted to identify the mechanisms involved in the process of phenytoin-induced gingival overgrowth using the following keywords: Phenytoin; Anticonvulsant; Gingival Overgrowth; Gingival Enlargement, Gingival Hyperplasia; Drug Induced Gingival Enlargement; Drug Induced Gingival Overgrowth Results: According to the available evidence, several mechanisms have been proposed addressing the pathophysiological mechanism of phenytoin induced gingival overgrowth both at a cellular and molecular level. Evidence suggests that the inflammatory changes in the gingival tissues orchestrate the interaction between phenytoin and fibroblasts particularly resulting in an increase in the extracellular matrix content. Conclusion: However, the mechanism of production of inflammatory mediators is not fully understood. This, together with the high prevalence of Phenytoin induced gingival overgrowth, warrants further research in this area in order to develop treatment and preventive strategies for the management of this condition.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review summarizes proposed cellular and molecular mechanisms of phenytoin-induced gingival overgrowth, emphasizing inflammatory changes that alter phenytoin–fibroblast interactions and increase extracellular matrix content. It concludes that the production of inflammatory mediators is not fully understood and that further research is needed to develop treatment and preventive strategies.

Key findings

  • Phenytoin-induced gingival overgrowth is multifactorial; evidence suggests inflammatory changes in gingival tissues orchestrate the interaction between phenytoin and fibroblasts, particularly increasing extracellular matrix content.
  • Proposed mechanisms include TGF-β/CTGF signaling, MMP/TIMP-1 imbalance, reduced collagen phagocytosis via integrins, local folate deficiency, androgen metabolism, epithelial–mesenchymal transition, altered apoptosis, and TRPA1/TRPV1 calcium signaling.
  • Phenytoin, cyclosporine, and calcium channel blockers account for 50%, 30%, and 10–20% of drug-induced gingival overgrowth, respectively; salivary secretion of unbound phenytoin is 10% of the level in blood.
  • The review concludes that the mechanism of inflammatory mediator production is not fully understood and that no treatment or prevention exists for management of this condition.

Methods

  • Narrative review based on a literature search of PubMed/Embase/Web of Science/Cochrane Central database using keywords: Phenytoin; Anticonvulsant; Gingival Overgrowth; Gingival Enlargement; Gingival Hyperplasia; Drug Induced Gingival Enlargement; Drug Induced Gingival Overgrowth, with no time or language restriction.
  • No primary data or sample; the paper synthesizes available evidence on cellular and molecular mechanisms.
  • Main analysis is a narrative synthesis of proposed pathophysiological mechanisms; no quantitative meta-analysis is described.

Limitations

  • Stated: the trigger mechanisms are inconclusive, the mechanism of production of inflammatory mediators is not fully understood, and there is no treatment or prevention for the condition.
  • Stated: prevalence figures vary significantly by population and do not take severity of overgrowth into account.
  • Evident from the text: as a narrative review, it does not describe systematic inclusion/exclusion criteria, quality appraisal, or quantitative synthesis, and it presents no primary data to validate the proposed mechanisms.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.2174/1874210601913010430

Cites

75 of 75 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

15 of 67 cited sources checked · 1 supported · 1 flagged · accuracy not yet measured

  • Premisereasoning
    § 2. MECHANISMS OF PHENYTOIN GINGIVAL OVERGROWTH · p. 3

    Phenytoin decreases MMP-1 by increasing the expression of TIMP-1.

    “The result is that phenytoin decreases the MMP-1 by increasing the expression of TIMP-1.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [44] Kato T, Okahashi N, Kawai S, et al. Impaired degradation of matrix collagen in human gingival fibroblasts by the antiepileptic drug phenytoin. J Periodontol 2005; 76 (6) : 941-50. source
    • cites [49] Ganesh PR. Immunoexpression of interleukin-6 in drug-induced gingival overgrowth patients. Contemp Clin Dent 2016; 7 (2) : 140-5. source

      The References section names a study reporting that phenytoin suppresses expression of both MMP-1 and TIMP-1, contrary to the claimed increase in TIMP-1. The Discussion attributes increased TIMP production to IL-6, not directly to phenytoin, and says it has no effect on MMP secretion. No page numbers are available in our copy. (LLM, conf=0.84)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [50] Vizovišek M, Fonović M, Turk B. Cysteine cathepsins in extracellular matrix remodeling: Extracellular matrix degradation and beyond. Matrix Biol 2019; 75-76 : 141-59. source
  • Premisecitation
    § The Open Dentistry Journal · p. 2

    Phenytoin is known to cause folate deficiencies locally or systemically.

    “Phenytoin is known to cause folate deficiencies locally or systemically.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [4] Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: A unifying hypothesis. Oral Dis 2015; 21 (1) : e51-61. source

      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
  • Premisecitation
    § 2. MECHANISMS OF PHENYTOIN GINGIVAL OVERGROWTH · p. 2

    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].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [4] Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: A unifying hypothesis. Oral Dis 2015; 21 (1) : e51-61. source
  • Premisecitation
    § The Open Dentistry Journal · p. 2

    These organisms produce established dental plaque biofilms that aggravate the inflammatory process.

    “These organisms produce established dental plaque biofilms aggravating the inflammatory process [28, 29].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [28] Karimzadeh I, Namazi S, Borhani-Haghighi A, Khosropanah H. Phenytoin-induced gingival over growth: A review. Soc Pharmacy J 2015; 1 (1)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [29] Trackman PC, Kantarci A. Molecular and clinical aspects of drug-induced gingival overgrowth. J Dent Res 2015; 94 (4) : 540-6. source

      The Introduction discusses inflammation in drug-induced gingival overgrowth, but does not connect it to organisms producing dental plaque biofilms. Searches for plaque, biofilm, bacteria, and microbial causes found no passage in our copy addressing that relationship; page numbers were not available. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
  • Premisecitation
    § 2. MECHANISMS OF PHENYTOIN GINGIVAL OVERGROWTH · p. 3

    Reduced AP-1 activates TIMP-1 gene expression.

    “Reduced AP-1 activates the TIMP-1 gene expression.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [44] Kato T, Okahashi N, Kawai S, et al. Impaired degradation of matrix collagen in human gingival fibroblasts by the antiepileptic drug phenytoin. J Periodontol 2005; 76 (6) : 941-50. source
    • cites [49] Ganesh PR. Immunoexpression of interleukin-6 in drug-induced gingival overgrowth patients. Contemp Clin Dent 2016; 7 (2) : 140-5. source

      The Discussion (page unavailable) says IL-6 increases TIMP production by fibroblasts, but it does not discuss AP-1 or activation of TIMP-1 gene expression. Searches for reduced AP-1 and for AP-1-mediated TIMP regulation found no passage addressing that mechanism in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [50] Vizovišek M, Fonović M, Turk B. Cysteine cathepsins in extracellular matrix remodeling: Extracellular matrix degradation and beyond. Matrix Biol 2019; 75-76 : 141-59. source
  • May combine two claims. 18
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Premisecitation
    § The Open Dentistry Journal · p. 2

    Gingival tissue is in a constant state of injury and repair, resulting in an increase in chemical mediators such as cytokines, chemokines and an abundance of inflammatory cells.

    “their Gingival tissue is in a constant state of injury and repair. This results in an increase in chemical mediators such as cytokines, chemokines and an abundance of inflammatory cells [28, 29].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [28] Karimzadeh I, Namazi S, Borhani-Haghighi A, Khosropanah H. Phenytoin-induced gingival over growth: A review. Soc Pharmacy J 2015; 1 (1)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [29] Trackman PC, Kantarci A. Molecular and clinical aspects of drug-induced gingival overgrowth. J Dent Res 2015; 94 (4) : 540-6. source

      The Introduction (page unavailable) describes inflammation and changes in inflammatory-cell populations in gingival tissue, particularly in drug-induced overgrowth. It does not say that gingival tissue is constantly undergoing injury and repair, or that this process increases cytokines, chemokines and inflammatory cells. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § 2. MECHANISMS OF PHENYTOIN GINGIVAL OVERGROWTH · p. 2

    CTGF is a known producer of fibrosis and increases proliferation of fibroblasts due to mitogenic, angiogenic and chemotactic activities.

    “CTGF is a known producer of fibrosis. It also increases the proliferation of fibroblasts due to its mitogenic, angiogenic and chemotactic activities [36].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] Gonzalez AC, Costa TF, Andrade ZA, Medrado AR. Wound healing - A literature review. An Bras Dermatol 2016; 91 (5) : 614-20. source

      The Proliferative Stage describes fibroblast proliferation, and the Remodeling Stage discusses fibrosis, but neither attributes these effects to CTGF. Searches for CTGF, connective tissue growth factor, and CCN2 found no passage in our copy addressing CTGF’s proposed fibrogenic, mitogenic, angiogenic, or chemotactic activities. Page numbers were not available in the indexed passages. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § 2. MECHANISMS OF PHENYTOIN GINGIVAL OVERGROWTH · p. 3

    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].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [4] Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: A unifying hypothesis. Oral Dis 2015; 21 (1) : e51-61. source

      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

  • May combine two claims.

    Premisecitation
    § 2. MECHANISMS OF PHENYTOIN GINGIVAL OVERGROWTH · p. 3

    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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [4] Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: A unifying hypothesis. Oral Dis 2015; 21 (1) : e51-61. source

      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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § REFERENCES · p. 4

    Phenytoin treatment decreases the proportion of apoptotic cells in gingival fibroblasts compared to a serum-free control culture.

    “The role of phenytoin in death receptor-induced apoptosis of gingival fibroblasts has been explored in a laboratory study suggesting that phenytoin treatment decreases the proportion of apoptotic cells in gingival fibroblasts compared to a serum-free control culture.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [75] Kasai H, Allen JT, Mason RM, Kamimura T, Zhang Z. TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res 2005; 6 : 56. source

      The Methods (Cell culture; page unavailable) describe serum-free culture of A549 alveolar epithelial cells, and the Results (siRNA-mediated Smad2 gene silencing; page unavailable) concern TGF-β1-induced EMT. Searches for phenytoin, gingival fibroblasts, death receptor-induced apoptosis, and apoptotic-cell proportions found no passage addressing the claimed comparison. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § 1. INTRODUCTION · p. 1

    'Gingival hyperplasia' is a misnomer because enlargement is an increase in extracellular tissue volume and not an increase in the number of cells.

    “Nevertheless, 'gingival hyperplasia' is a misnomer as enlargement is rather an increase in extracellular tissue volume and not an increase in the number of cells [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Newman MG, Takei HH, Klokkevold PR, Carranza FA. Carranza’s Clinical Periodontology 11th ed. 2012; 118-30.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § 2. MECHANISMS OF PHENYTOIN GINGIVAL OVERGROWTH · p. 2

    Gingival overgrowth is due to an increase in extracellular matrix content or an increase in the number of cells or both.

    “Gingival overgrowth, the enlargement of gingival tissues, is due to an increase in the Extracellular Matrix (ECM) content or increase in the number of cells or both1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Gittaboyina S, Mana TK, Koduganti RR, Reddy PV. Amlodipine induced gingival enlargement. J Oral Res Rev 2016; 8 (1) : 23. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § 1. INTRODUCTION · p. 1

    Gingival overgrowth is a well-known and established side effect of phenytoin.

    “Gingival overgrowth is a well-known and established side effect of phenytoin [13 - 15].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Grusovin MG. The treatment of periodontal diseases in elderly patients. Oral rehabilitation for compromised and elderly patients 2019; 29-47. source
    • cites [14] Fabiana CM, Frederick SR, Xavier M. Side Effects of phenytoin in the oral cavity: A review. J Oral Health Dent Sci 2018; 2 : 104.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [15] Doufexi A, Mina M, Ioannidou E. Gingival overgrowth in children: Epidemiology, pathogenesis, and complications. A literature review. J Periodontol 2005; 76 (1) : 3-10. source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given
    § 2. MECHANISMS OF PHENYTOIN GINGIVAL OVERGROWTH · p. 2

    In gingival tissue, the effects of TGF-β are mainly via CTGF.

    “In the gingival tissue, the effects of TGF-β are mainly via CTGF.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § The Open Dentistry Journal · p. 2

    Phenytoin in saliva is absorbed or diffused via the sulcular epithelium into the serum, causing a double exposure to phenytoin via systemic circulation and saliva reabsorption.

    “Phenytoin in the saliva is absorbed or diffused via the sulcular epithelium into the serum causing a double exposure to phenytoin via two pathways, mainly from the systemic circulation and partly from the reabsorption pathway of the saliva.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Man Y, Hart VJ, Ring CJ, Sanjar S, West MR. Loss of epithelial integrity resulting from E-cadherin dysfunction predisposes airway epithelial cells to adenoviral infection. Am J Respir Cell Mol Biol 2000; 23 (5) : 610-7. source

  • May combine two claims.

    Interpretationreasoning
    § 2. MECHANISMS OF PHENYTOIN GINGIVAL OVERGROWTH · p. 2

    Phenytoin enhances IL-13 secretion, thus TGF-β expression and produces its active form.

    “Phenytoin enhances IL-13 secretion, thus TGF-β expression and produces its active form.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 2. MECHANISMS OF PHENYTOIN GINGIVAL OVERGROWTH · p. 2

    The immune system can be stimulated by phenytoin via induction of lymphoid overgrowth and cell-mediated immunological reaction via IL-1β, TNFα, IL-6, IL-8 and medullasin.

    “The immune system could be stimulated by the drug phenytoin via mechanisms including the induction of lymphoid overgrowth and cell-mediated immunological reaction via interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNFα), IL-6 and IL-8 and also medullasin [ 31].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Morand DN, Davideau JL, Clauss F, Jessel N, Tenenbaum H, Huck O. Cytokines during periodontal wound healing: Potential application for new therapeutic approach. Oral Dis 2017; 23 (3) : 300-11. source

  • May combine two claims.

    Premisecitation
    § The Open Dentistry Journal · p. 2

    The prevalence of drug induced gingival overgrowth varies significantly and depends upon the population being investigated.

    “However, the prevalence varies significantly and depends upon the population being investigated [ 21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Growth factors and cytokines in wound healing. Wound Repair Regen 2008; 16 (5) : 585-601. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § The Open Dentistry Journal · p. 2

    Phenytoin, cyclosporine and calcium channel blockers account for 50%, 30% and 10-20% of drug induced gingival overgrowth, respectively.

    “In terms of prevalence, phenytoin, cyclosporine and calcium channel blockers account for 50%, 30% and 10-20% of drug induced gingival overgrowth, respectively [13, 19, 20].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Grusovin MG. The treatment of periodontal diseases in elderly patients. Oral rehabilitation for compromised and elderly patients 2019; 29-47. source
    • cites [19] Saleem S, Verma S, Yousuf I, Wani MA, Asmi R. Diphenylhydantoin induced severe gingival hyperplasia. JMS SKIMS 2017; 20 (1) : 44-6. source
    • cites [20] Taleghani F, Sheikhnejad H, Shidfar S, Hamzelouie E, Zohri Z. Drug induced gingival enlargement. J Chem Pharmaceutic Res 2016; 8 (1) : 439-46.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given
    § 2. MECHANISMS OF PHENYTOIN GINGIVAL OVERGROWTH · p. 2

    The occurrence of fibrosis requires both TGF-β and CTGF.

    “The occurrence of fibrosis requires both TGF-β and Connective Tissue Growth Factor (CTGF).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 2. MECHANISMS OF PHENYTOIN GINGIVAL OVERGROWTH · p. 3

    Phenytoin reduces intracellular folic acid and induces production of mediators such as TGF-β and TNF-α.

    “Phenytoin reduces intracellular folic acid and induces the production of mediators such as TGF-β and TNF-α [ 45].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Fugii A, Kobayashi S. Nifedipine inhibits calcium uptake of nifedipine-sensitive gingival fibroblast. J Dent Res 1990; 67 : 332.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § 2. MECHANISMS OF PHENYTOIN GINGIVAL OVERGROWTH · p. 2

    TGF-β acts mainly on fibroblasts and endothelial cells and results in collagen and matrix synthesis.

    “It acts mainly on fibroblasts and endothelial cells and results in collagen and matrix synthesis [ 33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Nickel J, Ten Dijke P, Mueller TD. TGF-β family co-receptor function and signaling. Acta Biochim Biophys Sin (Shanghai) 2018; 50 (1) : 12-36. source

  • May combine two claims.

    Premisecitation
    § 2. MECHANISMS OF PHENYTOIN GINGIVAL OVERGROWTH · p. 2

    Cathepsins and MMPs release LAP from TGF-β and activate TGF-β.

    “Cathepsins and Matrix Metalloproteinases (MMPs) release the LAP from TGF- β and activate TGF-β [35].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Uzel MI, Kantarci A, Hong HH, et al. Connective tissue growth factor in drug-induced gingival overgrowth. J Periodontol 2001; 72 (7) : 921-31. source

  • May combine two claims.

    Premisecitation
    § REFERENCES · p. 4

    Phenytoin does not augment the proliferative rate of HGFs whereas it induces extracellular matrix accumulation of collagen.

    “Further, phenytoin did not augment the proliferative rate of HGFs whereas it induced extracellular matrix accumulation of collagen [72].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] López-González MJ, Luis E, Fajardo O, et al. TRPA1 channels mediate human gingival fibroblast response to phenytoin. J Dent Res 2017; 96 (7) : 832-9. source

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given
    § CONCLUSION · p. 4

    The mechanism of production of inflammatory mediators is not fully understood.

    “However, the mechanism of the production of inflammatory mediators is not fully understood.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § 2. MECHANISMS OF PHENYTOIN GINGIVAL OVERGROWTH · p. 3

    EP-3 receptors are found in gingival fibroblasts but not in lung or kidney fibroblasts.

    “EP-3 receptors are found in gingival fibroblasts but not in lung or kidney fibroblasts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § REFERENCES · p. 4

    TRPA1, TRPV1 and TRPV1b are expressed in human gingival fibroblasts, in which phenytoin increases intracellular calcium levels by acting on these ion channels.

    “The calcium-permeable ion channels TRPA1 [74], Transient receptor potential channels, of the vanilloid subtype (TRPV1), and its capsaicin-insensitive isoform TRPV1b are expressed in Human Gingival Fibroblasts (HGFs), in which phenytoin increase the intracellular calcium levels by acting on the mentioned ion channels [ 72].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] López-González MJ, Luis E, Fajardo O, et al. TRPA1 channels mediate human gingival fibroblast response to phenytoin. J Dent Res 2017; 96 (7) : 832-9. source

  • May combine two claims.

    Premisecitation
    § 2. MECHANISMS OF PHENYTOIN GINGIVAL OVERGROWTH · p. 3

    Phenytoin acts on macrophages, enhancing production of IL-1β, which enhances expression of COX-2 through NF-κB.

    “Phenytoin acts on macrophages, enhancing the production of IL-1β, which enhances the expression of Cyclooxygenase 2 (COX-2) through the transcription factor (nuclear factorkappaB [NF-κB].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Man Y, Hart VJ, Ring CJ, Sanjar S, West MR. Loss of epithelial integrity resulting from E-cadherin dysfunction predisposes airway epithelial cells to adenoviral infection. Am J Respir Cell Mol Biol 2000; 23 (5) : 610-7. source

  • May combine two claims.

    Premisecitation
    § 2. MECHANISMS OF PHENYTOIN GINGIVAL OVERGROWTH · p. 3

    PGE-2 acts on EP-3 receptors in fibroblasts and enhances TGF-β1 stimulation of JNK-MAP kinase pathway of CTGF expression.

    “PGE-2 acts on EP-3 receptors in fibroblasts and enhances the TGF-β1 stimulation of JNK -MAP kinase pathway of CTGF expression [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Man Y, Hart VJ, Ring CJ, Sanjar S, West MR. Loss of epithelial integrity resulting from E-cadherin dysfunction predisposes airway epithelial cells to adenoviral infection. Am J Respir Cell Mol Biol 2000; 23 (5) : 610-7. source
24 of 24

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting explanations of whether cell numbers increase in gingival overgrowth

    Major

    The introduction says gingival enlargement is not an increase in the number of cells, but the mechanisms section says an increase in cell numbers can cause gingival overgrowth.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 5

  1. Ahmed R, Sharma A, Halawa A. Post-transplant gingival hyperplasia: A brief review. J Renal Transplant Sci 2019; 2 (2) : 85-90.
  2. Nagata T, Ninomiya M, Mihara C, Kido J, Nishikawa S, Kataoka M. Etiology of drug-induced gingival overgrowth. Curr Issu Periodontics 2016; 7 : 37-44.
  3. Karimzadeh I, Namazi S, Borhani-Haghighi A, Khosropanah H. Phenytoin-induced gingival over growth: A review. Soc Pharmacy J 2015; 1 (1)
  4. Iman K, Soha N, Afshin BH, et al. Phenytoin-induced gingival over growth: A review soc. Pharm J 2015; 1 (1) e827
  5. Fugii A, Kobayashi S. Nifedipine inhibits calcium uptake of nifedipine-sensitive gingival fibroblast. J Dent Res 1990; 67 : 332.

Cited by

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Related

Authors
Farook, F. F., M. Nizam, M. N., & Alshammari, A.
Affiliations
King Saud bin Abdulaziz University for Health Sciences (SA)
ORCID
Farook, Fathima Fazrina
Venue
The Open Dentistry Journal
Publisher
Bentham Science Publishers Ltd.
Published
2019-12-31
Volume
13
Issue
1
Pages
430-435
ISSN
1874-2106 (ISSN-L)
DOI
10.2174/1874210601913010430
OpenAlex
W2998682265
Semantic Scholar
4d9e9bb12015212876aeaa7d93597230d71d9c39
Cited by
18
References
75
Citations by year
2026: 2 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 3
FWCI
2.52
Type
journal article
Language
en
Open access
Licence
Locations
The Open Dentistry Journal (publishedVersion, cc-by)
Funders
King Abdullah International Medical Research Center
Topics
  • Health Sciences › Health Professions › Pharmacy › Oral and gingival health research
  • Health Sciences › Dentistry › Periodontics › Oral Health Pathology and Treatment
  • Health Sciences › Medicine › Pharmacology › Drug-Induced Adverse Reactions
Keywords
phenytoin, drug-induced gingival hyperplasia, gingival hyperplasia, antiepileptic drugs, gingivitis, fibroblasts, extracellular matrix, collagen, inflammatory mediators, pathophysiological mechanisms

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-12.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-12.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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