The Open Dentistry Journal




ISSN: 1874-2106 ― Volume 14, 2020
REVIEW ARTICLE

An Update on the Mechanisms of Phenytoin Induced Gingival Overgrowth



Fathima Fazrina Farook1, 2, *, Mohamed Nuzaim M. Nizam3, Abdulsalam Alshammari1, 2
1 Department of Preventive Dental Science, College of Dentistry, King Saud Bin Abdul Aziz University for Health Sciences, Riyadh, Saudi Arabia
2 King Abdullah International Medical Research Centre, Riyadh, Saudi Arabia
3 Department of Obstetrics and Gynecology, University of Malaya, Kuala Lumpur, Malaysia

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.

Keywords: Anticonvulsant, Gingival overgrowth, Gingival enlargement, Phenytoin, Drug induced gingival enlargement, Drug induced gingival overgrowth.


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 13
First Page: 430
Last Page: 435
Publisher Id: TODENTJ-13-430
DOI: 10.2174/1874210601913010430

Article History:

Received Date: 08/09/2019
Revision Received Date: 13/10/2019
Acceptance Date: 16/11/2019
Electronic publication date: 31/12/2019
Collection year: 2019

© 2019 Farook et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at Department of Preventive Dental Science, King Saud Bin Abdulaziz University for Health Sciences, 11426 Riyadh, Saudi Arabia / King Abdullah International Medical Research Centre, Riyadh, Saudi Arabia; E-mail: fazrinaf@ksau-hs.edu.sa





1. INTRODUCTION

Gingival Enlargement (GE) or Gingival Overgrowth (GO) is a clinical condition that alters the position of the gingival margin and comprises an increase in the size of the gingiva [1Gittaboyina S, Mana TK, Koduganti RR, Reddy PV. Amlodipine induced gingival enlargement. J Oral Res Rev 2016; 8(1): 23.
[http://dx.doi.org/10.4103/2249-4987.182486]
]. GO was previously described as hypertrophic gingivitis or gingival hyperplasia. 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 [2Newman MG, Takei HH, Klokkevold PR, Carranza FA. Carranza’s Clinical Periodontology 11th ed. 2012; 118-30.]. It may be caused due to plaque induced inflammatory conditions, medications [3Ahmed R, Sharma A, Halawa A. Post-transplant gingival hyperplasia: A brief review. J Renal Transplant Sci 2019; 2(2): 85-90., 4Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: A unifying hypothesis. Oral Dis 2015; 21(1): e51-61.
[http://dx.doi.org/10.1111/odi.12264] [PMID: 24893951]
], hereditary causes and systemic diseases [5Al Sharrad A, Said KN, Farook FF, et al. Awareness of the relationship between systemic and periodontal diseases among physicians and dentists in Saudi Arabia and Kuwait: Cross-sectional Study. Open Dent J 2019; 13: 288-95.
[http://dx.doi.org/10.2174/1874210601913010288]
-7Beaumont J, Chesterman J, Kellett M, Durey K. Gingival overgrowth: Part 1: Aetiology and clinical diagnosis. Br Dent J 2017; 222(2): 85-91.
[http://dx.doi.org/10.1038/sj.bdj.2017.71] [PMID: 28127024]
].

Medication induced gingival overgrowth, is an unwanted side effect of systemic medication on periodontal tissues [7Beaumont J, Chesterman J, Kellett M, Durey K. Gingival overgrowth: Part 1: Aetiology and clinical diagnosis. Br Dent J 2017; 222(2): 85-91.
[http://dx.doi.org/10.1038/sj.bdj.2017.71] [PMID: 28127024]
]. It was reported in the early 1960’s in dental literature and is sometimes referred to as “Drug Induced Gingival enlargement or Overgrowth” or “DIGO” [7Beaumont J, Chesterman J, Kellett M, Durey K. Gingival overgrowth: Part 1: Aetiology and clinical diagnosis. Br Dent J 2017; 222(2): 85-91.
[http://dx.doi.org/10.1038/sj.bdj.2017.71] [PMID: 28127024]
, 8Kulkarni AV, Kini R, Rao PK, Bhandarkar GP, Kashyap RR. Drug induced gingival enlargement: Dentist’s dilemma. Cukurova Med J 2018; 43(3): 722-5.
[http://dx.doi.org/10.17826/cumj.397485]
]. The three drugs most frequently implicated are phenytoin, calcium channel blockers such as nifedipine [9Nishikawa S, Nagata T, Morisaki I, Oka T, Ishida H. Pathogenesis of drug-induced gingival overgrowth. A review of studies in the rat model. J Periodontol 1996; 67(5): 463-71.
[http://dx.doi.org/10.1902/jop.1996.67.5.463] [PMID: 8724703]
], amlodipine, and verapamil [10Murakami S, Mealey BL, Mariotti A, Chapple ILC. Dental plaque-induced gingival conditions. J Clin Periodontol 2018; 45(Suppl. 20): S17-27.
[http://dx.doi.org/10.1111/jcpe.12937] [PMID: 29926503]
] and lastly, an immune-suppressant, cyclosporine [11Ponnaiyan D, Jegadeesan V, Cyclosporine A. Cyclosporine A: Novel concepts in its role in drug-induced gingival overgrowth. Dent Res J (Isfahan) 2015; 12(6): 499-506.
[http://dx.doi.org/10.4103/1735-3327.170546] [PMID: 26759584]
, 12Nagata T, Ninomiya M, Mihara C, Kido J, Nishikawa S, Kataoka M. Etiology of drug-induced gingival overgrowth. Curr Issu Periodontics 2016; 7: 37-44.]. Gingival overgrowth is a well-known and established side effect of phenytoin [13Grusovin MG. The treatment of periodontal diseases in elderly patients.Oral rehabilitation for compromised and elderly patients 2019; 29-47.
[http://dx.doi.org/10.1007/978-3-319-76129-9_3]
-15Doufexi A, Mina M, Ioannidou E. Gingival overgrowth in children: Epidemiology, pathogenesis, and complications. A literature review. J Periodontol 2005; 76(1): 3-10.
[http://dx.doi.org/10.1902/jop.2005.76.1.3] [PMID: 15830631]
]. Other drugs for example sodium valproate [16Suneja B, Chopra S, Thomas AM, Pandian J. A clinical evaluation of gingival overgrowth in children on antiepileptic drug therapy. J Clin Diagn Res 2016; 10(1): ZC32-6.
[http://dx.doi.org/10.7860/JCDR/2016/16443.7069] [PMID: 26894172]
] and erythromycin [17Samudrala P, Chava VK, Chandana TS, Suresh R. Drug-induced gingival overgrowth: A critical insight into case reports from over two decades. J Indian Soc Periodontol 2016; 20(5): 496-502.
[http://dx.doi.org/10.4103/jisp.jisp_265_15] [PMID: 29242684]
] have been implicated in case reports, but the occurrence is rare [18Dongari-Bagtzoglou A. Research, science and therapy committee, american academy of periodontology. Drug-associated gingival enlargement. J Periodontol 2004; 75(10): 1424-31.
[http://dx.doi.org/10.1902/jop.2004.75.10.1424] [PMID: 15562922]
].

In terms of prevalence, phenytoin, cyclosporine and calcium channel blockers account for 50%, 30% and 10-20% of drug induced gingival overgrowth, respectively [13Grusovin MG. The treatment of periodontal diseases in elderly patients.Oral rehabilitation for compromised and elderly patients 2019; 29-47.
[http://dx.doi.org/10.1007/978-3-319-76129-9_3]
, 19Saleem S, Verma S, Yousuf I, Wani MA, Asmi R. Diphenylhydantoin induced severe gingival hyperplasia. JMS SKIMS 2017; 20(1): 44-6.
[http://dx.doi.org/10.33883/jms.v20i1.311]
, 20Taleghani F, Sheikhnejad H, Shidfar S, Hamzelouie E, Zohri Z. Drug induced gingival enlargement. J Chem Pharmaceutic Res 2016; 8(1): 439-46.]. However, the prevalence varies significantly and depends upon the population being investigated [21Barrientos 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.
[http://dx.doi.org/10.1111/j.1524-475X.2008.00410.x] [PMID: 19128254]
]. The stated figures do not take into account the severity of the overgrowth. Various risk factors have been identified for drug induced gingival overgrowth, such as age (children and teenagers) [15Doufexi A, Mina M, Ioannidou E. Gingival overgrowth in children: Epidemiology, pathogenesis, and complications. A literature review. J Periodontol 2005; 76(1): 3-10.
[http://dx.doi.org/10.1902/jop.2005.76.1.3] [PMID: 15830631]
], demographic variables, drug variables, periodontal variables [22Angelopoulos AP, Goaz PW. Incidence of diphenylhydantoin gingival hyperplasia. Oral Surg Oral Med Oral Pathol 1972; 34(6): 898-906.
[http://dx.doi.org/10.1016/0030-4220(72)90228-9] [PMID: 4509004]
], genetic factors and concomitant medication [23Farook FF, Said KN. A review of the effectiveness of antiseptic mouth rinses for oral health. J Oral Hyg Health 2018; 6: 246.
[http://dx.doi.org/10.4172/2332-0702.1000246]
].

Phenytoin, introduced in 1938, is now an established and effective treatment of acute repetitive seizures, partial-onset and generalized tonic-clonic seizures and status epilepticus [24Corrêa JD, Queiroz-Junior CM, Costa JE, Teixeira AL, Silva TA. Phenytoin-induced gingival overgrowth: A review of the molecular, immune, and inflammatory features. ISRN Dent 2011; 2011
[http://dx.doi.org/10.5402/2011/497850]
]. Phenytoin was later used as an antiarrhythmic drug in cardiology [25Bigger JT Jr, Schmidt DH, Kutt H. Relationship between the plasma level of diphenylhydantoin sodium and its cardiac antiarrhythmic effects. Circulation 1968; 38(2): 363-74.
[http://dx.doi.org/10.1161/01.CIR.38.2.363] [PMID: 5666850]
]. However, currently, its usage as antiarrhythmic purpose is abandoned, but still reserves their importance in the treatment of epilepsy [24Corrêa JD, Queiroz-Junior CM, Costa JE, Teixeira AL, Silva TA. Phenytoin-induced gingival overgrowth: A review of the molecular, immune, and inflammatory features. ISRN Dent 2011; 2011
[http://dx.doi.org/10.5402/2011/497850]
, 26Guldiken B, Rémi J, Noachtar S. Cardiovascular adverse effects of phenytoin. J Neurol 2016; 263(5): 861-70.
[http://dx.doi.org/10.1007/s00415-015-7967-1] [PMID: 26645393]
].

Considering the fact that it is a major first-line antiepileptic drug (AED) in the treatment of partial and secondarily generalized seizures, it is important to know the mechanisms of phenytoin induced gingival overgrowth in order to minimize the occurrence of this adverse effect. A comprehensive understanding of the pathogenesis of this unwanted side effect is mandatory to develop suitable regimens for its management [23Farook FF, Said KN. A review of the effectiveness of antiseptic mouth rinses for oral health. J Oral Hyg Health 2018; 6: 246.
[http://dx.doi.org/10.4172/2332-0702.1000246]
, 27Mavrogiannis M, Ellis JS, Thomason JM, Seymour RA. The management of drug-induced gingival overgrowth. J Clin Periodontol 2006; 33(6): 434-9.
[http://dx.doi.org/10.1111/j.1600-051X.2006.00930.x] [PMID: 16677333]
].

As of now, in the literature several studies have aimed to ascertain the pathogenesis of drug-induced GO. However, the trigger mechanisms for such conditions are yet inconclusive. Therefore, the aim of this work was to revisit the most relevant studies published about phenytoin-induced gingival overgrowth and outline the possible mechanisms associated with this condition.

A 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 with no time or language restriction.

2. MECHANISMS OF PHENYTOIN INDUCED GINGIVAL OVERGROWTH

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. Increase in the ECM content could be due to increased production or reduced degradation or a combination. An increase in the number of cells may be due to increased proliferation or reduced apoptosis or both. In gingival overgrowth, the expression of genes related to these mechanisms are either increased or decreased. Inflammatory mediators play a major role in altering the expression of the genes related to gingival overgrowth [4Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: A unifying hypothesis. Oral Dis 2015; 21(1): e51-61.
[http://dx.doi.org/10.1111/odi.12264] [PMID: 24893951]
]. Some studies have shown that phenytoin decreases the production of ECM and therefore decreases collagen synthesis [28Karimzadeh I, Namazi S, Borhani-Haghighi A, Khosropanah H. Phenytoin-induced gingival over growth: A review. Soc Pharmacy J 2015; 1(1)], confirmed by a reduction in mRNA expression of type I and type III collagen. It is evident that gingival overgrowth is due to the impairment in the balance between synthesis and degradation of ECM [20Taleghani F, Sheikhnejad H, Shidfar S, Hamzelouie E, Zohri Z. Drug induced gingival enlargement. J Chem Pharmaceutic Res 2016; 8(1): 439-46., 28Karimzadeh I, Namazi S, Borhani-Haghighi A, Khosropanah H. Phenytoin-induced gingival over growth: A review. Soc Pharmacy J 2015; 1(1)]. Phenytoin enhances the production of inflammatory mediators [29Trackman PC, Kantarci A. Molecular and clinical aspects of drug-induced gingival overgrowth. J Dent Res 2015; 94(4): 540-6.
[http://dx.doi.org/10.1177/0022034515571265] [PMID: 25680368]
]. Salivary secretion of unbound phenytoin is 10% of the level in the blood. In addition, dental plaque contains phenytoin and its primary metabolite, the para-hydroxyl form [2Newman MG, Takei HH, Klokkevold PR, Carranza FA. Carranza’s Clinical Periodontology 11th ed. 2012; 118-30.]. A high concentration of phenytoin and lower tissue levels of the para-hydroxyl metabolite increases the severity of the gingival overgrowth [2Newman MG, Takei HH, Klokkevold PR, Carranza FA. Carranza’s Clinical Periodontology 11th ed. 2012; 118-30.].

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. Thus, gingival sulcular tissue is more susceptible to the effects of phenytoin causing gingival overgrowth [30Man 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.
[http://dx.doi.org/10.1165/ajrcmb.23.5.4046] [PMID: 11062139]
]. However, currently, the sources and the mechanisms of the production of inflammatory mediators in the gingival overgrowth tissues are unclear [30Man 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.
[http://dx.doi.org/10.1165/ajrcmb.23.5.4046] [PMID: 11062139]
].

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 [28Karimzadeh I, Namazi S, Borhani-Haghighi A, Khosropanah H. Phenytoin-induced gingival over growth: A review. Soc Pharmacy J 2015; 1(1), 29Trackman PC, Kantarci A. Molecular and clinical aspects of drug-induced gingival overgrowth. J Dent Res 2015; 94(4): 540-6.
[http://dx.doi.org/10.1177/0022034515571265] [PMID: 25680368]
]. Another possible mechanism is phenytoin related stimulation in the growth of microorganisms such as Bacteroides, actinomyces, Prevotella intermedia, Porphyromonas gingivalis and Treponema denticola and fusiform bacteria [28Karimzadeh I, Namazi S, Borhani-Haghighi A, Khosropanah H. Phenytoin-induced gingival over growth: A review. Soc Pharmacy J 2015; 1(1)]. These organisms produce established dental plaque biofilms aggravating the inflammatory process [28Karimzadeh I, Namazi S, Borhani-Haghighi A, Khosropanah H. Phenytoin-induced gingival over growth: A review. Soc Pharmacy J 2015; 1(1), 29Trackman PC, Kantarci A. Molecular and clinical aspects of drug-induced gingival overgrowth. J Dent Res 2015; 94(4): 540-6.
[http://dx.doi.org/10.1177/0022034515571265] [PMID: 25680368]
]. The abundant inflammatory mediators contribute to the gingival overgrowth. Phenytoin is known to cause folate deficiencies locally or systemically. Folate is necessary for many vital cellular functions such as nucleic acid metabolism and cell proliferation. As a result, phenytoin induced folate deficiency can cause degenerative changes in gingival epithelium. Degenerative materials induce an inflammatory response [4Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: A unifying hypothesis. Oral Dis 2015; 21(1): e51-61.
[http://dx.doi.org/10.1111/odi.12264] [PMID: 24893951]
].

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 (TNF-α), IL-6 and IL-8 and also medullasin [31Morand 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.
[http://dx.doi.org/10.1111/odi.12469] [PMID: 26945691]
]. The mediator medullasin activates the inflammatory response via modulating cytokines [31Morand 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.
[http://dx.doi.org/10.1111/odi.12469] [PMID: 26945691]
].

IL-13 induces the expression of TGF-β, which is a cytokine found in high concentrations in platelets, macrophages, neutrophils, and fibroblasts [32Seymour RA, Ellis JS, Thomason JM. Risk factors for drug-induced gingival overgrowth. J Clin Periodontol 2000; 27(4): 217-23.
[http://dx.doi.org/10.1034/j.1600-051x.2000.027004217.x] [PMID: 10783833]
, 33Nickel J, Ten Dijke P, Mueller TD. TGF-β family co-receptor function and signaling. Acta Biochim Biophys Sin (Shanghai) 2018; 50(1): 12-36.
[http://dx.doi.org/10.1093/abbs/gmx126] [PMID: 29293886]
]. It acts mainly on fibroblasts and endothelial cells and results in collagen and matrix synthesis [33Nickel J, Ten Dijke P, Mueller TD. TGF-β family co-receptor function and signaling. Acta Biochim Biophys Sin (Shanghai) 2018; 50(1): 12-36.
[http://dx.doi.org/10.1093/abbs/gmx126] [PMID: 29293886]
]. This cytokine is maintained in the inactive form by binding non-covalently to a protein called Latency-Associated Protein (LAP) and stored within the cell as a homodimer [34Mohan V, Talmi-Frank D, Arkadash V, Papo N, Sagi I. Matrix metalloproteinase protein inhibitors: Highlighting a new beginning for metalloproteinases in medicine. Metalloprot Med 2016; 3: 31.
[http://dx.doi.org/10.2147/MNM.S65143]
]. Cathepsins and Matrix Metalloproteinases (MMPs) release the LAP from TGF- β and activate TGF-β [35Uzel MI, Kantarci A, Hong HH, et al. Connective tissue growth factor in drug-induced gingival overgrowth. J Periodontol 2001; 72(7): 921-31.
[http://dx.doi.org/10.1902/jop.2001.72.7.921] [PMID: 11495141]
]. IL-13 also increases the expression of MMP-2, MMP-9 and cathepsins [38Mittal R, Patel AP, Debs LH, et al. Intricate functions of matrix metalloproteinases in physiological and pathological conditions. J Cell Physiol 2016; 231(12): 2599-621.
[http://dx.doi.org/10.1002/jcp.25430] [PMID: 27187048]
]. Phenytoin enhances IL-13 secretion, thus TGF-β expression and produces its active form.

The occurrence of fibrosis requires both TGF-β and Connective Tissue Growth Factor (CTGF). In the gingival tissue, the effects of TGF-β are mainly via CTGF. However, in the gingival overgrowth tissue, the TGF-β is in a higher concentration in the initial period whereas the concentration of CTGF remains high at a constant level [36Gonzalez AC, Costa TF, Andrade ZA, Medrado AR. Wound healing - A literature review. An Bras Dermatol 2016; 91(5): 614-20.
[http://dx.doi.org/10.1590/abd1806-4841.20164741] [PMID: 27828635]
]. This implicates that TGF-β induces the expression of CTGF through a cascade effect. CTGF is a known producer of fibrosis. It also increases the proliferation of fibroblasts due to its mitogenic, angiogenic and chemotactic activities [36Gonzalez AC, Costa TF, Andrade ZA, Medrado AR. Wound healing - A literature review. An Bras Dermatol 2016; 91(5): 614-20.
[http://dx.doi.org/10.1590/abd1806-4841.20164741] [PMID: 27828635]
].

The degradation of collagen occurs via two mechanisms. One is extracellularly, by collagenases and the second intracellularly following collagen phagocytosis [37Jabłońska-Trypuć A, Matejczyk M, Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhibit Med Chem 2016; 31(sup1): 177-83.]. MMPs are a family with 25 enzymes that are endopeptidases [38Mittal R, Patel AP, Debs LH, et al. Intricate functions of matrix metalloproteinases in physiological and pathological conditions. J Cell Physiol 2016; 231(12): 2599-621.
[http://dx.doi.org/10.1002/jcp.25430] [PMID: 27187048]
]. The action of MMPs depends on Calcium and Zinc; MMPs can be secreted or are membrane associated and vital in ECM metabolism [39Malemud CJ. Matrix metalloproteinases (MMPs) in health and disease: An overview. Front Biosci 2006; 11: 1696-701.
[http://dx.doi.org/10.2741/1915] [PMID: 16368548]
]. As, MMPs are collagenases, stromelysins, and gelatinases, they are involved in tissue remodeling of ECM especially tissue degradation [38Mittal R, Patel AP, Debs LH, et al. Intricate functions of matrix metalloproteinases in physiological and pathological conditions. J Cell Physiol 2016; 231(12): 2599-621.
[http://dx.doi.org/10.1002/jcp.25430] [PMID: 27187048]
, 39Malemud CJ. Matrix metalloproteinases (MMPs) in health and disease: An overview. Front Biosci 2006; 11: 1696-701.
[http://dx.doi.org/10.2741/1915] [PMID: 16368548]
]. MMP-1, also known as collagenase-1, degrades the fibrillar collagen through activating the inactive collagenase [39Malemud CJ. Matrix metalloproteinases (MMPs) in health and disease: An overview. Front Biosci 2006; 11: 1696-701.
[http://dx.doi.org/10.2741/1915] [PMID: 16368548]
]. Any altered balance due to either activation or inhibition results in a change in the amount of ECM. Thus, inhibition of MMPs causes excessive accumulation of connective tissues in the ECM [40Maita E, Sato M, Yamaki K. Effect of tranilast on matrix metalloproteinase-1 secretion from human gingival fibroblasts in vitro. J Periodontol 2004; 75(8): 1054-60.
[http://dx.doi.org/10.1902/jop.2004.75.8.1054] [PMID: 15455731]
-42Iman K, Soha N, Afshin BH, et al. Phenytoin-induced gingival over growth: A review soc. Pharm J 2015; 1(1)e827].

Natural MMP inhibitors exist in all animal tissues [43Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol 2008; 214(2): 199-210.
[http://dx.doi.org/10.1002/path.2277] [PMID: 18161745]
]. One of the main MMP inhibitor families is Tissue Inhibitors of Metalloproteinases (TIMPs) consisting of four types. MMP-1 mediated ECM remodeling, the degradation of ECM, is inhibited by TIMP-1, resulting in excessive accumulation of connective tissue in ECM. In addition, TIMP-1 has growth-promoting activity in several types of cells [44Kato 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.
[http://dx.doi.org/10.1902/jop.2005.76.6.941] [PMID: 15948689]
].

Phenytoin causes the inhibition of collagen degradation via MMPs/TIMP-1 [44Kato 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.
[http://dx.doi.org/10.1902/jop.2005.76.6.941] [PMID: 15948689]
, 45Fugii A, Kobayashi S. Nifedipine inhibits calcium uptake of nifedipine-sensitive gingival fibroblast. J Dent Res 1990; 67: 332.]. Phenytoin reduces intracellular folic acid and induces the production of mediators such as TGF-β and TNF-α [45Fugii A, Kobayashi S. Nifedipine inhibits calcium uptake of nifedipine-sensitive gingival fibroblast. J Dent Res 1990; 67: 332.]. The three main drug categories (phenytoin, cyclosporine and calcium channel blockers) causing drug induced gingival overgrowth have an inhibitory action on cation channels. Based on the available evidence, a unified theory has been proposed [4Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: A unifying hypothesis. Oral Dis 2015; 21(1): e51-61.
[http://dx.doi.org/10.1111/odi.12264] [PMID: 24893951]
]. The antiepileptic action of phenytoin is mainly through the inhibition of sodium channels. However, phenytoin also inhibits the calcium channels, including in the gingival fibroblasts [46Modéer T, Brunius G, Mendez C, Juntti-Berggren L, Berggren PO. Influence of phenytoin on cytoplasmic free Ca2+ level in human gingival fibroblasts. Scand J Dent Res 1991; 99(4): 310-5.
[http://dx.doi.org/10.1111/j.1600-0722.1991.tb01033.x] [PMID: 1771377]
, 47Ariel M, Eilam Y, Jablonska M, et al. On the mechanism of folate transport in isolated intestinal epithelial cells. J Pharmacol Exp Ther 1982; 223: 224-46.
[PMID: 7120120]
]. 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 [4Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: A unifying hypothesis. Oral Dis 2015; 21(1): e51-61.
[http://dx.doi.org/10.1111/odi.12264] [PMID: 24893951]
]. Cellular uptake of folic acid occurs through two mechanisms. The first is passive diffusion and the second cation dependent active transport [4Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: A unifying hypothesis. Oral Dis 2015; 21(1): e51-61.
[http://dx.doi.org/10.1111/odi.12264] [PMID: 24893951]
, 48Crott JW, Liu Z, Keyes MK, et al. Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines. J Nutr Biochem 2008; 19(5): 328-35.
[http://dx.doi.org/10.1016/j.jnutbio.2007.05.003] [PMID: 17681772]
]. The cation dependent active cellular intake of folic acid is impaired by phenytoin [4Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: A unifying hypothesis. Oral Dis 2015; 21(1): e51-61.
[http://dx.doi.org/10.1111/odi.12264] [PMID: 24893951]
]. This can result in a systemic and localized folate deficiency in the gingival tissue.

Decreased cellular folic acid leads to reduced expression of E-cadherin and SMAD (SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways) which reduces the expression of the AP-1 gene. Reduced AP-1 activates the TIMP-1 gene expression. The result is that phenytoin decreases the MMP-1 by increasing the expression of TIMP-1. As a result of this, collagen accumulates in ECM and causes gingival overgrowth [44Kato 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.
[http://dx.doi.org/10.1902/jop.2005.76.6.941] [PMID: 15948689]
, 49Ganesh PR. Immunoexpression of interleukin-6 in drug-induced gingival overgrowth patients. Contemp Clin Dent 2016; 7(2): 140-5.
[http://dx.doi.org/10.4103/0976-237X.183048] [PMID: 27307657]
, 50Vizovišek M, Fonović M, Turk B. Cysteine cathepsins in extracellular matrix remodeling: Extracellular matrix degradation and beyond. Matrix Biol 2019; 75-76: 141-59.
[PMID: 29409929]
]..

Cathepsin degrades ECM components such as type 1 collagen, laminin and proteoglycans.

As phenytoin inhibits cathepsin, the result is the accumulation of ECM components [42Iman K, Soha N, Afshin BH, et al. Phenytoin-induced gingival over growth: A review soc. Pharm J 2015; 1(1)e827, 51Yamada H, Nishimura F, Naruishi K, et al. Phenytoin and cyclosporin A suppress the expression of MMP-1, TIMP-1, and cathepsin L, but not cathepsin B in cultured gingival fibroblasts. J Periodontol 2000; 71(6): 955-60.
[http://dx.doi.org/10.1902/jop.2000.71.6.955] [PMID: 10914799]
, 52Kataoka M, Kido J, Shinohara Y, Nagata T. Drug-induced gingival overgrowth-A review. Biol Pharm Bull 2005; 28(10): 1817-21.
[http://dx.doi.org/10.1248/bpb.28.1817] [PMID: 16204928]
].

Integrins are a large family of heterodimeric transmembrane receptors. Each heterodimer consists of α and β subunits. In mammals, there are 17α and 8β subunits that can form 40 different integrins through different combinations. The α1β1 integrin recognizes type IV collagen preferentially and the α2β1 integrin recognizes type 1 collagen preferentially [53Soory M, Suchak A. The effects of human mast-cell products and of phenytoin on androgen 5alpha-reductase expression in human gingival fibroblasts. Arch Oral Biol 2001; 46(9): 847-55.
[http://dx.doi.org/10.1016/S0003-9969(01)00037-1] [PMID: 11420057]
]. Studies have indicated that α2β1 integrins serve as specific receptors of type I collagen in fibroblasts. For collagen phagocytosis, collagen should adhere to the fibroblast as the first step. It has been also shown that α2 integrin plays a critical role in the phagocytic regulation of collagen internalization by adhering to collagen [53Soory M, Suchak A. The effects of human mast-cell products and of phenytoin on androgen 5alpha-reductase expression in human gingival fibroblasts. Arch Oral Biol 2001; 46(9): 847-55.
[http://dx.doi.org/10.1016/S0003-9969(01)00037-1] [PMID: 11420057]
]. Phenytoin reduces the collagen internalization, therefore causing degradation either by reducing the affinity of integrins to collagens or reducing the expression of integrins. A proposed mechanism for the reduced expression of integrins is diminished intracellular calcium due to the calcium channel antagonist effect of phenytoin. Hence, collagen accumulation in the ECM will result in gingival overgrowth [28Karimzadeh I, Namazi S, Borhani-Haghighi A, Khosropanah H. Phenytoin-induced gingival over growth: A review. Soc Pharmacy J 2015; 1(1)].

Another mechanism through which phenytoin induces gingival overgrowth is by the conversion of androgens to their active metabolites. Studies have shown that fibroblasts of the gingiva have the ability to metabolize testosterone to its active metabolite 5α-dihydrotestosterone, enhanced by the addition of phenytoin to the cultured fibroblasts [54Soory M, Suchak A. Effects of alkaline phosphatase and its inhibitor levamisole on the modulation of androgen metabolism by nicotine and minocycline in human gingival and oral periosteal fibroblasts. Arch Oral Biol 2003; 48(1): 69-76.
[http://dx.doi.org/10.1016/S0003-9969(02)00157-7] [PMID: 12615144]
]. ECM synthesis could be enhanced by the stimulatory effect of phenytoin on the type 2 isoenzyme of 5α-reductase activity. This action takes place in either a ligand-dependent manner through the stimulation of their own receptors, or a ligand-independent manner, through the direct stimulation of the androgen receptor. Type 2 reductase of 5α-reductase, via the production of 5α-dihydrotestosterone, has an anabolic role in gingiva by activating the fibroblast cells to produce more collagen fibers or decrease collagenase activity [54Soory M, Suchak A. Effects of alkaline phosphatase and its inhibitor levamisole on the modulation of androgen metabolism by nicotine and minocycline in human gingival and oral periosteal fibroblasts. Arch Oral Biol 2003; 48(1): 69-76.
[http://dx.doi.org/10.1016/S0003-9969(02)00157-7] [PMID: 12615144]
]. Some authors have suggested that a trigger of alkaline phosphatase may mediate some of the matrix stimulatory actions of androgen metabolites [55Patil MM, Sahoo J, Kamalanathan S, Pillai V. Phenytoin induced osteopathy-Too common to be neglected. J Clin Diagn Res 2015; 9(11): OD11-2. [JCDR].
[http://dx.doi.org/10.7860/JCDR/2015/15224.6820] [PMID: 26674262]
]. Others have mentioned the role of oestrogens to increase the local level of dihydrotestosterone and thereby stimulating collagen formation. Oestrogen enhances the incorporation of proline in collagen molecules being synthesized in the gingival fibroblasts [56Brunius G, Yucel-Lindberg T, Shinoda K, Modéer T. Effect of phenytoin on interleukin-1 beta production in human gingival fibroblasts challenged to tumor necrosis factor alpha in vitro. Eur J Oral Sci 1996; 104(1): 27-33.
[http://dx.doi.org/10.1111/j.1600-0722.1996.tb00042.x] [PMID: 8653494]
].

Phenytoin acts on macrophages, enhancing the production of IL-1β, which enhances the expression of Cyclooxygenase 2 (COX-2) through the transcription factor (nuclear factor-kappaB [NF-κB]. COX-2 is the main enzyme in the production of Prostaglandins (PGs) from arachidonic acid. One such important prostaglandin is PGE2 [30Man 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.
[http://dx.doi.org/10.1165/ajrcmb.23.5.4046] [PMID: 11062139]
]. Transcription of TGF-β and its receptors are enhanced by PGE-2 [57Kuru L, Yilmaz S, Kuru B, Köse KN, Noyan U. Expression of growth factors in the gingival crevice fluid of patients with phenytoin-induced gingival enlargement. Arch Oral Biol 2004; 49(11): 945-50.
[http://dx.doi.org/10.1016/j.archoralbio.2004.04.010] [PMID: 15353252]
]. EP-3 receptors are found in gingival fibroblasts but not in lung or kidney fibroblasts. PGE-2 acts on EP-3 receptors in gingival fibroblasts and enhances the TGF-β1 stimulation of JNK -MAP kinase pathway of CTGF expression [30Man 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.
[http://dx.doi.org/10.1165/ajrcmb.23.5.4046] [PMID: 11062139]
].

Platelet Derived Growth Factor (PDGF), produced by platelets, macrophages, endothelial cells, and fibroblasts, is believed to enhance mitogenic activity and chemotaxis [58Finkenzeller G, Totzke F, Fitzke E, Marmé D, Dieter P. Over-expression of protein kinase C-alpha enhances platelet-derived growth factor- and phorbol ester- but not calcium ionophore-induced formation of prostaglandins in NIH 3T3 fibroblasts. FEBS Lett 1993; 321(1): 11-4.
[http://dx.doi.org/10.1016/0014-5793(93)80610-7] [PMID: 8467904]
]. Phenytoin is also known to increase the production of PDGF. PDGF activates the cytosolic phospholipase A2 enzyme which releases arachidonic acid from the cell membrane by increasing intracellular calcium. Apart from the indirect effect of PDGF, there is a direct effect by increasing the expression of COX-2 which has been proven in some studies [59Manimegalai AG, Rao SH, Ravindran D. Fibronectin in periodontal health and disease. J Orofac Sci 2016; 8(1): 12.
[http://dx.doi.org/10.4103/0975-8844.181918]
, 60Smith PC. Role of myofibroblasts in normal and pathological periodontal wound healing. Oral Dis 2018; 24(1-2): 26-9.
[http://dx.doi.org/10.1111/odi.12773] [PMID: 29480623]
].

Epithelial Mesenchymal Transition (EMT) is a biological process of acquisition of the mesenchymal phenotype by the epithelial cells where it acquires an increased migratory capacity, invasiveness and importantly inhibition to apoptosis and enhanced ECM production. Normally, a polarized epithelial cell interacts with the basement membrane via its basal surface [61Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003; 112(12): 1776-84.
[http://dx.doi.org/10.1172/JCI200320530] [PMID: 14679171]
-63Zavadil J, Böttinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 2005; 24(37): 5764-74.
[http://dx.doi.org/10.1038/sj.onc.1208927] [PMID: 16123809]
]. In EMT, there is a degradation of the basement membrane at the rete ridges and transformed epithelial cells migrate to the connective tissue. EMT is involved in several processes such as embryonic development, cancer progression, and epithelial injury [64Takeuchi R, Matsumoto H, Arikawa K, et al. Phenytoin-induced gingival overgrowth caused by death receptor pathway malfunction. Oral Dis 2017; 23(5): 653-9.
[http://dx.doi.org/10.1111/odi.12651] [PMID: 28160766]
]. The process of EMT involves the loss of the polarity of epithelial cells, cell-cell and cell matrix adhesion, remodeling and rearrangement to gain the features of mesenchymal cells [64Takeuchi R, Matsumoto H, Arikawa K, et al. Phenytoin-induced gingival overgrowth caused by death receptor pathway malfunction. Oral Dis 2017; 23(5): 653-9.
[http://dx.doi.org/10.1111/odi.12651] [PMID: 28160766]
].

E-cadherin is important in epithelial cell contact which is essential for the barrier function of epithelial tissue [65Sume SS, Kantarci A, Lee A, Hasturk H, Trackman PC. Epithelial to mesenchymal transition in gingival overgrowth. Am J Pathol 2010; 177(1): 208-18.
[http://dx.doi.org/10.2353/ajpath.2010.090952] [PMID: 20489142]
, 66Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 2002; 110(3): 341-50.
[http://dx.doi.org/10.1172/JCI0215518] [PMID: 12163453]
]. In EMT, there is a reduction in the levels of E-cadherin expression which results in the loss of integrity and barrier function of the epithelial cells [66Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 2002; 110(3): 341-50.
[http://dx.doi.org/10.1172/JCI0215518] [PMID: 12163453]
]. In EMT, a specific marker for fibroblast, Fibroblast Specific Protein-1 (FSP-1) and also fibronectin, and an alternatively spliced form of fibronectin (ED-A isoform), 19 are secreted and found in elevated levels [66Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 2002; 110(3): 341-50.
[http://dx.doi.org/10.1172/JCI0215518] [PMID: 12163453]
-68Strutz F, Zeisberg M, Ziyadeh FN, et al. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int 2002; 61(5): 1714-28.
[http://dx.doi.org/10.1046/j.1523-1755.2002.00333.x] [PMID: 11967021]
].

Transforming Growth Factor (TGF-β) down regulates E-cadherin and potently stimulates the epithelial mesenchymal transition and at the same time, TGF-β increases the expression of MMP-9 and MMP-2 which degrade type IV collagen in the basement membrane and allow migration of epithelial cells and interact with connective tissue [69Li Y, Yang J, Dai C, Wu C, Liu Y. Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis. J Clin Invest 2003; 112(4): 503-16.
[http://dx.doi.org/10.1172/JCI200317913] [PMID: 12925691]
-71Sharma PK, Misra AK, Chugh A, Chugh VK, Gonnade N, Singh S. Gingival hyperplasia: Should drug interaction be blamed for? Indian J Pharmacol 2017; 49(3): 257-9.
[http://dx.doi.org/10.4103/ijp.IJP_57_17] [PMID: 29033487]
]. Some types of integrins activate the latent TGF-β and can promote EMT.

Forkhead box transcription factors (FOXO) proteins belong to a Forkhead family of transcription factors. It is involved in the activation or inhibition of many genes related to important cellular functions [59Manimegalai AG, Rao SH, Ravindran D. Fibronectin in periodontal health and disease. J Orofac Sci 2016; 8(1): 12.
[http://dx.doi.org/10.4103/0975-8844.181918]
]. Importantly, it reduces anabolic metabolism, increases apoptosis and arrests the cell cycle. FOXO-1 enhances the production of TGF-β contributing to gingival overgrowth. Phenytoin is known to inhibit FOXO-1 [72López-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.
[http://dx.doi.org/10.1177/0022034517695518] [PMID: 28571526]
, 73Ramírez-Rámiz A, Brunet-LLobet L, Lahor-Soler E, Miranda-Rius J. On the cellular and molecular mechanisms of drug-induced gingival overgrowth. Open Dent J 2017; 11: 420-35.
[http://dx.doi.org/10.2174/1874210601711010420] [PMID: 28868093]
].

A recent study has revealed that Transient Receptor Potential Ankyrin (TRPA1) channels have an important role to play in the pathophysiologic mechanism of phenytoin-induced GE. The calcium-permeable ion channels TRPA1 [74Viana F. TRPA1 channels: Molecular sentinels of cellular stress and tissue damage. J Physiol 2016; 594(15): 4151-69.
[http://dx.doi.org/10.1113/JP270935] [PMID: 27079970]
], 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 [72López-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.
[http://dx.doi.org/10.1177/0022034517695518] [PMID: 28571526]
]. Further, phenytoin did not augment the proliferative rate of HGFs whereas it induced extracellular matrix accumulation of collagen [72López-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.
[http://dx.doi.org/10.1177/0022034517695518] [PMID: 28571526]
].

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. This is in response to the upregulation of cellular FLICE-Like Inhibitory Protein (c-FLIP), the cellular inhibitor of apoptosis 2 (cIAP2) and downregulation of Fas-Associated Protein with Death Domain (FADD), caspase-3, caspase-8, caspase-9 and TNF Receptor Associated Factor 2(TRAF2) by the effect of phenytoin on Receptor-Interacting serine/threonine-Protein Kinase 1(RIPK1) activity and (B-cell lymphoma 2) Bcl-2 activity [75Kasai 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.
[http://dx.doi.org/10.1186/1465-9921-6-56] [PMID: 15946381]
].

3. SUMMARY FINDING(S) FROM THE STUDY

Although several mechanisms, both at a cellular and molecular level, have been proposed for phenytoin induced gingival overgrowth, there is a lack of understanding in these mechanisms of phenytoin induced gingival overgrowth. Hence, there is no treatment or prevention for the management of this condition. This prompts the necessity of future research in this field, particularly at a molecular level.

CONCLUSION

Phenytoin induced gingival overgrowth is a side effect with multifactorial etiology. 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 ECM content. However, the mechanism of the 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.

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest financial or otherwise.

ACKNOWLEDGEMENTS

We would like to acknowledge Dr. Susanna Wright of King Abdullah International Medical Research Center for her assistance in editing the manuscript.

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