{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T18:14:47Z","timestamp":1791051287893,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2020,11,7]],"date-time":"2020-11-07T00:00:00Z","timestamp":1604707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Introduction. The administration of several classes of drugs can lead to the onset of gingival overgrowth: anticonvulsants, immunosuppressants, and calcium channel blockers. Among the anticonvulsants, the main drug associated with gingival overgrowth is diphenylhydantoin. Materials and Methods. In this study, we compared the effects of diphenylhydantoin and gabapentin on 57 genes belonging to the \u201cExtracellular Matrix and Adhesion Molecule\u201d pathway, present in human fibroblasts of healthy volunteers. Results. Both molecules induce the same gene expression profile in fibroblasts as well as a significant upregulation of genes involved in extracellular matrix deposition like COL4A1, ITGA7, and LAMB3. The two treatments also induced a significant downregulation of genes involved in the expression of extracellular matrix metalloproteases like MMP11, MMP15, MMP16, MMP24, and transmembrane receptor ITGB4. Conclusions. Data recorded in our study confirmed the hypothesis of a direct action of these drugs at the periodontium level, inducing an increase in matrix production, a reduction in its degradation, and consequently resulting in gingival hyperplasia.<\/jats:p>","DOI":"10.3390\/ijerph17218229","type":"journal-article","created":{"date-parts":[[2020,11,8]],"date-time":"2020-11-08T19:03:37Z","timestamp":1604862217000},"page":"8229","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Drug-Induced Gingival Overgrowth: A Pilot Study on the Effect of Diphenylhydantoin and Gabapentin on Human Gingival Fibroblasts"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3550-1812","authenticated-orcid":false,"given":"Dorina","family":"Lauritano","sequence":"first","affiliation":[{"name":"Centre of Neuroscience of Milan, Department of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Moreo","sequence":"additional","affiliation":[{"name":"Centre of Neuroscience of Milan, Department of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Limongelli","sequence":"additional","affiliation":[{"name":"Interdisciplinary Department of Medicine, University of Bari, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Tregambi","sequence":"additional","affiliation":[{"name":"Centre of Neuroscience of Milan, Department of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Palmieri","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, via Belmoro 8, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Carinci","sequence":"additional","affiliation":[{"name":"Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1902\/jop.2005.76.6.941","article-title":"Impaired degradation of matrix collagen in human gingival fibroblasts by the antiepileptic drug phenytoin","volume":"76","author":"Kato","year":"2005","journal-title":"J. Periodontol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1111\/j.1600-0757.1999.tb00175.x","article-title":"The role of drugs in the pathogenesis of gingival overgrowth. A collective review of current concepts","volume":"21","author":"Hallmon","year":"1999","journal-title":"Periodontol. 2000"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1046\/j.1365-2362.2001.00869.x","article-title":"Prevalence and risk of gingival enlargement in patients treated with anticonvulsant drugs","volume":"31","author":"Brunet","year":"2001","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"420","DOI":"10.2174\/1874210601711010420","article-title":"On the Cellular and Molecular Mechanisms of Drug-Induced Gingival Overgrowth","volume":"11","year":"2017","journal-title":"Open Dent. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s40780-017-0088-5","article-title":"Drug-induced gingival hyperplasia: A retrospective study using spontaneous reporting system databases","volume":"3","author":"Hatahira","year":"2017","journal-title":"J. Pharm. Health Care Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1902\/jop.2001.72.7.921","article-title":"Connective tissue growth factor in phenytoin-induced gingival overgrowth","volume":"72","author":"Uzel","year":"2001","journal-title":"J. Periodontol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"182","DOI":"10.4103\/0972-124X.113066","article-title":"Drug-induced gingival overgrowth: The nemesis of gingival unravelled","volume":"17","author":"Bharti","year":"2013","journal-title":"J. Indian Soc. Periodontol."},{"key":"ref_8","first-page":"1424","article-title":"Research, Science and therapy committee, american academy of periodontology. Drug-associated gingival enlargement","volume":"75","year":"2004","journal-title":"J. Periodontol."},{"key":"ref_9","unstructured":"Newman, M.G., Takei, H., Klokkevold, P.R., and Carranza, F.A. (2006). Carranza\u2019s Clinical Periodontology, Elsevier. [10th ed.]."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1111\/j.0013-9580.2004.47003.x","article-title":"The relative impact of anxiety, depression, and clinical seizure features on health-related quality of life in epilepsy","volume":"45","author":"Johnson","year":"2004","journal-title":"Epilepsia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1007\/s00018-003-2108-x","article-title":"Cellular and molecular action of the putative GABA-mimetic, gabapentin","volume":"60","author":"Maneuf","year":"2003","journal-title":"Cell Mol. Life Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2058738419827765","DOI":"10.1177\/2058738419827765","article-title":"Gabapentin affects the expression of inflammatory mediators on healthy gingival cells","volume":"33","author":"Candotto","year":"2019","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.archoralbio.2016.02.006","article-title":"Biological roles of KFG, CTGF and TGF-\u03b2 in cyclosporine-A and phenytoin-induced gingival overgrowth: A comparative experimental animal study","volume":"66","author":"Radwan","year":"2016","journal-title":"Arch. Oral. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/jcpe.12333","article-title":"Role of Shh and TGF in cyclosporine-enhanced expression of collagen and \u03b1-SMA by gingival fibroblast","volume":"42","author":"Chung","year":"2015","journal-title":"J. Clin. Periodontol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Lauritano, D., Moreo, G., Limongelli, L., Palmieri, A., and Carinci, F. (2020). Drug-Induced Gingival Overgrowth: The Effect of Cyclosporin A and Mycophenolate Mophetil on Human Gingival Fibroblasts. Biomedicines, 8.","DOI":"10.3390\/biomedicines8070221"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C(T) method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_17","first-page":"795","article-title":"Gabapentin (Neurontin) as add-on therapy in patients with partial seizueres: A double-blind, placebo-controlled study","volume":"35","author":"Anhut","year":"1994","journal-title":"Int. Gabapentin Study Group Epilepsia"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Inselman, A.L., and Hansen, D.K. (2014). Phenytoin. Encyclopedia of Toxicology, Academic Press. [3rd ed.].","DOI":"10.1016\/B978-0-12-386454-3.00771-5"},{"key":"ref_19","first-page":"263","article-title":"Drug-induced gingival enlargements","volume":"64","author":"Desai","year":"1998","journal-title":"J. Can. Dent. Assoc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e229587","DOI":"10.1136\/bcr-2019-229587","article-title":"Cyclosporine A and amlodipine induced gingival overgrowth in a kidney transplant recipient: Case presentation with literature review","volume":"12","author":"Nanda","year":"2019","journal-title":"BMJ Case Rep."},{"key":"ref_21","first-page":"95","article-title":"Immunohistochemical study of experimentally drug-induced gingival overgrowth","volume":"60","author":"Bobic","year":"2019","journal-title":"Rom. J. Morphol. Embryol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"639468","DOI":"10.1155\/2013\/639468","article-title":"The Possible Potential Therapeutic Targets for Drug Induced Gingival Overgrowth","volume":"2013","author":"Subramani","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"ref_23","unstructured":"Farronato, G.P. (2007). L\u2019odontostomatologia per L\u2019igienista Dentale, PICCIN."},{"key":"ref_24","unstructured":"Kasper, D., Fauci, A., Hauser, S., Longo, D., Jameson, J., and Loscalzo, J. (1991). Harrison\u2019s Principles of Internal Medicine, McGrawHill."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1902\/jop.2007.060165","article-title":"Distinctive Molecular Composition of Human Gingival Interdental Papilla","volume":"78","author":"Csiszar","year":"2007","journal-title":"J. Periodontol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2909","DOI":"10.1073\/pnas.73.8.2909","article-title":"Diphenylhydantoin (Dilantin) gingival hyperplasia: Drug-induced abnormality of connective tissue","volume":"73","author":"Hassell","year":"1976","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1001\/jama.1939.02800130028009","article-title":"The treatment of epilepsy with sodium diphenyl hydantoinate","volume":"11","author":"Kimball","year":"1939","journal-title":"J. Am. Med Assoc."},{"key":"ref_29","first-page":"339","article-title":"Dilantin gingival hyperplasia. Newer concepts related to etiology and treatment","volume":"25","author":"Strean","year":"1959","journal-title":"N. Y. State Dent. J."},{"key":"ref_30","first-page":"1350","article-title":"Behandling af epilepsi med diphenylhydantoin","volume":"101","author":"Faurbye","year":"1939","journal-title":"Ugeskr Laeg"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2058738419828259","DOI":"10.1177\/2058738419828259","article-title":"Phenytoin and gingival mucosa: A molecular investigation","volume":"33","author":"Candotto","year":"2019","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"383","DOI":"10.17219\/acem\/30428","article-title":"The significante of Matrix Metalloproteinases in Oral Diseases","volume":"25","author":"Maciejczyk","year":"2016","journal-title":"Adv. Clin. Exp. Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Lauritano, D., Palmieri, A., Lucchese, A., Di Stasio, D., Moreo, G., and Carinci, F. (2020). Role of Cyclospoine in Gingival Hyperplasia: An In Vitro Study on Gingival Fibroblasts. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21020595"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1177\/154411130401500305","article-title":"Connective tissue metabolism and gingival overgrowth","volume":"15","author":"Trackman","year":"2004","journal-title":"Crit. Rev. Oral. Biol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1016\/j.transproceed.2017.01.080","article-title":"Lack of Association Between TGF-\u03b21 and MDR1 Genetic Polymorphisms and Cyclosporine-Induced Gingival Overgrowth in Kidney Transplant Recipients: A Meta-analysis","volume":"49","author":"Wang","year":"2017","journal-title":"Transplant. Proc."},{"key":"ref_36","first-page":"2610","article-title":"A transforming growth factorbeta1 signal peptide variant increases secretion in vitro and is associated with increased incidence of invasive breast cancer","volume":"63","author":"Dunning","year":"2003","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1902\/jop.2001.72.6.808","article-title":"The influence of transforming growth factor-beta(1) gene polymorphisms on the severity of gingival overgrowth associated with concomitant use of cyclosporin A and a calcium channel blocker","volume":"72","author":"Linden","year":"2001","journal-title":"J. Periodontol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"208","DOI":"10.2353\/ajpath.2010.090952","article-title":"Epithelial to Mesenchymal Transition in Gingival Overgrowth","volume":"177","author":"Sume","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1902\/jop.1999.70.3.294","article-title":"Regulates Interleukin-1\u00df and Interleukin-6 Expression in Gingiva: Implications for Gingival Overgrowth","volume":"70","author":"Myrillas","year":"1999","journal-title":"J. Periodontol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"366","DOI":"10.2165\/00023210-199708050-00003","article-title":"Polypharmacy with Anticonvulsants","volume":"8","author":"Leach","year":"1997","journal-title":"CNS Drugs"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1016\/j.ajpath.2015.02.004","article-title":"Prevention of Phenytoin-Induced Gingival Overgrowth by Lovastatin in Mice","volume":"185","author":"Assaggaf","year":"2015","journal-title":"Am. J. Pathol."}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/17\/21\/8229\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:30:30Z","timestamp":1760178630000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/17\/21\/8229"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,7]]},"references-count":41,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["ijerph17218229"],"URL":"https:\/\/doi.org\/10.3390\/ijerph17218229","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,7]]}}}