OJST  Vol.4 No.9 , September 2014
Phenytoin Effects on Proliferation and Induction of IL1β and PGE2 in Pediatric and Adults’ Gingival Fibroblasts
ABSTRACT
Background: Gingival Overgrowth (GO) is a well documented and unwanted side effect that occurs mainly as a result of certain antiseizure, phenytoin. The aim of this study was to compare the effect of phenytoin on proliferation and production of IL1β and PGE2 in cultured human gingival fibroblasts (HGF) of children and adults. Materials and Methods: Normal HGFs were obtained from 4 healthy children and 4 adult and then were cultured with phenytoin (20 mg/ml). MTT test was used to evaluate the proliferation and ELISA to determine the level of IL1β and PGE2 production by HGFs. Analysis of proliferation were assessed by Independent T-Test and ANOVA analysis was used to assess the level of IL1β and PGE2 production with an a error level less than 0.05. Results: The proliferation of HGF was not affected significantly by phenytoin in both cultured fibroblast sources (P > 0.05). Phenytoin induced a significantly higher formation of IL1β and PGE2 in child’s HGFs as compared to adult’s HGFs (P < 0.05). Conclusion: The results suggest that different inflammatory responses and cytokine formation by child’s and adult’s HGFs are the probable key elements that cause different reactions of phenytoin therapy. More advanced and systematic studies are needed to verify these findings.

Cite this paper
Vahabi, S. , Moslemi, M. , Nazemisalman, B. and Yadegari, Z. (2014) Phenytoin Effects on Proliferation and Induction of IL1β and PGE2 in Pediatric and Adults’ Gingival Fibroblasts. Open Journal of Stomatology, 4, 452-462. doi: 10.4236/ojst.2014.49061.
References
[1]   Maitu, E., Sato, M. and Yamaki, K. (2004) Effect of Tranilast on Martin Metalloproteinase-1 Secretion from Human Gingival Fibroblast in Vitro. Journal of Periodontology, 75, 1054-1060.
http://dx.doi.org/10.1902/jop.2004.75.8.1054

[2]   Brunet, L., Miranda, J., Fere, M., Berini, L. and Mendieta, C. (1996) Gingival Enlargement Induced by Drugs. Drug Safety, 15, 219-231.
http://dx.doi.org/10.2165/00002018-199615030-00007

[3]   Gronzalez, O. and Gonzalez, J.M. (2009) Morphological and Phenotypic Difference in Fibroblasts Obtained from Gingival Overgrowth Secondary to Phenytoin: Pilot Study. Revista Odontologica Mexicana, 13, 17-23.

[4]   Perucca, E. (2005) An Introduction to Antiepileptic Drugs. Epilepsia, 46, 31-37.
http://dx.doi.org/10.1111/j.1528-1167.2005.463007.x

[5]   Lucches, J., Cortelli, S.H. and Rodrigues, J. (2008) Server Phenytoin-Induced Gingival Enlargement Associated with Periodontitis. General Dentistry, 56, 199-203.

[6]   Reynolds, E.H. (1975) Chronic Antiepileptic Toxicity, a Review. Epilepsia, 16, 319-352.
http://dx.doi.org/10.1111/j.1528-1157.1975.tb06062.x

[7]   Bhatia, A. and Prakash, S. (2004) Topical Phenytoin for Wound Healing. Dermatology Online Journal, 10, 5.

[8]   Doufexi, A., Mina, M. and Loannidou, E. (2005) Gingival Overgrowth in Children: Epidemiology, Pathogenesis and Complications, a Literature Review. Journal of Periodontology, 76, 3-10.
http://dx.doi.org/10.1902/jop.2005.76.1.3

[9]   Morisaki, K.K., Loyola-Rodriguez, J.P., Nagata, T., and Ishida, H. (1993) Nifediphine-Induced Gingival Overgrowth in the Presence or Absence of Gingival Inflammation in Rats. Journal of Periodontal Research, 28, 396-403.

[10]   Ishikawa, S., Nagata, T., Morisaki, I., Oka, T. and Ishida, H. (1996) Pathogenesis of Drug Induced Gingival Over-growth, A Review of Studies in the Rat Model. Journal of Periodontology, 67, 463-471.
http://dx.doi.org/10.1902/jop.1996.67.5.463

[11]   Seymour, R.A. (1992) Heasann PA: Drugs and the Periodontium. Journal of Clinical Periodontology, 19, 1-11.
http://dx.doi.org/10.1111/j.1600-051X.1992.tb01140.x

[12]   Hassel, T.M. and Hefti, A.F. (1991) Drug Induced Gingival Overgrowth: Old Problem, New Problem. Critical Reviews in Oral Biology Medicine, 2, 103-137.

[13]   Barclay, S., Thomason, T.M., Idle, J.R. and Seymour, R.A. (1992) The Incidence and Severity of Nifediphine Induced Gingival Overgrowth. Journal of Clinical Periodontology, 19, 311-314.
http://dx.doi.org/10.1111/j.1600-051X.1992.tb00650.x

[14]   Seymour, R.A., Thomason, J.M. and Ellis, J.S. (1996) The Pathogenesis of Drug Induced Gingival Overgrowth. Journal of Clinical Periodontology, 23, 165-175.
http://dx.doi.org/10.1111/j.1600-051X.1996.tb02072.x

[15]   Easley, J. (1967) Methods of Determining Alveolar Osseous Form. Journal of Periodontology, 38, 112.

[16]   Friedman, N. (1955) Periodontal Osseous Surgery, Osteoplasty and Osteoectomy. Journal of Periodontology, 26, 257.

[17]   Goldman, H.M. and Cohen, D.W. (1958) The Infrabony Pocket: Classification and Treatment. Journal of Periodontology, 29, 272.
http://dx.doi.org/10.1902/jop.1958.29.4.272

[18]   Ochsenbein, C. (1986) A Primer for Osseous Surgery. The International Journal of Periodontics and Restorative Dentistry, 6, 9.

[19]   Carranza, F.A., Take, H. and Newman, M. (2006) Clinical Periodontology. Chap. 18. 10th Edition, W.B. Saunders Co., Philadelphia, 63, 270-272, 920-922.

[20]   Guncu, G.N., Caglayan, F., Dincel, A., Bozkurt, A., Sayg, S. and Karabulut, E. (2006) Plasma and Gingival Curricular Fluid Phenytoin Concentrations as Risk Factors for Gingival Overgrowth. Journal of Periodontology, 77, 2005-2010.
http://dx.doi.org/10.1902/jop.2006.060103

[21]   Seymour, R. (2006) Effects of Medications on the Periodontal Tissues in Health and Disease. Journal of Periodontology, 40, 120-129.

[22]   Yamada, H., Nishimura, F., Naruishi, K., Chou, H. and Takashiba, S.H. (2000) Phenytoin and Cyclosporine a Suppress the Expression of MMP-1, TTMP-1 and Cathepsin, but Not Cathepsin B in Cultured Gingival Fibroblasts. Journal of Periodontology, 71, 955-960.
http://dx.doi.org/10.1902/jop.2000.71.6.955

[23]   Kataoka, M., Kido, J., Shinohara, Y. and Nagata, T. (2005) Drug-Induced Gingival Overgrowth—A Review. Biological and Pharmaceutical Bulletin, 28, 1817-1821.
http://dx.doi.org/10.1248/bpb.28.1817

[24]   Halmoon, W.W. and Rossmann, J.A. (1999) The Role of Drugs in the Pathogenesis of Gingival Overgrowth, a Collective Review of Current Concepts. Periodontology 2000, 21, 176-196.
http://dx.doi.org/10.1111/j.1600-0757.1999.tb00175.x

[25]   Everts, V., Van der zee, E., Creemers, L. and Beertsen, W. (1996) Phagocytosis and Intracellular Digestion of Collagen Its Role in Turn over and Remodeling. The Histochemical Journal, 28, 229-245.
http://dx.doi.org/10.1007/BF02409011

[26]   O’valle, F., Mesa, F.L., Gomez-Murales, M., et al. (1994) Immunhistochemical Study of 30 Cases of Cyclosporine A-Induced Gingival Overgrowth. Journal of Periodontology, 65, 742-730.
http://dx.doi.org/10.1902/jop.1994.65.7.724

[27]   Trackman, P.C. and Kantarci, A. (2004) Connective Tissue Metabolism and Gingival Overgrowth. Critical Reviews in Oral Biology Medicine, 15, 165-175.
http://dx.doi.org/10.1177/154411130401500305

[28]   Okahashi, N., Kato, T., Ohno, T., Inaba, H., Kawai, S. and Amano, A. (2006) Effect of Phenytoin on Collagen Accumulation by Human Gingival Fibroblasts Exposed to TNF-α in Vitro. Oral Diseases, 12, 156-162.
http://dx.doi.org/10.1111/j.1601-0825.2005.01175.x

[29]   Yucel-Linberg, T., Brunius, G., Shinoda, K. and Modeer, T. (1996) Effect of Phenytoin on Interlukin-1β Production in Human Gingival Fibroblasts Challenged to Tumor Necrosis Factor α in Vitro. European Journal of Oral Sciences, 104, 27-33.
http://dx.doi.org/10.1111/j.1600-0722.1996.tb00042.x

[30]   Modeer, T., Anduren, I., Bengston, A. and Anderson, G. (1996) Interleukin-1β and Phenytoin Reduce α1 (1) Procollagen mRNA Expression in Human Gingival Fibroblasts. Journal of Periodontal Research, 31, 563-568.
http://dx.doi.org/10.1111/j.1600-0765.1996.tb00521.x

[31]   Yucel-Lindberg, T., Leiner, U.H. and Modeer, T. (1995) Effects and Interactions of Tumour Necrosis Factor α and Bradykinin on Interleukin-1 Production in Gingival Fibroblasts. Journal of Periodontal Research, 30, 186-191.
http://dx.doi.org/10.1111/j.1600-0765.1995.tb01272.x

[32]   Newman, M.G., Takei, H.H. and Carranza, F.A. (2002) Clinical Periodontology. Chap. 25. 9th Edition, W.B. Saunders Co., Philadelphia, 406-408.

[33]   Lindhe, J., Liljenberg, B. and Listgarten, M. (1980) Some Microbiological and Histological Features of Periodontal Disease in Man. Journal of Periodontology, 51, 264-269.
http://dx.doi.org/10.1902/jop.1980.51.5.264

[34]   Mattson, L. (1978) Development of Gingivitis in Preschool Children and Young Adults: A Comparative Experimental Study. Journal of Clinical Periodontology, 5, 24-28.
http://dx.doi.org/10.1111/j.1600-051X.1978.tb01903.x

[35]   Gillett, R., Cruckley, A. and Johnson, N.W. (1986) The Nature of the Inflammatory Infiltrates in Childhood Gingivitis, Juvenile Periodontitis and Adult Periodontitis: Immunocytochemical Studies Using a Monoclonal Antibody to HLA Dr. Journal of Clinical Periodontology, 13, 281-286.
http://dx.doi.org/10.1111/j.1600-051X.1986.tb02223.x

[36]   Gillette, R., Longhurst, P. and Johnson, N.W. (1980) Electron Microscope Quantification of Inflammatory Infiltrates in Childhood Gingivitis. Journal of Periodontal Research, 15, 255-258.
http://dx.doi.org/10.1111/j.1600-0765.1980.tb00282.x

[37]   Longhurst, P., Johnson, N.W. and Hopps, R.M. (1977) Differences in Lymphocyte and Plasma Cell Densities in Inflamed Gingival from Adults and Young Children. Journal of Periodontology, 48, 705-709.
http://dx.doi.org/10.1902/jop.1977.48.11.705

[38]   Seymour, G.J., Grouch, M.S. and Powell, R.N. (1982) The Identification of Lymphoid Cell Subpopulations in Section of Human Lymphoid Tissue and Gingivitis in Children Use in Monoclonal Antibodies. Journal of Periodontal Research, 17, 247-252.
http://dx.doi.org/10.1111/j.1600-0765.1982.tb01151.x

[39]   Shaw, J., Hughes, C.M., Lagan, K.M. and Bell, P.M. (2007) The Clinical Effect of Topical Phenytoin on Wound Healing: A Systemic Review. British Journal of Dermatology, 157, 997-1004.
http://dx.doi.org/10.1111/j.1365-2133.2007.08160.x

[40]   Al-Ubady, S.H., Al-Janabi, N. and Suhaila, A. (1981) Effect of Phenytoin on Mitotic Activity of Gingival Tissue and Cultured Fibroblast. Journal of Periodontology, 52, 747-749.
http://dx.doi.org/10.1902/jop.1981.52.12.747

[41]   Pour Abbas, R., Niknafs, B. and Shirmohamadi, A. (2006) The Effect of PHT on PDL and Gingival Fibroblasts Proliferation in Cell Culture. Medical Journal of Tabriz University of Medical Sciences & Health Services, 28, 45-48.

[42]   Modeer, T., Karsten, J., Weintraub, A., Gidlund, M. and Sundqvist, K.G. (1989) Phenytoin Induces Interlukin-1 Production in Vitro. Life Sciences, 44, 35-40.
http://dx.doi.org/10.1016/0024-3205(89)90215-4

[43]   Kato, T., Okahashi, N., Kaeai, S., Kato, T., Inaba, H., Morisaki, I. and Amano, A. (2005) Impaired Degradation of Matrix Collagen in Human Gingival Fibroblast by the Antiepileptic Drug Phenytoin. Journal of Periodontology, 76, 941-950.
http://dx.doi.org/10.1902/jop.2005.76.6.941

[44]   Brunius, G., Modeer, T., Inuma, M. and Lerner, U.H. (1992) Phenytoin Potentiates Interlukin-1 Induced Prostaglandin Biosynthesis in Human Gingival Fibroblast. British Journal of Pharmacology, 106, 574-578.
http://dx.doi.org/10.1111/j.1476-5381.1992.tb14377.x

[45]   Modeer, T., Brunius, G. and Lerner, H. (1992) Enhanced Prostaglandin Biosynthesis in Human Gingival Fibroblasts Isolated from Patients Treated with Phenytoin. Journal of Oral Pathology Medicine, 21, 251-255.
http://dx.doi.org/10.1111/j.1600-0714.1992.tb01005.x

[46]   Bartold, P.M. (1988) The Effect of Interleukin-1 β on Hyaluronic Acid Synthesized by Adult Human Gingival Fibroblasts in Vitro. Journal of Periodontal Research, 23, 139-147.
http://dx.doi.org/10.1111/j.1600-0765.1988.tb01347.x

[47]   Noguchi, K., Tominaga, Y., Matsushita, K., Izumi, Y., et al. (2001) Upregulation of Matrix Metalloproteinase-1 Production by Prostaglandin F2α in Human Gingival Fibroblasts. Journal of Periodontal Research, 36, 334-339.
http://dx.doi.org/10.1034/j.1600-0765.2001.360510.x

[48]   Mahanonda, R., Sa-Ard-Iam, N., Montreekachon, P., et al. (2007) IL-8 and IDO Expression by Human Gingival Fibroblasts via TLRs. The Journal of Immunology, 178, 1151-1157.
http://dx.doi.org/10.4049/jimmunol.178.2.1151

[49]   Yu, M.J., Yang, P.S. and Ge, S.H. (2008) Biological Effects on Phenytoin on Cultures Human Periodontal Ligament Fibroblasts in Vitro. West China Journal of Stomatology, 26, 215-218.

[50]   Lee, P.Y., Tsai, P.S., Huang, Y.H. and Huang, C.J. (2008) Inhibition of Toll-Like Receptor-4, Nuclear Factor-κB and Mitogen-Activated Protein Kinase by Lignocaine May Involve Voltage-Sensitive Sodium Channels. Clinical and Experimental Pharmacology and Physiology, 35, 1052-1058.
http://dx.doi.org/10.1111/j.1440-1681.2008.04962.x

[51]   Black, J.A., Liu, S., Itanis, S.C. and Saab, C.Y. (2006) Long-Term Protection of Central Axons with Phenytoin in Monophasic and Chronic-Relapsing EAE. Brain, 129, 3196-3208.
http://dx.doi.org/10.1093/brain/awl216

[52]   Domeij, H., Mdeer, T., Anduren, I., Mustafa, M. and Brunius, G. (2000) Effect of Phenytoin on Production on Interlukin-6 and Interleukin-8 in Human Gingival Fibroblast. Journal of Oral Pathology & Medicine, 29, 491-499.
http://dx.doi.org/10.1034/j.1600-0714.2000.291003.x

[53]   Dongari, A.I., Warren, D.W. and Berton, M.T. (1997) CD40 Expression by Gingival Fibroblasts: Correlation of Phenotype with Function. International Immunology, 9, 1233-1241.
http://dx.doi.org/10.1093/intimm/9.9.1233

[54]   Seymour, R.A., Ellis, S.S. and Thomason, J.M. (2000) Risk Factors for Drug Induced Gingival Overgrowth. Journal of Clinical Periodontology, 27, 217-223.
http://dx.doi.org/10.1034/j.1600-051x.2000.027004217.x

[55]   Greenwood, R., Tennison, M.B. and Maguire, J.H. (1986) Phenytoin-Induced Gingival Overgrowth and Antiepileptic Co-Administration. Epilepsia, 27, 540.

[56]   Majola, M., Mcfadyen, M., Connolly, C., Nair, Y., Govender, M. and Laher, M. (2000) Factors Influencing Phenytoin-Induced Gingival Enlargement. Journal of Clinical Periodontology, 27, 506-512.
http://dx.doi.org/10.1034/j.1600-051x.2000.027007506.x

[57]   Kitamura, K., Morisaxi, I., Adachi, C., et al. (1990) Gingival Overgrowth Induced by Cyclosporine A in Rats. Archives of Oral Biology, 35, 483-486.
http://dx.doi.org/10.1016/0003-9969(90)90213-T

[58]   Johnson, B.D, Natayanon, A. and Pieters, H. (1990) Effects of Cell Donor Age on Synthetic Properties of Fibroblasts Obtained from Phenytoin-Induced Gingival Hyperplasia. Journal of Periodontal Research, 25, 74-80.
http://dx.doi.org/10.1111/j.1600-0765.1990.tb00895.x

[59]   Sooriyamorthy, M., Horvey, W. and Gower, D.B. (1968) The Use of Human Gingival Fibroblasts in Cultured for Studying the Effect of Phenytoin on Testosterone Metabolic. Archives of Oral Biology, 33, 353-359.
http://dx.doi.org/10.1016/0003-9969(88)90069-6

[60]   Sooriyamorhy, M., Gower, D.B. and Eley, B.M. (1990) Androgen Metabolism in Gingival Hyperplasia Induced by Nifedipine and Cyclosporine. Journal of Periodontal Research, 25, 25-30.
http://dx.doi.org/10.1111/j.1600-0765.1990.tb01204.x

[61]   Soory, M. and Kasasa, S.C. (1997) The Effects of Epidermal Growth Factor, Interleukin-1, and Phenytoin, Alone and in Combination, on C19 Steroid Conversions in Fibroblasts. Journal of Periodontology, 68, 819-826.
http://dx.doi.org/10.1902/jop.1997.68.9.819

[62]   Barclay, S., Thomson, J.M. and Idle, J.R. (1992) The Incidence and Severity of Nifedipine Induced Gingival Overgrowth. Journal of Clinical Periodontology, 19, 311-314.
http://dx.doi.org/10.1111/j.1600-051X.1992.tb00650.x

[63]   Pinkham, J.R. and Cassmassimo, P.S. (2005) Pediatric Dentistry Infancy through Adolescence. 4th Edition, W.B. Saunders Co., Philadelphia, 394-413.

[64]   Dahllof, G. and Modeer, T. (1986) The Effect of a Plaque Control Program on the Development of Phenytoin-Induced Gingival Overgrowth. A 2-Year Longitudinal Study. Journal of Clinical Periodontology, 13, 845-849.
http://dx.doi.org/10.1111/j.1600-051X.1986.tb02241.x

 
 
Top