Table of Contents
ISRN Dentistry
Volume 2011, Article ID 497850, 8 pages
http://dx.doi.org/10.5402/2011/497850
Review Article

Phenytoin-Induced Gingival Overgrowth: A Review of the Molecular, Immune, and Inflammatory Features

1Department of Oral Surgery and Pathology, School of Dentistry, Federal University of Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil
2Department of Clinical Medicine, School of Medicine, Federal University of Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil

Received 19 May 2011; Accepted 13 June 2011

Academic Editors: M. Del Fabbro and S. E. Widmalm

Copyright © 2011 Jôice Dias Corrêa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. D. E. McLeod, D. Stoeckel, J. Contreras, and E. Reyes, “Severe postpartum gingival enlargement,” Journal of Periodontology, vol. 80, no. 8, pp. 1365–1369, 2009. View at Publisher · View at Google Scholar · View at Scopus
  2. “Guidelines for epidemiologic studies on epilepsy. Comission on Epidemiology and Prognosis, International League Against Epilepsy,” Epilepsia, vol. 34, pp. 592–596, 1993.
  3. J. W. Sander and S. D. Shorvon, “Epidemiology of the epilepsies,” Journal of Neurology Neurosurgery and Psychiatry, vol. 61, no. 5, pp. 433–443, 1996. View at Google Scholar · View at Scopus
  4. W. R. Garnett, E. K. St Louis, T. R. Henry, and T. Bramley, “Transitional polytherapy: tricks of the trade for monotherapy to monotherapy AED conversions,” Current Neuropharmacology, vol. 7, no. 2, pp. 83–95, 2009. View at Publisher · View at Google Scholar · View at Scopus
  5. M. Maschio, L. Dinapoli, A. Vidiri et al., “The role side effects play in the choice of antiepileptic therapy in brain tumor-related epilepsy: a comparative study on traditional antiepileptic drugs versus oxcarbazepine,” Journal of Experimental and Clinical Cancer Research, vol. 28, no. 1, article 60, 2009. View at Publisher · View at Google Scholar · View at Scopus
  6. O. P. Kimball, “The treatment of epilepsy with sodium diphenyl hydantoinate,” The Journal of the American Medical Association, vol. 112, pp. 1244–1245, 1939. View at Google Scholar
  7. G. N. Guncu, F. Cxaglayan, A. Dincxel, A. Bozkurt, S. Sayg, and E. Karabulut, “Plasma and gingival crevicular fluid phenytoin concentrations as risk factors for gingival overgrowth,” Journal of Periodontology, vol. 77, pp. 2005–2010, 2006. View at Google Scholar
  8. T. Modéer, H. Domeij, I. Andurén, M. Mustafa, and G. Brunius, “Effect of phenytoin on the production of interleukin-6 and interleukin-8 in human gingival fibroblasts,” Journal of Oral Pathology and Medicine, vol. 29, no. 10, pp. 491–499, 2000. View at Publisher · View at Google Scholar · View at Scopus
  9. G. Dahllof, H. Preber, S. Eliasson, H. Ryden, J. Karsten, and T. Modeer, “Periodontal condition of epileptic adults treated long-term with phenytoin or carbamazepine,” Epilepsia, vol. 34, no. 5, pp. 960–964, 1993. View at Google Scholar · View at Scopus
  10. A. P. Gregoriou, P. E. Schneider, and P. R. Shaw, “Phenobarbital-induced gingival overgrowth? Report of two cases and complications in management,” ASDC Journal of Dentistry for Children, vol. 63, no. 6, pp. 408–413, 1996. View at Google Scholar · View at Scopus
  11. J. Katz, N. Givol, G. Chaushu, S. Taicher, and J. Shemer, “Vigabatrin-induced gingival overgrowth,” Journal of Clinical Periodontology, vol. 24, no. 3, pp. 180–182, 1997. View at Google Scholar
  12. American Academy of Periodontology, “Informational paper: drug associated gingival enlargement,” Journal of Periodontology, vol. 75, pp. 1424–1431, 2004. View at Google Scholar
  13. R. A. Seymour, J. S. Ellis, and J. M. Thomason, “Risk factors for drug-induced gingival overgrowth,” Journal of Clinical Periodontology, vol. 27, no. 4, pp. 217–223, 2000. View at Google Scholar · View at Scopus
  14. K. Lin, L. M. Guilhoto, and E. M. T. Yacubian, “Drug-induced gingival enlargement—part II. Antiepileptic drugs: not only phenytoin is involved,” Journal of Epilepsy and Clinical Neurophysiology, vol. 13, no. 2, pp. 83–88, 2007. View at Google Scholar · View at Scopus
  15. R. I. Marshall and P. M. Bartold, “A clinical review of drug-induced gingival overgrowths,” The Australian Dental Journal, vol. 44, no. 4, pp. 219–232, 1999. View at Google Scholar · View at Scopus
  16. C. M. Kanno, J. A. Oliveira, J. F. Garcia, A. L. Castro, and M. M. Crivelini, “Effects of cyclosporin, phenytoin, and nifedipine on the synthesis and degradation of gingival collagen in tufted capuchin monkeys (Cebus apella): histochemical and mmp-1 and -2 and collagen i gene expression analyses,” Journal of Periodontology, vol. 79, no. 1, pp. 114–122, 2008. View at Publisher · View at Google Scholar · View at Scopus
  17. T. M. Hassell and A. F. Hefti, “Drug-induced gingival overgrowth: old problem, new problem,” Critical Reviews in Oral Biology and Medicine, vol. 2, no. 1, pp. 103–137, 1991. View at Google Scholar · View at Scopus
  18. S. B. F. Martorelli, F. B. M. Andrade, F. O. Martorelli, E. V. Marinho, J. F. Melo, and A. C. L. Silva, “Atypical gingival overgrowth phenytoin-induced—a case report,” International Journal of Dentistry, vol. 7, pp. 69–72, 2008. View at Google Scholar
  19. W. W. Chee and C. E. Jansen, “Phenytoin hyperplasia occurring in relation to titanium implants: a clinical report,” The International Journal of Oral and Maxillofacial Implants, vol. 9, no. 1, pp. 107–109, 1994. View at Google Scholar · View at Scopus
  20. L. Brunet, J. Miranda, P. Roset, L. Berini, M. Farré, and C. Mendieta, “Prevalence and risk of gingival enlargement in patients treated with anticonvulsant drugs,” The European Journal of Clinical Investigation, vol. 31, no. 9, pp. 781–788, 2001. View at Publisher · View at Google Scholar · View at Scopus
  21. W. S. McLaughlin, D. E. Ball, R. A. Seymour, F. Kamali, and K. White, “The pharmacokinetics of phenytoin in gingival crevicular fluid and plasma in relation to gingival overgrowth,” Journal of Clinical Periodontology, vol. 22, no. 12, pp. 942–945, 1995. View at Google Scholar · View at Scopus
  22. M. P. Majola, M. L. McFadyen, C. Connolly, Y. P. Nair, M. Govender, and M. H. Laher, “Factors influencing phenytoin-induced gingival enlargement,” Journal of Clinical Periodontology, vol. 27, no. 7, pp. 506–512, 2000. View at Google Scholar · View at Scopus
  23. I. Marakoglu, U. K. Gursoy, H. Cakmak, and K. Marakoglu, “Phenytoin-induced gingival overgrowth in un-cooperated epilepsy patients,” Yonsei Medical Journal, vol. 45, no. 2, pp. 337–340, 2004. View at Google Scholar · View at Scopus
  24. H. Yamada, F. Nishimura, K. Furuno et al., “Serum phenytoin concentration and IgG antibody titre to periodontal bacteria in patients with phenytoin-induced gingival overgrowth,” Journal of the International Academy of Periodontology, vol. 3, no. 2, pp. 42–47, 2001. View at Google Scholar · View at Scopus
  25. Y. Soga, F. Nishimura, Y. Ohtsuka et al., “CYP2C polymorphisms, phenytoin metabolism and gingival overgrowth in epileptic subjects,” Life Sciences, vol. 74, no. 7, pp. 827–834, 2004. View at Publisher · View at Google Scholar · View at Scopus
  26. M. Peñarrocha-Diago, J. V. Bagán-Sebastián, and F. Vera-Sempere, “Diphenylhydantoin-induced gingival overgrowth in man: a clinico-pathological study,” Journal of Periodontology, vol. 61, no. 9, pp. 571–574, 1990. View at Google Scholar · View at Scopus
  27. D. E. Ball, W. S. McLaughlin, R. A. Seymour, and F. Kamali, “Plasma and saliva concentrations of phenytoin and 5-[4-hydroxyphenyl]-5-phenylhydantoin in relation to the incidence and severity of phenytoin-induced gingival overgrowth in epileptic patients,” Journal of Periodontology, vol. 67, no. 6, pp. 597–602, 1996. View at Google Scholar · View at Scopus
  28. F. Kamali, W. S. McLaughlin, D. E. Ball, and R. A. Seymour, “The effect of multiple anticonvulsant therapy on the expression of phenytoin-induced gingival overgrowth,” Journal of Clinical Periodontology, vol. 26, no. 12, pp. 802–805, 1999. View at Google Scholar · View at Scopus
  29. P. C. Trackman and A. Kantarci, “Connective tissue metabolism and gingival overgrowth,” Critical Review Oral Biology and Medicine, vol. 15, no. 3, pp. 165–175, 2004. View at Google Scholar · View at Scopus
  30. T. G. Modéer, M. Brunius, M. Iinuma, and U. H. Lerner, “Phenytoin potentiates interleukin-1-induced prostaglandin biosynthesis in human gingival fibroblasts,” The British Journal of Pharmacology, vol. 106, no. 3, pp. 574–578, 1992. View at Google Scholar · View at Scopus
  31. T. Modéer, I. Andurén, A. Bengtsson, and G. Andersson, “Interleukin-1 beta and phenytoin reduce alpha 1 procollagen mRNA expression in human gingival fibroblasts,” Journal of Periodontal Research, vol. 31, no. 8, pp. 563–569, 1996. View at Google Scholar · View at Scopus
  32. L. C. Spolidorio, H. F. G. Gonzaga, and D. M. P. Spolidorio, “Quantitative analysis of gingival tissues of rats treated with phenytoin and cyclosporine,” Pesquisa Odontológica Brasileira, vol. 14, pp. 327–333, 2000. View at Google Scholar
  33. J. Guimarães Jr., “Hiperplasia gengival medicamentosa—parte I,” Journal of Epilepsy and Clinical Neurophysiology, vol. 13, no. 1, pp. 33–36, 2007. View at Google Scholar · View at Scopus
  34. T. Kato, N. Okahashi, S. Kawai et al., “Impaired degradation of matrix collagen in human gingival fibroblasts by the antiepileptic drug phenytoin,” Journal of Periodontology, vol. 76, no. 6, pp. 941–950, 2005. View at Publisher · View at Google Scholar · View at Scopus
  35. M. Ogino, J. Kido, M. Bando et al., “Alpha 2 integrin +807 polymorphism in drug-induced gingival overgrowth,” Journal of Dental Research, vol. 84, no. 12, pp. 1183–1186, 2005. View at Publisher · View at Google Scholar · View at Scopus
  36. L. Brunet, J. Miranda, M. Farré, L. Berini, and C. Mendieta, “Gingival enlargement induced by drugs,” Drug Safety, vol. 15, no. 3, pp. 219–231, 1996. View at Google Scholar · View at Scopus
  37. M. Kataoka, H. Seto, C. Wada, J. I. Kido, and T. Nagata, “Decreased expression of alpha2 integrin in fibroblasts isolated from cyclosporine A-induced gingival overgrowth in rats,” Journal of Periodontal Research, vol. 38, no. 5, pp. 533–537, 2003. View at Publisher · View at Google Scholar · View at Scopus
  38. F. Inoue and J. V. Harrison, “Folic acid and phenytoin hyperplasia,” The Lancet, vol. 2, p. 86, 1984. View at Google Scholar · View at Scopus
  39. C. Williams, T. Poppell, D. Brock, and S. Low, “Phenytoin induced gingival overgrowth: effect of folic acid supplementation,” Clinical Research, vol. 35, p. 61, 1987. View at Google Scholar
  40. T. D. Poppell, S. D. Keeling, J. F. Collins, and T. M. Hassell, “Effect of folic acid on recurrence of phenytoin-induced gingival overgrowth following gingivectomy,” Journal of Clinical Periodontology, vol. 18, no. 2, pp. 134–139, 1991. View at Publisher · View at Google Scholar · View at Scopus
  41. V. N. Prasad, H. S. Chawla, A. Goyal, K. Gauba, and P. Singhi, “Folic acid and phenytoin induced gingival overgrowth—is there a preventive effect,” Journal of the Indian Society of Pedodontics and Preventive Dentistry, vol. 22, no. 2, pp. 82–91, 2004. View at Google Scholar · View at Scopus
  42. R. S. Brown, P. T. Di Stanislao, W. T. Beaver, and W. K. Bottomley, “The administration of folic acid to institutionalized epileptic adults with phenytoin-induced gingival hyperplasia. A double-blind, randomized, placebo-controlled, parallel study,” Oral Surgery Oral Medicine and Oral Pathology, vol. 71, no. 5, pp. 565–568, 1991. View at Google Scholar · View at Scopus
  43. R. Serra, A. G. Al-Saidi, N. Angelov, and S. Nares, “Suppression of LPS-induced matrix-metalloproteinase responses in macrophages exposed to phenytoin and its metabolite, 5-[p-hydroxyphenyl-], 5-phenylhydantoin,” Journal of Inflammation, vol. 7, article 48, 2010. View at Publisher · View at Google Scholar · View at Scopus
  44. L. H. Engelholm, S. Ingvarsen, H. J. Jürgensen et al., “The collagen receptor uPARAP/Endo180,” Frontiers in Bioscience, vol. 1, pp. 2103–2114, 2009. View at Google Scholar · View at Scopus
  45. A. Kantarci, P. Augustin, E. Firatli et al., “Apoptosis in gingival overgrowth tissues,” Journal of Dental Research, vol. 86, no. 9, pp. 888–892, 2007. View at Publisher · View at Google Scholar · View at Scopus
  46. T. A. Wynn, “Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases,” Journal of Clinical Investigation, vol. 117, no. 3, pp. 524–529, 2007. View at Publisher · View at Google Scholar · View at Scopus
  47. T. A. Wynn, “Cellular and molecular mechanisms of fibrosis,” Journal of Pathology, vol. 214, no. 2, pp. 199–210, 2008. View at Publisher · View at Google Scholar · View at Scopus
  48. A. M. Suzuki, A. Yoshimura, Y. Ozaki, T. Kaneko, and Y. Hara, “Cyclosporin A and phenytoin modulate inflammatory responses,” Journal of Dental Research, vol. 88, no. 12, pp. 1131–1136, 2009. View at Publisher · View at Google Scholar · View at Scopus
  49. K. Saito, S. Mori, N. Tanda, and S. Sakamoto, “Expression of p53 protein and Ki-67 antigen in gingival hyperplasia induced by nifedipine and phenytoin,” Journal of Periodontology, vol. 70, no. 6, pp. 581–586, 1999. View at Publisher · View at Google Scholar · View at Scopus
  50. A. M. Iacopino, D. Doxey, C. W. Cutler et al., “Phenytoin and cyclosporine A specifically regulate macrophage phenotype and expression of platelet-derived growth factor and interleukin-1 in vitro and in vivo: possible molecular mechanism of drug-induced gingival hyperplasia,” Journal of Periodontology, vol. 68, no. 1, pp. 73–83, 1997. View at Google Scholar · View at Scopus
  51. M. I. Uzel, A. Kantarci, H. H. Hong et al., “Connective tissue growth factor in drug-induced gingival overgrowth,” Journal of Periodontology, vol. 72, no. 7, pp. 921–931, 2001. View at Publisher · View at Google Scholar · View at Scopus
  52. H. H. Hong, M. I. Uzel, C. Duan, M. C. Sheff, and P. C. Trackman, “Regulation of lysyl oxidase, collagen, and connective tissue growth factor by TGF-b1 and detection in human gingival,” Laboratory Investigation, vol. 79, no. 12, pp. 1655–1667, 1999. View at Google Scholar · View at Scopus
  53. E. J. Feres-Filho, Y. J. Choi, X. Han, T. E. Takala, and P. C. Trackman, “Pre- and post-translational regulation of lysyl oxidase by transforming growth factor-beta 1 in osteoblastic MC3T3-E1 cells,” Journal of Biological Chemistry, vol. 270, no. 51, pp. 30797–30803, 1995. View at Publisher · View at Google Scholar · View at Scopus
  54. M. R. Duncan, K. S. Frazier, S. Abramson et al., “Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis, down-regulation by cAMP,” The FASEB Journal, vol. 13, no. 13, pp. 1774–1786, 1999. View at Google Scholar · View at Scopus
  55. T. Mori, S. Kawara, M. Shinozaki et al., “Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: a mouse fibrosis model,” Journal of Cellular Physiology, vol. 181, no. 1, pp. 153–159, 1999. View at Publisher · View at Google Scholar · View at Scopus
  56. Y. Chen, I. E. Blom, S. A. R. Goldschmeding, D. J. Abraham, and A. Leask, “CTGF expression in mesangial cells: involvement of SMADS, MAP kinase, and PKC,” Kidney International, vol. 62, no. 4, pp. 1149–1159, 2002. View at Publisher · View at Google Scholar · View at Scopus
  57. S. S. Sume, A. Kantarci, A. Lee, H. Hasturk, and P. C. Trackman, “Epithelial to mesenchymal transition in gingival overgrowth,” The American Journal of Pathology, vol. 177, no. 1, pp. 208–218, 2010. View at Publisher · View at Google Scholar · View at Scopus
  58. K. Okada, T. Sugiura, E. Kuroda, S. Tsuji, and U. Yamashita, “Phenytoin promotes Th2 type immune response in mice,” Clinical and Experimental Immunology, vol. 124, no. 3, pp. 406–413, 2001. View at Publisher · View at Google Scholar · View at Scopus
  59. H. E. Bazan, Y. Tao, M. A. Decoster, and N. G. Bazan, “Platelet-activating factor induces cyclooxygenase-2 gene expression in corneal epithelium. Requirement of calcium in the signal transduction pathway,” Investigative Ophthalmology and Visual Science, vol. 38, no. 12, pp. 2492–2501, 1997. View at Google Scholar · View at Scopus
  60. G. Lonnemann, G. Engler-Blum, G. A. Muller, and C. A. Dinarello, “Cytokines in human renal interstitial fibrosis. II. Intrinsic interleukin [IL]-1 synthesis and IL-1 dependent production of IL-6 and IL-8 by cultured kidney fibroblasts,” Kidney International, vol. 47, no. 3, pp. 845–854, 1995. View at Google Scholar · View at Scopus
  61. R. M. Silver, “Interstitial lung disease of systemic sclerosis,” International Review of Immunology, vol. 12, pp. 281–291, 1995. View at Google Scholar · View at Scopus
  62. R. E. Dill, W. L. Davis, and E. R. Zimmermann, “Quantitation of phagocytic cells in phenytoin-induced connective tissue proliferation in the rat,” Journal of Periodontology, vol. 59, no. 3, pp. 190–197, 1988. View at Google Scholar · View at Scopus
  63. F. Nishimura, H. Naruishi, K. Naruishi et al., “Cathepsin-L, a key molecule in the pathogenesis of drug-induced and I-cell disease-mediated gingival overgrowth: a study with cathepsin-L-deficient micey,” The American Journal of Pathology, vol. 161, no. 6, pp. 2047–2052, 2002. View at Google Scholar · View at Scopus
  64. H. Yamada, F. Nishimura, K. Naruishi 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,” Journal of Periodontology, vol. 71, no. 6, pp. 955–960, 2000. View at Google Scholar · View at Scopus
  65. R. E. Dill and A. M. Iacopino, “Myofibroblasts in phenytoin-induced hyperplastic connective tissue in the rat and in human gingival overgrowth,” Journal of Periodontology, vol. 68, no. 4, pp. 375–380, 1997. View at Google Scholar · View at Scopus
  66. G. C. Armitage, “Development of a classification system for periodontal diseases and conditions,” Annals of Periodontology, vol. 4, no. 1, pp. 1–6, 1999. View at Google Scholar · View at Scopus
  67. R. I. Marshall and P. M. Bartold, “Medication induced gingival overgrowth,” Oral Diseases, vol. 4, no. 2, pp. 130–151, 1998. View at Google Scholar · View at Scopus
  68. T. C. O'Neil and K. H. Figures, “The effects of chlorhexidine and mechanical methods of plaque control on the recurrence of gingival hyperplasia in young patients taking phenytoin,” The British Dental Journal, vol. 152, no. 4, pp. 130–133, 1982. View at Publisher · View at Google Scholar · View at Scopus
  69. G. Dahllöf and T. Modéer, “The effect of a plaque control program on the development of phenytoin-induced gingival overgrowth, a 2-year longitudinal study,” Journal of Clinical Periodontology, vol. 13, no. 9, pp. 845–849, 1986. View at Google Scholar · View at Scopus
  70. T. Modéer and G. Dahllöf, “Development of phenytoin-induced gingival overgrowth in non-institutionalized epileptic children subjected to different plaque control programs,” Acta Odontologica Scandinavica, vol. 45, no. 2, pp. 81–85, 1987. View at Google Scholar · View at Scopus
  71. K. Takada, H. Sugiyama, K. Umezawa, J. Mega, and M. Hirasawa, “The subgingival microflora in phenytoin-induced gingival hyperplasia,” Journal of Periodontal Research, vol. 38, no. 5, pp. 477–481, 2003. View at Publisher · View at Google Scholar · View at Scopus
  72. S. Akiyama, A. Amano, T. Kato, Y. Takada, K. R. Kimura, and I. Morisaki, “Relationship of periodontal bacteria and Porphyromonas gingivalis fimA variations with phenytoin-induced gingival overgrowth,” Oral Diseases, vol. 12, no. 1, pp. 51–56, 2006. View at Publisher · View at Google Scholar · View at Scopus
  73. H. Miyazaki, “Association between phenytoin-induced gingival hyperplasia and periodontopathic bacteria in institutionalized patients with severe motor and intellectual disabilities,” Kokubyo Gakkai Zasshi, vol. 77, no. 2, pp. 140–148, 2010. View at Google Scholar · View at Scopus
  74. Q. T. Smith, M. M. Wilson, G. R. Germaine, and B. L. Philstrom, “Microbial flora and clinical parameters in phenytoin associated gingival overgrowth,” Journal of Periodontal Research, vol. 18, no. 1, pp. 56–66, 1983. View at Google Scholar · View at Scopus
  75. T. Kawai and S. Akira, “TLR signaling,” Cell Death and Differentiation, vol. 13, no. 5, pp. 816–825, 2006. View at Publisher · View at Google Scholar · View at Scopus
  76. T. M. Hassell, R. C. Page, A. S. Narayanan, and C. G. Cooper, “Diphenylhydantoin [Dilantin] gingival hyperplasia: drug-induced abnormality of connective tissue,” Proceedings of the National Academy of Sciences of the United States of America, vol. 73, no. 8, pp. 2909–2912, 1976. View at Google Scholar · View at Scopus
  77. D. C. Bergen, “Pharmacokinetics of phenytoin, reminders and discoveries,” Epilepsy Currents, vol. 9, pp. 102–104, 2009. View at Google Scholar
  78. M. E. Veronese, P. I. Mackenzie, C. J. Doecke, M. E. McManus, J. O. Miners, and D. J. Birkett, “Tolbutamide and phenytoin hydroxylations by cDNA-expressed human liver cytochrome P4502C9,” Biochemical and Biophysical Research Communications, vol. 175, no. 3, pp. 1112–1118, 1991. View at Publisher · View at Google Scholar · View at Scopus
  79. T. M. Hassell, “Stimulation and inhibition of fibroblast subpopulations by phenytoin and phenytoin metabolites, pathogenetic role in gingival enlargement,” Pediatric Dental Journal, vol. 3, pp. 137–153, 1981. View at Google Scholar
  80. T. M. Hassell and E. J. Stanek, “Evidence that healthy human gingiva contains functionally heterogeneous fibroblast subpopulations,” Archives of Oral Biology, vol. 28, no. 7, pp. 617–625, 1983. View at Google Scholar · View at Scopus
  81. A. Pagliarini, G. Stabellini, F. Carinci, G. Calura, M. Tognon, and R. Evangelisti, “Heterogeneity of fibroblasts derived from human free and attached gingiva. Glycosaminoglycan synthesis and effects of phenytoin [PHT] treatment,” Journal of Oral Pathology and Medicine, vol. 24, no. 2, pp. 72–77, 1995. View at Google Scholar · View at Scopus
  82. G. H. Cockey, J. A. Boughman, E. L. Harris, and T. M. Hassell, “Genetic control of variation in human gingival fibroblast proliferation rate,” In Vitro Cellular and Developmental Biology, vol. 25, no. 3, pp. 255–258, 1989. View at Google Scholar · View at Scopus