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 PP  Vol.4 No.2 , April 2013
Phenytoin-Induced Elevation of the Intracellular Calcium Concentration by Stimulation of Calcium-Sensing Receptors in Gingival Fibroblasts
Abstract: Background:The mechanism concerning gingival overgrowth as a side effect of phenytoin, a therapeutic drug for epilepsy has been still unclear. As one of mechanisms, by measuring the intracellular calcium concentration ([Ca2+]i) of the gingival fibroblasts, it has been advocated that there is relationship between gingival overgrowth and phenytoin-induced alterations in the [Ca2+]i in gingival fibroblasts. To confirm that phenytoin elevates the [Ca2+]i, and if so, to find out its mode of action. Methods: The [Ca2+]i was measured with the Ca2+-sensitive fluorescent dye fura-2/AM. Cells were soaked in a flexiperm chamber and perfused by a saline. Drugs at appropriate concentrations were added to the perfusate. Results: Phenytoin concentration-dependently elevated the [Ca2+]i. NPS2390, a calcium-sensing receptor (CaSR) blocker, significantly suppressed the phenytoin-induced [Ca2+]i elevation. U73122, a phospholipase C (PLC) inhibitor, inihibited the phenytoin-induced [Ca2+]i elevation. TMB-8, a blocker of inositol triphophate (IP3) receptors in ER, significantly depressed the phenytoin-induced [Ca2+]i elevation. m-3M3FBS, a PLC activator, enhanced the phenytoin-induced [Ca2+]i elevation. From the findings obtained, it is discussed as follows: The Ca2+-free saline and NPS2390, a CaSR antagonist, inhibited the phenytoin-induced [Ca2+]i rise; These results indicate that CaSRs exist in gingival fibroblasts and that CaSRs are involved in the phenytoin-induced [Ca2+]i rise; U73122 and TMB-8 depressed the phenytoin-induced [Ca2+]i elevation and furthermore, m-3M3FBS enhanced the phenytoin-induced [Ca2+]i elevation, showing that the Ca2+ release from the ER is involved in the phenytoin-induced [Ca2+]i elevation. Conclusion: We have concluded that phenytoin elevates the [Ca2+]i by activating CaSRs and enhancing the Ca2+ release from the Ca2+ stores in gingival fibroblasts.
Cite this paper: T. Hattori, K. Nakano and T. Kawakami, "Phenytoin-Induced Elevation of the Intracellular Calcium Concentration by Stimulation of Calcium-Sensing Receptors in Gingival Fibroblasts," Pharmacology & Pharmacy, Vol. 4 No. 2, 2013, pp. 261-265. doi: 10.4236/pp.2013.42037.
References

[1]   E. Bondon-Guitton, H. Bagheri and J. L. Montastruc, “Drug-Induced Gingival Overgrowth: A Study in the French Pharmacovigilance Database,” Journal of Clinical Periodontology, Vol. 39, No. 6, 2012, pp. 513-518. doi:10.1111/j.1600-051X.2012.01878.x

[2]   A. S. Narayanan, D. F. Meyers and R. C. Page, “Regulation of Collagen Production in Fibroblasts Cultured from Normal and Phenytoin-Induced Hyperplastic Human Gingiva,” Journal of Periodontological Research, Vol. 23, No. 2, 1988, pp. 118-121. doi:10.1111/j.1600-0765.1988.tb01343.x

[3]   C. M. Kanno, J. A. Oliveira, J. F. Garcia, A. L. Castro and M. M. Criverini, “Effects of Cyclosporine, Phenytoin, and Nifedipine on the Synthesis and Degradation of Gingival Collagen in Tuffed Capuchin Monkeys (Celbus paella): Histochemical and MMP-1 and -2 and Collagen I Gene Expression Analysis,” Journal of Periodontology, Vol. 79, No. 1, 2008, pp. 114-122. doi:10.1902/jop.2008.070267

[4]   M. F. Akhter, S. L. Quayum, A. B. Ali and Z. Mamoon, “Drug-Induced Gin-gival Overgrowth-Review,” Bangladesh Journal of Physiology and Pharmacology, Vol. 25, No. 1-2, 2009, pp. 26-29.

[5]   G. H. Cockey, J. A. Boughman, E. L. Harris and T. M. Hassel, “Genetic Control of Variation in Human Gingival Fibroblast Proliferation Rate,” In Vitro Cellular and Developmental Biology, Vol. 25, No. 3, 1989, pp. 255-258. doi:10.1007/BF02628463

[6]   O. A. González and J. M. González, “Morphological and Phenotypic Differences in Fibroblasts Obtained from Gingival Overgrowth Secondary to Phenytoin: A Pilot Study,” Revista Odontológica Mexicana, Vol. 13, 2009, pp. 17-23.

[7]   T. Kato, N. Okahashi, T. Ohno, H. Inaba, S. Kawai and A. Amano, “Effect of Phenytoin on Collagen Accumulation by Human Gingival Fibroblasts Exposed to TNF-α in Vitro,” Oral Desease, Vol. 12, No. 2, 2006, pp. 156-162. doi:10.1111/j.1601-0825.2005.01175.x

[8]   Y. Fujimori, S. Maeda, M. Saeki, I. Morisaki and Y. Kamisaki, “Inhibition by Nifedipine of Adherenceand Activated Macrophage-Induced Death of Human Gingival Fibroblasts,” European Journal of Pharmacology, Vol. 415, No. 1, 2001, pp. 95-103. doi:10.1016/S0014-2999(01)00810-X

[9]   T. Modéer, G. Brunius, C. Mendez, L. Juntti-Beggren and P. O. Berggren, “Influence of Phenytoin on cytoplasmic Free Ca2+ Level in Human Gingival Fibroblasts,” Scandinavian Journal of Dental Research, Vol. 99, No. 4, 1991, pp. 310-315.

[10]   T. Hattori, T. Ara and Y. Fujinami, “Pharmacological Evidences for the Stimulation of Calcium-Sensing Receptors by Nifedipine in Gingival Fibroblasts,” Journal of Pharmacology and Pharmacotherapeutics, Vol. 2, No. 1, 2011, pp. 30-35. doi:10.4103/0976-500X.77111

[11]   J. O. Kwak, J. Kwak, H. W. Kim, K. J. Oh, Y. T. Kim, S. M. Jung and S. H. Cha, “The Extracellular Calcium Sensing Receptor Is Expressed in Mouse Mesangial Cells and Modulates Cell Proliferation,” Experimental and Molecular Medicine, Vol. 37, No. 5, 2005, pp. 457-465. doi:10.1038/emm.2005.56

[12]   C. Remy, P. Kirchhof, P. Hafner, S. M. Busque, M. K. Müller, J. P. Geibel and C. A. Wagner, “Stimulatory Pathways of the Calcium-Sensing Receptor on Acid Secretion in Freshly Isolated Human Gastric Glands,” Cellular Physiology and Biochemistry, Vol. 19, No. 2, 2007, pp. 33-42. doi:10.1159/000099190

[13]   O. Kifor, I. Kifor and E. D. Brown, “Effects of High Extracellular Calcium Concentrations on Phosphoinositide Turnover and Inositol Phosphate Metabolism in Dispersed Bovine Parathyroid Cells,” Journal of Bone and Mineral Research, Vol. 7, No. 11, 1992, pp. 1327-1336. doi:10.1002/jbmr.5650071113

[14]   M. A. Rodrigues, D. A. Gimes, M. F. Leite, W. Grant, L. Zhang, W. Lam, Y. C. Cheng, A. M. Bennett and M. H. Nathanson, “Nucleoplasmic Calcium Is Required for Cell Proliferation,” Journal of Biological Chemistry, Vol. 282, No. 23, 2007, pp. 17061-17068. doi:10.1074/jbc.M700490200

[15]   L. Munaron, “Calcium Signaling and Control of Cell Proliferation by Tyrosine Kinase Receptors (Review),” International Journal of Molecular Medicine, Vol. 10, No. 6, 2002, pp. 671-676.

[16]   L. Munaron, S. Antoniotti and D. Lovisolo, “Intracellular Calcium Signals and Control of Cell Proliferation: How Many Mechanisms?” Journal of Cellular and Molecular Medicine, Vol. 8, No. 2, 2004, pp. 161-168. doi:10.1111/j.1582-4934.2004.tb00271.x

[17]   Y. S. Bae, T. G. Lee, J. C. Park, J. H. Hur, Y. Kim, K. Heo, J. Y. Kwak, P. G. Suh and S. H. Ryu, “Identification of a Compound that Directly Stimulates Phospholipase C Activity,” Molecular Pharmacology, Vol. 63, No. 5, 2003, pp. 1043-1050. doi:10.1124/mol.63.5.1043

[18]   B. Srinu, O. Banji, M. Kumar, S. R. Teja and T. Praveen, “Cell Communication and Ion Channels: A Review,” International Journal of Research in Pharmacy and Chemistry, Vol. 1, No. 1, 2011, pp. 91-100.

 
 
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