Impaired Degradation of Matrix Collagen in Human Gingival Fibroblasts by the Antiepileptic Drug Phenytoin

Kato, Takahiro; Okahashi, Nobuo; Kawai, Shinji; Kato, Takafumi; Inaba, Hiroaki; Morisaki, Ichijiro; Amano, Atsuo

doi:10.1902/jop.2005.76.6.941

Cited by 54 publications

(56 citation statements)

References 64 publications

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“…The study of Modeer et al [30] agrees with our results, and also shows that the inhibitive effect of IL-1β on expression of collagen genes increases in presence of phenytoin. One other study has showed that the simultaneous presence of TNF-α and phenytoin stimulates the production of IL-1α by fibroblasts and suggested that the simultaneous presence of three inflammatory mediators, TNF-α, IL-1α, and PGE 2 , could raise the effects of collagenase enzyme [43]. Brunius et al [29] have proposed that phenytoin cannot stimulate the IL-1β production solely, and that the concurrent presence of TNF-α is necessary for inducing IL-1β and PGE 2 production.…”

Section: Rate Of Proliferationmentioning

confidence: 99%

Phenytoin Effects on Proliferation and Induction of IL1<i>β</i> and PGE2 in Pediatric and Adults’ Gingival Fibroblasts

Vahabi¹,

Moslemi²,

Nazemisalman³

et al. 2014

OJST

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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.

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Section: Rate Of Proliferationmentioning

confidence: 99%

Phenytoin Effects on Proliferation and Induction of IL1<i>β</i> and PGE2 in Pediatric and Adults’ Gingival Fibroblasts

Vahabi¹,

Moslemi²,

Nazemisalman³

et al. 2014

OJST

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“…[1][2][3][4][5] and phenytoin increases gene expression of the platelet derived growth factor β chain in macrophage and monocytes. The antibacterial activity of phenytoin contributed to removal of Staphylococcus aureus, Escherichia coli, Klebsiella species, Pseudomonas.…”

Section: Introductionmentioning

confidence: 99%

Topical phenytoin dressing versus conventional dressing in diabetic ulcers

et al. 2017

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Background: Diabetic foot ulcer is estimated to affect 15% of all diabetic individuals during their lifetime. Management requires a multisystem approach. Various techniques have been tried to treat chronic ulcers, but none was proved to be ideal.Methods: This is a prospective randomised comparative study, where 56 patients with diabetic foot ulcers admitted in dept of surgery SSG hospital, Baroda, india were divided into two comparable groups. Of which 28 underwent topical phenytoin dressings, remaining 28 underwent Betadine dressing (5% w/v povidone – iodine solution). The variables were compared after 14 days based on rate of granulation tissue formation as percentage of ulcer surface area, wound culture-sensitivity and duration of hospital stay. Chi square test was used to compare the data at each of the assessment point in both groups. Results: In Phenytoin group, the mean rate of healthy granulation tissue formation was 60.71%, and mean hospital stay was 23.96 days with negative culture sensitivity was 54%. The Betadine group showed, the mean rate of granulation tissue formation was 11%, and mean hospital stay was 35 days with negative culture sensitivity was 18%.Conclusions: Topical phenytoin dressing considered as superior and cost effective in management of diabetic ulcers.

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“…Under normal physiological condition, the degradation of the extracellular matrix is enabled by the enzymatic activities of collagenases and matrix metalloproteinases (MMPs) coupled with a negative regulatory control by tissue inhibitor of MMPs (TIMP), which acts to inhibit the function of MMPs. It has been observed that phenytoin induced GO tissues expressed reduced levels of MMP-1, 2 and 3, while expressing elevated levels of TIMP-1 mRNA, both of which together could disrupt the matrix degradation machinery (Kato et al, 2005;Kanno et al, 2008). Besides, it may also be noted that phenytoin interferes with the cellular calcium influx (Brunet et al, 1996) and hepatic 5,10-methylenetetrahydrofolate reductase activity, both of which consequently affects the metabolism of folates.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Mutation Analysis of PIK3CA, p14ARF, p16INK4a and p21^Waf1/Cip1Genes is Suggestive of a Non- Neoplastic Nature of Phenytoin Induced Gingival Overgrowth

Swamikannu

Kumar²,

Jayesh³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: Dilantin sodium (phenytoin) is an antiepileptic drug, which is routinely used to control generalized tonic clonic seizure and partial seizure episodes. A few case reports of oral squamous cell carcinomas arising from regions of phenytoin induced gingival overgrowth (GO), and overexpression of mitogenic factors and p53 have presented this condition as a pathology with potential to transform into malignancy. We recently investigated the genetic status of p53 and H-ras, which are known to be frequently mutated in Indian oral carcinomas in GO tissues and found them to only contain wild type sequences, which suggested a non-neoplastic nature of phenytoin induced GO. However, besides p53 and H-ras, other oncogenes and tumor suppressors such as PIK3CA, p14ARF, p16INK4a and p21 Waf1/Cip1 , are frequently altered in oral squamous cell carcinoma, and hence are required to be analyzed in phenytoin induced GO tissues to be affirmative of its non-neoplastic nature. Methods: 100ng of chromosomal DNA isolated from twenty gingival overgrowth tissues were amplified with primers for exons 9 and 20 of PIK3CA, exons 1α, 1β and 2 of p16INK4a and p14ARF, and exon 2 of p21 Waf1/Cip1 , in independent reactions. PCR amplicons were subsequently gel purified and eluted products were sequenced. Results: Sequencing analysis of the twenty samples of phenytoin induced gingival growth showed no mutations in the analyzed exons of PIK3CA, p14ARF, p16INK4a and p21 Waf1/Cip1 . Conclusion: The present data indicate that the mutational alterations of genes, PIK3CA, p14ARF, p16INK4a and p21 Waf1/Cip1 that are frequently mutated in oral squamous cell carcinomas are rare in phenytoin induced gingival growth. Thus the findings provide further evidence that phenytoin induced gingival overgrowth as a non-neoplastic lesion, which may be considered as clinically significant given the fact that the epileptic patients are routinely administered with phenytoin for the rest of their lives to control seizure episodes. Keywords:Cancer from gingival overgrowth -phenytoin induced gingival carcinoma -drug induced gingival carcinoma RESEARCH ARTICLEComprehensive Mutation Analysis of PIK3CA, p14ARF, p16INK4a and p21 Waf1/Cip1

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Impaired Degradation of Matrix Collagen in Human Gingival Fibroblasts by the Antiepileptic Drug Phenytoin

Cited by 54 publications

References 64 publications

Phenytoin Effects on Proliferation and Induction of IL1<i>β</i> and PGE2 in Pediatric and Adults’ Gingival Fibroblasts

Phenytoin Effects on Proliferation and Induction of IL1<i>β</i> and PGE2 in Pediatric and Adults’ Gingival Fibroblasts

Topical phenytoin dressing versus conventional dressing in diabetic ulcers

Comprehensive Mutation Analysis of PIK3CA, p14ARF, p16INK4a and p21^Waf1/Cip1Genes is Suggestive of a Non- Neoplastic Nature of Phenytoin Induced Gingival Overgrowth

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Impaired Degradation of Matrix Collagen in Human Gingival Fibroblasts by the Antiepileptic Drug Phenytoin

Cited by 54 publications

References 64 publications

Phenytoin Effects on Proliferation and Induction of IL1&lt;i&gt;β&lt;/i&gt; and PGE2 in Pediatric and Adults’ Gingival Fibroblasts

Phenytoin Effects on Proliferation and Induction of IL1&lt;i&gt;β&lt;/i&gt; and PGE2 in Pediatric and Adults’ Gingival Fibroblasts

Topical phenytoin dressing versus conventional dressing in diabetic ulcers

Comprehensive Mutation Analysis of PIK3CA, p14ARF, p16INK4a and p21Waf1/Cip1Genes is Suggestive of a Non- Neoplastic Nature of Phenytoin Induced Gingival Overgrowth

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Phenytoin Effects on Proliferation and Induction of IL1<i>β</i> and PGE2 in Pediatric and Adults’ Gingival Fibroblasts

Phenytoin Effects on Proliferation and Induction of IL1<i>β</i> and PGE2 in Pediatric and Adults’ Gingival Fibroblasts

Comprehensive Mutation Analysis of PIK3CA, p14ARF, p16INK4a and p21^Waf1/Cip1Genes is Suggestive of a Non- Neoplastic Nature of Phenytoin Induced Gingival Overgrowth