Phenytoin Increases Gene Expression for Platelet‐Derived Growth Factor B Chain in Macrophages and Monocytes

Abstract

The mechanism by which phenytoin (PHT) induces gingival overgrowth remains unclear. We hypothesized that PHT increases macrophage production of platelet-derived growth factor (PDGF), an important cytokine in connective tissue growth and repair, and that excessive production PDGF in gingiva could lead to redundant growth. To test the hypothesis, rat peritoneal macrophages and human blood monocytes were cultured in the presence of PHT (5 to 20 micrograms/ml medium) or an equal volume of its solvent for 3 days and tested for expression of PDGF-B mRNA by in situ hybridization. Approximately 300 cells/culture well were examined (3 wells/drug level) for positive indication of PDGF-B mRNA. Data were compared by chi square test. All levels of PHT in both cell types induced a 2- to 8-fold increase in PDGF-B mRNA positive cells, significant in all cases at P < 0.001. Northern blot analysis of RNA from similarly cultured rat macrophages confirmed these findings. Cells treated with 10 micrograms PHT/ml medium or solvent revealed 2.2 +/- 0.3 and 1.0 +/- 0.2 (mean +/- SEM) arbitrary units PDGF mRNA respectively (t tests, P < 0.05). Additionally, rat macrophages were cultured in presence of 5 micrograms PHT/medium or its solvent and medium was analyzed for PDGF secretion by radioimmunoassay. Mean values (+/- SEM) were 1.28 +/- 0.49 and 0.78 +/- 0.07 ng/mg protein respectively (t test, P < 0.05). These data showed that PHT augmented the expression of c-sis, the gene for PDGF-B, and offered a possible explanation for PHT-induced gingival overgrowth.

In vivo association of immunophenotyped macrophages expressing CD163 with PDGF-B in gingival overgrowth-induced by three different categories of medications

“…35 The present study showed elevated expression of CD163 in group II compared to groups III and IV. This is in accordance with Dill et al 36 and Iacopino et al 6 as they concluded that PNT, CsA, and nifedipine GO tissues contain subpopulations of macrophages and other inflammatory cells. These cells differ from those in healthy control gingival tissues.…”

“…This observation is convenient with Plemons et al 38 who found that healthy gingiva is in a continuous state of wound repair and support the hypothesis that CSA-induced GO is associated with enhanced macrophage PDGF-B gene expression rather than an increase in the number of PDGF-B producing macrophages. In addition, Dill et al 36 analyzed RNA isolated from GO associated with CsA and PNT and reported that expression of PDGF gene was 47-fold greater than control. This causes persistent proliferation of connective tissue, matrix formation, and fibrosis.…”

Out Come of Topical Phenytoin in the Management of Diabetic Ulcers

“…Its wound-related pharmacology has been investigated. 81 Phenytoin increases gene expression of the platelet-derived growth factor B chain in macrophages and monocytes. 82 Healthy granulation tissue appears earlier with phenytoin than with conventional saline dressings.…”

“…It is not known if phenytoin has intrinsic antibacterial activity, or whether the effect of phenytoin on the bacterial load of wounds is mediated indirectly by effects on inflammatory cells and neovascularization 12 . Local pain relief has also been observed with topical phenytoin therapy, which can be explained by its membrane-stabilizing action and the reduced inflammatory response 84,81 . Facilitation of nerve regeneration has also been reported with phenytoin 12 .…”

Influence of Low Level Sodium Fluoride on Expression of IGF-1 and IGF-2 Protein in Experimental Type 2 Diabetes with Periodontitis Model

“…The findings in this study are consistent with the possibility that the NaF acts through the stimulation of local bone cell production of IGFs and/or the enhancement of the biological activity of IGFs to stimulate proliferation of human periodontal cells. There are data suggesting that the activity of a number of anabolic agents may also be mediated by upregulation of the production and/or activity of growth factors, for instance, transforming growth factor (TGF)- 21) , platelet-derived growth factor (PDGF) 22) , epidermal growth factor (EGF) 23) , bone morphogenetic protein-2 (BMP-2) 24) , and IGFs 25,26) in various cells and tissues. Upregulation of local bone cell production and release of IGFs have been implicated in the activity of several anabolic agents.…”