Increased Accumulation of Sulfated Glycosaminoglycans in Cultures of Human Fibroblasts from Phenytoin-induced Gingival Overgrowth

Abstract

27514Long-term ingestion of phenytoin elicits gingival overgrowth. We investigated sulfated glycosaminoglycan (GAG) metabolism by human gingival fibroblasts from normal gingivae and from phenytoinenlarged gingivae. Incorporation, utilization, and subsequent loss of 35S04= was measured in pulse-chase experiments. Fibroblasts from overgrown gingivae demonstrated increased accumulation of sulfated glycosaminoglycans. The increase was due to elevated synthesis and not to decreased degradation.

Potentiation of fibroblast spreading by extracellular matrix from fibroblasts derived from phenytoin-induced gingival overgrowth

“…In a previous study we showed that human gingival fibroblasts derived from PHTinduced gingival overgrowth exhibit an increased synthesis of sulfated glycosaminoglycans in vitro (8,9). Recently, we have also shown that connective tissue from PHTinduced gingival overgrowth consists of an increased amount of PGs compared with normal gingiva (7).…”

“…There is an increased amount of proteoglycans (PGs) in PHT-induced lesions compared with normal gingival tissue (7). Furthermore, gingival fibroblasts derived from PHT-induced gingival overgrowth show increased synthesis of sulfated glycosaminoglycans compared with gingival fibroblasts from normal gingival tissue (8,9).…”

Effect of 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) enantiomers, major metabolites of phenytoin, on the occurrence of chronic-gingival hyperplasia: in vivo and in vitro study

“…Hassell reported that individual (genetically determined) differences in the metabolism of PHT and/or the host response to the drug probably determine whether a particular patient is susceptible to gingival hyperplasia [18]. Hypotheses with regard to inflammation from bacterial plaque [19], increased sulphated glycosaminoglycans [20], immunoglobulins [21], gingival fibroblast phenotype population differences [22], epithelial growth factor [23,24], pharmacokinetics and tissue binding [25], collagenase activation [26], disruption of fibroblast cellular sodium/calcium flux [27], folic acid [28] and a combination hypothesis [29] have also been reported. It is well recognized that in the body many drugs are converted to chemically reactive metabolites, which either uncouple integrated biochemical processes in the cell or covalently bind to macromolecules, such as proteins, lipids, and DNA, causing a variety of toxicities, including hypersensitivity reactions, cellular necrosis, and carcinogenesis [30,31].…”

Influence of phenytoin on cytoplasmic free Ca2+ level in human gingival fibroblasts

“…The mechanism behind this lack of response of these responder cells to further addition of PHT is so far unclear. This cell type represents a subpopulation of fibroblasts probably selected in vivo during PHT medication (5) and are characterized by an increased production of extracellular matrix compared to the normal gingival fibroblasts (20,21). Whether the observed decrease in the basal level of [Ca-"*]; in the responder fibroblasts derived during PHT medication is connected to a selection of such a subpopulation is so far unclear.…”