Three million phenytoin-treated epileptic Americans manifest some degree of gingival overgrowth. Four new drugs also have this side effect (cyclosporine-A, nifedipine, valproic acid, felodipine). It is estimated that 30-35 million persons will be taking such drugs within the coming decade. The pathogenesis of drug-induced gingival overgrowth must be elucidated in order to establish preventive and/or therapeutic strategies. An increase in the dimension of the connective tissue component is always observed in the gingival lesions. Cell culture studies have shown that the most likely mechanism is in vivo selection of phenotypically stable subpopulations of fibroblasts characterized by elevated collagen and glycosaminoglycan synthesis, and by secretion of an inactive collagenase. The broad aim of the proposed studies is to elucidate further the roles of phenytoin metabolites, fibroblast subpopulation selection, genetic predisposition, marginal inflammation and specific microorganisms in the pathogenesis of phenytoin-induced gingival overgrowth in man and a mongrel cat model system. We will determine the effect of 3 major phenytoin metabolites on culture human and feline gingival fibroblasts. We shall also derive single-cell clones from mixed parent populations of cells, perform interclone comparisons of synthetic parameters, growth characteristics, cell size distributions, and phenytoin response in vitro, and examine selected clones ultrastructurally to detect clonal heterogeneity. Experiments will be performed to ascertain the chemical nature of the glycosaminoglycans that are produced in excess by phenytoin-sensitive subpopulations of cells. A study of gingival cells from human twins will be undertaken to determine if the phenytoin """"""""responder"""""""" phenotype is, indeed, inherited as a genetic Mendelian recessive trait. The cat breeding study will continue to enhance the human twin experiments. Cytogenetic analyses (e.g., chromosome breakage, sister chromatid exchange) will be performed on fibroblasts from overgrown gingiva, with and without in vitro exposure to the drug. The additional and related phenytoid side effect, osteomalacca, will be studied in vitro using an osteoblast system to evaluate drug inhibition of bone metabolism. Knowledge gained from the proposed experiments should provide the rationale for development of novel prophylactic and therapeutic approaches in the control of gingival enlargement as well as similar and clinically more significant fibrotic-hyperplastic connective tissue lesions such as burn scar, keloid, arthritis, scleroderma, epidermolysis bullosa, systemic lupus erythematosis. New concepts in wound healing may also evolve.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE006671-07
Application #
3220181
Study Section
Physiology Study Section (PHY)
Project Start
1987-12-01
Project End
1991-07-31
Budget Start
1988-08-01
Budget End
1989-07-31
Support Year
7
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Florida
Department
Type
Schools of Dentistry/Oral Hygn
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Hassell, T M; Hefti, A F (1991) Drug-induced gingival overgrowth: old problem, new problem. Crit Rev Oral Biol Med 2:103-37
Burtner, A P; Low, D W; McNeal, D R et al. (1991) Effects of chlorhexidine spray on plaque and gingival health in institutionalized persons with mental retardation. Spec Care Dentist 11:97-100
Hassell, T M (1990) Gingival overgrowth: hereditary considerations. Compend Suppl :S511-4
Cockey, G H; Boughman, J A; Harris, E L et al. (1989) Genetic control of variation in human gingival fibroblast proliferation rate. In Vitro Cell Dev Biol 25:255-8
Flejter, W L; Astemborski, J A; Hassel, T M et al. (1989) Cytogenetic effects of phenytoin and/or carbamazepine on human peripheral leukocytes. Epilepsia 30:374-9
Somerman, M J; Archer, S Y; Hassell, T M et al. (1987) Enhancement by extracts of mineralized tissues of protein production by human gingival fibroblasts in vitro. Arch Oral Biol 32:879-83
McClanahan, J S; Maguire, J H (1986) High-performance liquid chromatographic determination of the enantiomeric composition of urinary phenolic metabolites of phenytoin. J Chromatogr 381:438-46
Hassell, T M; Provenza, D V; Foster, R A (1986) Synthetic activities of mass cultures and clones of human gingival fibroblasts. Experientia 42:66-9
Narayanan, A S; Hassell, T M (1985) Characterization of collagens in phenytoin-enlarged human gingiva. Coll Relat Res 5:513-8