Pathogenesis of phenytoin-induced gingival overgrowth. Several mechanisms are involved in the development of gingival overgrowth. Phenytoin induces a decrease in the Ca²⁺ cell influx leading to a reduction in the uptake of folic acid, thus limiting the production of active collagenase. The drug decreases collagen endocytosis through induction of a lower expression of -integrin by fibroblasts. Myofibroblasts seem to be stimulated by phenytoin. Other important elements directly responsible for phenytoin-induced gingival overgrowth are cytokines. Phenytoin-activated fibroblasts produce large amounts of IL-6, IL-1, and IL-8. Such mediators are capable of activating the proliferation of T cells and the recruitment of neutrophils to the involved tissues, establishing a direct interaction between the immune system and the connective tissue. This interaction seems to be highly associated with fibrotic diseases. Evidence also points toward a role of dental plaque in the etiology of PGO through induction of a local inflammatory response, which is essential for the gingival overgrowth. Growth factors such as CTGF, PDGF, FGF and TGF- are found in higher levels in fibrotic tissues and play a role in PGO. Phenytoin may affect the production of IL-13 by an activation of Th2 cells, as well as it may induce the release of TGF-, CTGF and other growth factors by macrophages, which leads, synergistically, to fibroblast proliferation, collagen biosynthesis, activation of TIMPs, inhibition of MMPs and ECM synthesis, characteristic processes observed in fibrotic lesions. PDGF-: platelet derived growth factor; FGF-2: fibroblast growth factor-2; TGF-: transforming growth factor-; CTGF: connective tissue growth factor; MMP: matrix metalloproteinase; TIMP: tissue inhibitor of metalloproteinase.