Role of Antioxidant Enzymes in Cyclosporine-Induced Gingival Hyperplasia

Objectives: Gingival overgrowth (GO) occurs frequently in patients receiving cyclosporine A (CsA), as an immunosuppressant therapy, following renal transplantation. GO is characterized by enlargement of the gingiva with epithelial thickening and overproduction of extracellular matrix components. The pathogenesis of the epithelial thickening in GO is probably multifactorial and still remains obscure. Since it has been shown that the oxidative stress is one of the possible mechanisms of CsA-induced nephrotoxicity and hepatotoxicity, in this study we aimed to investigate whether the effect of CsA on the gingiva is via changing the activation patterns of Glutathion peroxidase (GPx) and Glutathione reductase (GR). For this purpose we used an in vitro model, oral epithelial cells, in an attempt to identify the cellular mechanisms underlying gingival CsA damage.

Methods: The effect of increasing concentrations (0.5-50 mg/ml) of CsA were assessed in cultured KB cells (oral epithelial cell line) following 24 and 48 hours incubation on 1) cellular integrity using MTT assay, 2) GR activity that was determined by measuring the decrease in absorption at 340 nm as NADPH was used to reduce GSSG, 3) GPx activity that was defined as the number of mmol NADPH oxidized/min/no of cells, and 4) intracellular reactive oxygen species (ROS) using a repeated measures experimental design.

Results: CsA exhibited a dose but not time-dependent effect on enzyme activity and ROS level. Although CsA increased intracellular level of ROS and decreased both the GPx and GR activity after 24 hours, did not significantly change those variables after 48 hours.

Conclusions: These data indicate that the effect of CsA on oral epithelial cells is associated with changes in antioxidant defense balance as well as increases the ROS that act as powerful oxidants, which might account for some of the pathological effects of this drug.