To determine whether lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-alpha) are involved in the induction of superoxide dismutase (SOD) in gingival tissue, we examined their effect on induction of SOD isozymes in cultured normal (NGF) and phenytoin-induced hyperplastic (PHF) gingival fibroblasts. Treatment of both NGFs and PHFs with 10 to 50 ng/mL TNF-alpha for 24 hours increased the level of manganese SOD (MnSOD) to as much as four times the level of untreated cultures. PHFs, but not NGFs, were shown to be responsive to TNF-alpha in eliciting a significant increase in copper-zinc SOD (Cu/ZnSOD), albeit in a lesser amount than MnSOD. Additionally, treatment of both types of cells with 5 to 50 mg/mL of LPS for 24 hours also elicited an increase in the levels of MnSOD. Again, an LPS-induced increase in Cu/ZnSOD levels could only be demonstrated in PHFs, but not in NGFs. These observations were further confirmed by comparing the achromatic bands associated with SOD isozymes exhibited in the electrophoretogram using a nondenaturing polyacrylamide electrophoresis technique. These results indicate that TNF-alpha and LPS were capable of inducing both MnSOD and Cu/ZnSOD simultaneously in PHF fibroblasts. PHFs may be inherently more capable than NGFs in combating oxidative stress.