Phenolic phytochemicals are natural plant substances whose cellular effects have not been completely determined. Nordihydroguaiaretic acid (NDGA) and curcumin are two phenolic phytochemicals with similar molecular structures, suggesting that they possess comparable chemical properties particularly in terms of antioxidant activity. To examine this possibility in a cellular system, this study evaluated the capacities of NDGA and curcumin to function as antioxidants in inhibiting oxidative damage to DNA. Jurkat T-lymphocytes were pre-incubated for 30 min with 0-25 microM of either NDGA or curcumin to allow for uptake. The phenolic phytochemical-treated cells were then oxidatively challenged with 25 microM hydrogen peroxide (H2O2). Afterwards, cells were subjected to alkaline micro-gel electrophoresis (i.e. comet assay) to assess the extent of single-strand breaks in DNA. In a concentration-dependent manner, NDGA inhibited H2O2-induced DNA damage, whereas curcumin did not. In fact, incubating Jurkat T-lymphocytes with curcumin alone actually induced DNA damage. This effect of curcumin on DNA did not appear to reflect the DNA fragmentation associated with apoptosis because there was no proteolytic cleavage of poly-(ADP-ribose)-polymerase, which is considered an early marker of apoptosis. Curcumin-induced damage to DNA was prevented by pre-treatment of the cells with the lipophilic antioxidant, alpha-tocopherol, suggesting that curcumin damaged DNA through oxygen radicals. Therefore, it is concluded that NDGA has antioxidant activity but curcumin has prooxidant activity in cultured cells based on their opposite effects on DNA.