Curcumin mediates time and concentration dependent regulation of redox homeostasis leading to cytotoxicity in macrophage cells.

The present study was designed to test a hypothesis that curcumin may be modulating oxidative stress parameters including reactive oxygen species, non-protein thiols and expression of antioxidant genes in a concentration and time dependent manner in exhibiting cytotoxic effects in macrophage cell line RAW 264.7. The results have shown that curcumin elevated the reactive oxygen species levels accompanied by a decrease in levels of intracellular non-protein thiols at 2 h after its addition to cells. However, the levels of reactive oxygen species decreased and non-protein thiols content increased at 18 h after its addition. Whereas the expression of glutathione peroxidase (GPx), catalase, Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and heme oxygenase-1 (HO-1) increased with curcumin concentration and also with increase in time of incubation, the expression of Mn- superoxide dismutase (Mn-SOD) showed concentration dependant repression upon treatment with curcumin. The cell viability was significantly reduced at high concentration (25 microM) of curcumin treatment but not at low concentration (5 microM). Curcumin at 5 microM scavenged gamma-radiation induced reactive oxygen species and inhibited cell death. On the contrary, at 25 microM, curcumin increased radiation induced reactive oxygen species production and augmented cell death. Interestingly pretreatment with reducing agents glutathione (GSH) or N-acetyl-cysteine (NAC), modified the curcumin mediated redox changes and cell death differentially, due to the inhibition of cellular uptake of curcumin by GSH but not by NAC. The important finding of the study is that the concentration and time dependent dual effect of curcumin may be attributed to changes in oxidative stress and antioxidant gene expression levels leading to inhibition or promotion of cell death.