Inhibitory effects of curcumin and tetrahydrocurcuminoids on the tumor promoter-induced reactive oxygen species generation in leukocytes in vitro and in vivo.

Abstract

The inhibitory effects of curcumin and two tetrahydrocurcuminoids on tumor promoter‐induced oxidative stress in vitro and in vivo were investigated. Curcumin, tetrahydrocurcumin (THC) and dihydroxytetrahydrocurcumin (DHTHC) exhibited significant inhibitory effects on 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA)‐induced O2‐generation in differentiated HL‐60 cells. The inhibitory activity of THC was weaker than that of curcumin. This tendency was the inverse of the results of previous studies on in vitro antioxidative activity against lipid peroxidation. The curcuminoids inhibited TPA‐induced intracellular peroxide formation in differentiated HL‐60 cells. THC exhibited much weaker inhibition of intracellular peroxide formation than curcumin, suggesting that this inhibition might be attributable to the inhibition of O2‐generation. The inhibitory effects of curcuminoids on TPA‐induced H2O2 formation in female ICR mouse skin were further examined using the double‐TPA‐application model. Each TPA application induces two distinct biochemical events, 1) recruitment of inflammatory cells to the inflammatory regions and 2) activation of oxidant‐producing cells. Double pretreatment of mice with curcuminoids before each TPA treatment significantly suppressed double TPA application‐induced H2O2 formation in the mouse skin. Coadministrations of curcumin with either first or second TPA treatment significantly inhibited H2O2 formation. In addition, THC tends to show weaker inhibitory activities than curcumin in bioassays related to tumor promotion, i.e., inhibition of tumor promoter‐induced inflammation in mouse skin and Epstein‐Barr virus activation. These tendencies were parallel to those in the tumor‐suppressive potential of curcumin and THC in mouse skin, as previously reported. Thus, we concluded that curcuminoids significantly suppress TPA‐induced oxidative stress via both interference with infiltration of leukocytes into the inflammatory regions and inhibition of their activation.