Dimethoxycurcumin, a Synthetic Curcumin Analogue, Induces Heme Oxygenase-1 Expression through Nrf2 Activation in RAW264.7 Macrophages

Abstract

Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] induces heme oxygenase-1 (HO-1) expression via activation of the nuclear factor-erythroid-2-related factor 2 (Nrf2), whereas tetrahydrocurcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-3,5-heptanedione], one of curcumin in vivo metabolites, has no effect on HO-1 expression and Nrf2 activation. The aim of this study was to investigate whether dimethoxycurcumin [1,7-bis(4,3-dimethoxyphenyl)-1,6-heptadiene-3,5-dione], a synthetic curcumin analogue with higher metabolic stability over curcumin, could induce HO-1 expression to the same extent as curcumin in RAW264.7 macrophages. Dimethoxycurcumin and curcumin, but not tetrahydrocurcumin, induced HO-1 expression and Nrf2 nuclear translocation, suggesting that the unsaturated nature of the diarylheptanoid chain of the compounds are crucial for HO-1 expression and Nrf2 activation. Blockage of Nrf2 synthesis by small interfering RNA abolished HO-1 expression by dimethoxycurcumin, indicating that dimethoxycurcumin may induce HO-1 expression via Nrf2 activation. In comparison, dimethoxycurcumin and curcumin had about the same effect on HO-1 expression, suggesting that dimethoxycurcumin retains the HO-1-inducing activity of its parent compound curcumin in RAW264.7 macrophages.