Ginger (Zingiber officinale Rosc.), one of the most widely used species of the ginger family, has been reported to possess anti-inflammatory, antioxidant, and anti-carcinogenic activities. Although shogaol and gingerol are the major bioactive compounds present in ginger, their molecular mechanisms of action have not been well studied. The aim of the present study was to examine and compare the cancer chemopreventive and hepatoprotective activities of 6-shogaol and 6-gingeol via nuclear erythroid related factor 2 (Nrf2)/antioxidant response element (ARE) pathway in vitro and in vivo. The results showed that 6-shogaol more potently induced the ARE-luciferase activity as well as the related molecular events such as Nrf2 and heme oxygenase-1 (HO-1) inductions than 6-gingerol. Phosphorylations of mitogen- activated protein kinases (MAPKs) such as ERK, JNK and p38 were stimulated by 6-shogaol. The inductions of Nrf2 and HO-1 by 6-shogaol were blocked by the treatment of SB202190, a p38 specific inhibitor. In mice, the diethylnitrosamine (DEN)-mediated elevation of serum aspartate transaminase and alanine transaminase were decreased by 6-shogaol administration. 6-Shogaol treatment also induced the expression of Nrf2 and HO-1 in the liver. Phosphorylation of p38 was regulated by 6-shogaol. Taken together, 6-shogaol could be used as a potential natural chemopreventive agent through the induction of Nrf2/ARE-mediated phase II detoxifying enzyme via p38 pathway. (Cancer Prev Res 17, 0-109, 2012)

Keywords: 6-shogaol, 6-gingerol, Zingiber officinale, Ginger, Nrf2, Phase II detoxifying enzymes, Hemeoxygenase 1, Chemoprevention, MAPK, p38, HepG2 cells