TY - JOUR
T1 - Zerumbone, a tropical ginger sesquiterpene, activates phase II drug metabolizing enzymes
AU - Nakamura, Yoshimasa
AU - Yoshida, Chiho
AU - Murakami, Akira
AU - Ohigashi, Hajime
AU - Osawa, Toshihiko
AU - Uchida, Koji
N1 - Funding Information:
This study was supported by grants-in-aid for the Encouragement of Young Scientists (A) (No. 15780099) and in part by Special Coodination Funds of the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government. We thank Dr. Takeshi Kumagai of Kitasato University and Dr. Noriyuki Miyoshi of Nagoya University for their helpful discussions.
PY - 2004/8/13
Y1 - 2004/8/13
N2 - Zerumbone (ZER), a sesquiterpene compound occurring in tropical ginger Zingiber zerumbet Smith, has been implicated as one of the promising chemopreventive agents against colon and skin cancer. In the present study, we investigated the phase II detoxification enzymes induction of ZER using a cultured rat normal liver epithelial cell line. Exposure of RL34 cells to ZER resulted in the significant induction of glutathione S-transferase, while the reduced analogues of ZER (α-humulene and 8-hydroxy-α-humulene) did not show any inducing effect. Therefore, the electrophilic property, characterized by the reactivity with intracellular nucleophiles including protein sulfhydryls as well as low molecular weight thiols, at the 8-position α,β-unsaturated carbonyl group plays an important role in the induction of phase II enzymes. ZER induced nuclear localization of the transcription factor Nrf2 that binds to antioxidant response element (ARE) of the phase II enzyme genes, suggesting that ZER is a potential activator of the Nrf2/ARE-dependent detoxification pathway. This is consistent with the observation that ZER potentiated the gene expression of several Nrf2/ARE-dependent phase II enzyme genes, including γ-glutamylcysteine synthetase, glutathione peroxidase, and hemeoxygenase-1. The present study also implied the antioxidant role of this detoxification system activation by ZER in the neutralization of lipid peroxidation in hepatocytes, providing a new insight for cancer prevention.
AB - Zerumbone (ZER), a sesquiterpene compound occurring in tropical ginger Zingiber zerumbet Smith, has been implicated as one of the promising chemopreventive agents against colon and skin cancer. In the present study, we investigated the phase II detoxification enzymes induction of ZER using a cultured rat normal liver epithelial cell line. Exposure of RL34 cells to ZER resulted in the significant induction of glutathione S-transferase, while the reduced analogues of ZER (α-humulene and 8-hydroxy-α-humulene) did not show any inducing effect. Therefore, the electrophilic property, characterized by the reactivity with intracellular nucleophiles including protein sulfhydryls as well as low molecular weight thiols, at the 8-position α,β-unsaturated carbonyl group plays an important role in the induction of phase II enzymes. ZER induced nuclear localization of the transcription factor Nrf2 that binds to antioxidant response element (ARE) of the phase II enzyme genes, suggesting that ZER is a potential activator of the Nrf2/ARE-dependent detoxification pathway. This is consistent with the observation that ZER potentiated the gene expression of several Nrf2/ARE-dependent phase II enzyme genes, including γ-glutamylcysteine synthetase, glutathione peroxidase, and hemeoxygenase-1. The present study also implied the antioxidant role of this detoxification system activation by ZER in the neutralization of lipid peroxidation in hepatocytes, providing a new insight for cancer prevention.
KW - Antioxidant
KW - Cancer prevention
KW - Detoxification
KW - Electrophile
KW - Glutathione
KW - Glutathione S-transferase
KW - RL34
KW - Zerumbone
KW - α,β-unsaturated carbonyl
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U2 - 10.1016/j.febslet.2004.07.042
DO - 10.1016/j.febslet.2004.07.042
M3 - Article
C2 - 15304356
AN - SCOPUS:4143081630
VL - 572
SP - 245
EP - 250
JO - FEBS Letters
JF - FEBS Letters
SN - 0014-5793
IS - 1-3
ER -