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Papers In Press, published online ahead of print November 19, 2001
J. Biol. Chem, 10.1074/jbc.M109641200
Submitted on October 5, 2001
Revised on November 9, 2001
Accepted on November 19, 2001

Ebselen, a glutathione peroxidase mimetic seleno-organic compound, as a multifunctional antioxidant: Implication for inflammation-associated carcinogenesis

Yoshimasa Nakamura, Qing Feng, Takeshi Kumagai, Koji Torikai, Hajime Ohigashi, Toshihiko Osawa, Noriko Noguchi, Etsuo Niki, and Koji Uchida

Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi 464-8601

Corresponding Author: uchidak{at}agr.nagoya-u.ac.jp

Ebselen, a seleno-organic compound showing glutathione peroxidase-like activity, is one of the promising synthetic antioxidants. In the present study, we investigated the antioxidant activities of ebselen using a 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated mouse skin model. Double pretreatments of mouse skin with ebselen significantly inhibited TPA-induced formation of thiobarbituric acid-reacting substance (TBARS), known as an overall oxidative damage biomarker, in mouse epidermis, suggesting that ebselen indeed acts as an antioxidant in mouse skin. The antioxidative effect of ebselen is attributed to its selective blockade of leukocyte infiltration and activation leading to attenuation of the H2O2 level. In in vitro studies, ebselen inhibited TPA-induced superoxide generation in differentiated HL-60 cells and lipopolysaccharide-induced cyclooxygenase-2 protein expression in RAW 264.7 cells. In addition, we demonstrated for the first time that ebselen potentiated phase II enzyme activities including NAD(P)H:(quinone-acceptor) oxidoreductase and glutathione S-transferase in cultured hepatocytes and in mouse skin. These results strongly suggest that ebselen, a multifunctional antioxidant, is a potential chemopreventive agent in inflammation-associated carcinogenesis.


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