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J. Biol. Chem., Vol. 277, Issue 4, 2687-2694, January 25, 2002

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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^§

From the  Laboratory of Food and Biodynamics, Nagoya University Graduate School of Bioagricultural Sciences, Nagoya 464-8601, the ^¶ Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, and the  Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan

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, 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) oxidoreductase1 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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