Ebselen, a glutathione peroxidase mimetic seleno-organic compound, as a multifunctional antioxidant. Implication for inflammation-associated carcinogenesis.
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 H(2)O(2) 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.
Nakamura
Yoshimasa
Y
Laboratory of Food and Biodynamics, Nagoya University Graduate School of Bioagricultural Sciences, Nagoya 464-8601, Japan.
Feng
Qing
Q
Kumagai
Takeshi
T
Torikai
Koji
K
Ohigashi
Hajime
H
Osawa
Toshihiko
T
Noguchi
Noriko
N
Niki
Etsuo
E
Uchida
Koji
K
D000818:Animals; D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology*; D001393:Azoles / Q000737:chemistry* / Q000494:pharmacology*; D015153:Blotting, Western; D002273:Carcinogens; D002460:Cell Line; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000209:etiology; D004817:Epidermis / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000737:chemistry*; D005982:Glutathione Transferase / Q000378:metabolism; D018922:HL-60 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007249:Inflammation; D007527:Isoenzymes / Q000378:metabolism; D054833:Isoindoles; D007962:Leukocytes / Q000187:drug effects; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000187:drug effects; D008565:Membrane Proteins; D051379:Mice; D008813:Mice, Inbred ICR; D008956:Models, Chemical; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D016566:Organoselenium Compounds / Q000737:chemistry* / Q000494:pharmacology*; D018384:Oxidative Stress; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D013481:Superoxides / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors
D000975:Antioxidants; D001393:Azoles; D002273:Carcinogens; D007527:Isoenzymes; D054833:Isoindoles; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016566:Organoselenium Compounds; D017392:Thiobarbituric Acid Reactive Substances; D013481:Superoxides; C042986:ebselen; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D009247:NADH, NADPH Oxidoreductases; D005982:Glutathione Transferase; D013755:Tetradecanoylphorbol Acetate