Glutathione- and thioredoxin-related enzymes are modulated by sulfur-containing chemopreventive agents

Ying Hu 1 , 1 , Sabine Urig 1 , 2 , Sasa Koncarevic 2 , 3 , Xinjiang Wu 4 , 4 , Marina Fischer 5 , 5 , Stefan Rahlfs 6 , 6 , Volker Mersch-Sundermann 7 , 7  and Katja Becker 8 , 8
  • 1 Interdisciplinary Research Center, Justus Liebig University Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany
  • 2 Interdisciplinary Research Center, Justus Liebig University Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany
  • 3 Interdisciplinary Research Center, Justus Liebig University Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany
  • 4 Faculty of Medicine, Institute of Indoor and Environmental Toxicology, University Hospital of Giessen and Marburg, Aulweg 123, D-35385 Giessen, Germany
  • 5 Interdisciplinary Research Center, Justus Liebig University Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany
  • 6 Interdisciplinary Research Center, Justus Liebig University Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany
  • 7 Faculty of Medicine, Institute of Indoor and Environmental Toxicology, University Hospital of Giessen and Marburg, Aulweg 123, D-35385 Giessen, Germany
  • 8 Interdisciplinary Research Center, Justus Liebig University Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany

Abstract

We studied the effects of sulfur-containing chemopreventive agents, including allyl sulfides and isothiocyanates, on human redox networks. Isothiocyanates inhibited isolated redox-active enzymes in a time- and dose-dependent manner. As shown for the most active compound, benzyl isothiocyanate (BITC), on thioredoxin reductase, the inhibition has an initial competitive part (Ki=6.1±1.0 μM) followed by a time-dependent irreversible inhibition (k2=72.8±25.5 M -1 s-1). Also, glutathione reductase and glutathione S-transferase were irreversibly modified by BITC. Sulforaphane led to irreversible inhibition of the studied redox enzymes, but with 5–10 times lower k2 values. In contrast, allyl sulfides had only moderate effects on the tested enzymes. However, diallyl disulfide was found to react directly with reduced glutathione (k2=100 M -2 s-1). This reaction might contribute to enhanced oxidative stress and the induction of the selenoprotein glutathione peroxidase as determined on activity and transcript levels. All chemopreventive agents tested induced transcript levels of genes associated with cell cycle arrest and apoptosis. This upregulation was accompanied by a dose-dependent decrease in cell number. Our data indicate that modulation of cellular redox networks is likely to contribute to the effects of sulfur-containing chemopreventive agents.

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Biological Chemistry keeps you up-to-date with the latest advances in the molecular life sciences. The journal publishes Research Articles, Short Communications, Reviews and Minireviews. Areas include: general biochemistry/pathobiochemistry, structural biology, molecular and cellular biology, genetics and epigenetics, virology, molecular medicine, plant molecular biology/biochemistry and novel experimental methodologies.

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