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

• Published in: Biological chemistry Vol. 388; no. 10; pp. 1069 - 1081
• Main Authors: Hu, Ying, Urig, Sabine, Koncarevic, Sasa, Wu, Xinjiang, Fischer, Marina, Rahlfs, Stefan, Mersch-Sundermann, Volker, Becker, Katja
• Format: Journal Article
• Language: English
• Published: Germany Walter de Gruyter 01.10.2007
• Subjects: 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid - analogs & derivatives; 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid - pharmacology; A549 cells; Allyl Compounds - pharmacology; allyl sulfides; Anticarcinogenic Agents - pharmacology; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Disulfides - pharmacology; Dose-Response Relationship, Drug; enzyme inhibition; Glutathione - metabolism; Glutathione Peroxidase - antagonists & inhibitors; Glutathione Peroxidase - genetics; Glutathione Peroxidase - metabolism; Glutathione Transferase - antagonists & inhibitors; Glutathione Transferase - metabolism; Humans; isothiocyanates; Isothiocyanates - metabolism; Isothiocyanates - pharmacology; Oxidation-Reduction; redox networks; Sulfur Compounds - pharmacology; Thioredoxin-Disulfide Reductase - antagonists & inhibitors; Thioredoxin-Disulfide Reductase - metabolism; Thioredoxins - metabolism; transcript levels; Up-Regulation
• ISSN: 1431-6730; 1437-4315
• DOI: 10.1515/BC.2007.135

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 (K i=6.1±1.0 μM) followed by a time-dependent irreversible inhibition (k 2=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 k 2 values. In contrast, allyl sulfides had only moderate effects on the tested enzymes. However, diallyl disulfide was found to react directly with reduced glutathione (k 2=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.