Glutathione- and thioredoxin-related enzymes are modulated by sulfur-containing chemopreventive agents.
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 microM) 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.
Hu
Ying
Y
Interdisciplinary Research Center, Justus Liebig University Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany.
Urig
Sabine
S
Koncarevic
Sasa
S
Wu
Xinjiang
X
Fischer
Marina
M
Rahlfs
Stefan
S
Mersch-Sundermann
Volker
V
Becker
Katja
K
D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000498:Allyl Compounds / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004220:Disulfides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D013457:Sulfur Compounds / Q000494:pharmacology*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism*; D015854:Up-Regulation
D000498:Allyl Compounds; D016588:Anticarcinogenic Agents; D004220:Disulfides; D017879:Isothiocyanates; D013457:Sulfur Compounds; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; D013879:Thioredoxins; C028009:diallyl disulfide; C025953:amsonic acid; D005979:Glutathione Peroxidase; D013880:Thioredoxin-Disulfide Reductase; D005982:Glutathione Transferase; D005978:Glutathione