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

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 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.

Sulforaphane and its methylcarbonyl analogs inhibit the LPS-stimulated inflammatory response in human monocytes through modulating cytokine production, suppressing chemotactic migration and phagocytosis in a NF-κB- and MAPK-dependent manner

“…For instance, in vitro studies have demonstrated SF's ability to form adducts with cysteinerich Kelch-like ECH-associated protein 1 (Keap1) at distinct cysteine residues [45][46][47]. In another study, SF has been found to modulate the activities of glutathione-and thioredoxin-related enzymes likely through targeting the nucleophilic cysteine and selenocysteine residues in these enzymes [48]. IKKβ, an upstream component of the NF-B signaling pathway that is activated by phosphorylation at Ser176 and Ser181, is deemed to be redox-sensitive due to the presence of cysteine residues that may be crucial for its kinase activity.…”

The NADPH oxidase inhibitor diphenyleneiodonium activates the human TRPA1 nociceptor

“…Both MO and AUR easily form conjugates with the cysteine residues of thioredoxin, an enzyme related to NOX (10,15,41). APO may also be an electrophilic activator, although it has lower efficacy than DPI.…”

Anticancer Mechanism of Sulfur-Containing Compounds

“…The consequent depletion of GSH increases intracellular ROS and activates thioredoxin (Trx) system [101]. However, ITCs irreversibly inhibit the selenoprotein Trx reductase (TrxR), thus compromising the Trx system [101][102][103]. Furthermore, ITCs are able to oxidize a member of the Trx-dependent antioxidant system, namely peroxiredoxin (Prx), which exists in mammalian cells in six different forms at least.…”