A Glutathione S-Transferase π-Activated Prodrug Causes Kinase Activation Concurrent with S-Glutathionylation of Proteins

• Published in: Molecular pharmacology 2006-02, Vol.69 (2), p.501-508
• Main Authors: Townsend, Danyelle M., Findlay, Victoria J., Fazilev, Farit, Ogle, Molly, Fraser, Jacob, Saavedra, Joseph E., Ji, Xinhua, Keefer, Larry K., Tew, Kenneth D.
• Format: Article
• Language: English
• Subjects: 4-Aminobenzoic Acid - pharmacology; Animals; Azo Compounds - pharmacology; Cells, Cultured; Enzyme Activation - drug effects; Glutathione - metabolism; Glutathione S-Transferase pi - metabolism; Humans; Mice; Mitogen-Activated Protein Kinase Kinases - metabolism; Nitric Oxide - metabolism; para-Aminobenzoates; Prodrugs - pharmacology; Protein Processing, Post-Translational; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases - metabolism; Proteins - metabolism
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.105.018523

Nitric oxide (NO) is an endogenous, diffusible, transcellular messenger shown to affect regulatory and signaling pathways with impact on cell survival. Exposure to NO can impart direct post-translational modifications on target proteins such as nitration and/or nitrosylation. As an alternative, after interaction with oxygen, superoxide, glutathione, or certain metals, NO can lead to S-glutathionylation, a post-translational modification potentially critical to signaling pathways. A novel glutathione S-transferase π (GSTπ)-activated pro-drug, O2-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl}1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/NO), liberates NO and elicits toxicity in vitro and in vivo. We now show that PABA/NO induces nitrosative stress, resulting in undetectable nitrosylation, limited nitration, and high levels of S-glutathionylation. After a single pharmacologically relevant dose of PABA/NO, S-glutathionylation occurs rapidly (