Cell-mediated biotransformation of S-nitrosoglutathione

• Published in: Biochemical pharmacology 1998-03, Vol.55 (5), p.657-665
• Main Authors: Gordge, Michael P., Addis, Paolo, Noronha-Dutra, Alberto A., Hothersall, John S.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biotransformation; Cell Line; Chelating Agents - pharmacology; Culture Media, Conditioned; General pharmacology; Glutathione - analogs & derivatives; Glutathione - metabolism; Glutathione - pharmacokinetics; Homeostasis; Humans; Medical sciences; metal chelators; Nitrates - metabolism; nitric oxide; Nitric Oxide - metabolism; Nitrites - metabolism; Nitroso Compounds - metabolism; Nitroso Compounds - pharmacokinetics; oxidative stress; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Rats; S-Nitrosoglutathione; S-nitrosothiols; Swine
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(97)00498-X

Spontaneous release of nitric oxide (NO) from S-nitrosothiols cannot explain their bioactivity, suggesting a role for cellular metabolism or receptors. Using immortalised cells and human platelets, we have identified a cell-mediated mechanism for the biotransformation of the physiological S-nitrosothiol compound S-nitrosoglutathione (GSNO) into nitrite. We suggest the name “GSNO lyase” for this activity. GSNO lyase activity varied between cell types, being highest in a fibroblast cell line and lowest in platelets. In NRK 49F fibroblasts, GSNO lyase mediated a saturable, GSNO concentration-dependent accumulation of nitrite in conditioned medium, which was inhibited both by transition metal chelators and by subjecting cells to oxidative stress using a combination of the thiol oxidant diamide and Zn 2+, a glutathione reductase inhibitor. Activity was resistant, however, to both acivicin, an inhibitor of γ-glutamyl transpeptidase (EC 2.3.2.2) and to ethacrynic acid, an inhibitor of P i class glutathione-S-transferases (EC 2.5.1.18), thus neither of these enzymes could account for NO release. Although GSNO lyase does not explain the platelet-selective pharmacological properties of GSNO, cellular biotransformation suggests therapeutic avenues for targeted delivery of NO to other tissues.