Kinetic analysis of intracellular concentrations of reactive nitrogen species.
Reactive nitrogen species derived from NO have been implicated in cancer and other diseases, but their intracellular concentrations are largely unknown. To estimate them under steady-state conditions representative of inflamed tissues, a kinetic model was developed that included the effects of cellular antioxidants, amino acids, proteins, and lipids. For an NO concentration of 1 microM, total peroxynitrite (Per, the sum of ONOO(-) and ONOOH), NO(2)(*), and N(2)O(3) were calculated to have concentrations in the nanomolar, picomolar, and femtomolar ranges, respectively. The concentrations of NO(2)(*) and N(2)O(3) were predicted to decrease markedly with increases in glutathione (GSH) levels, due to the scavenging of each by GSH. Although lipids accelerate the oxidation of NO by O(2) (because of the high solubility of each in hydrophobic media), lipid-phase reactions were calculated to have little effect on NO(2)(*) or N(2)O(3) concentrations. The major sources of intracellular NO(2)(*) were found to be the reaction of Per with metals and with CO(2), whereas the major sinks were its reactions with GSH and ascorbate (AH(-)). The radical-scavenging ability of GSH and AH(-) caused 3-nitrotyrosine to be the only tyrosine derivative predicted to be formed at a significant rate. The major GSH reaction product was S-nitrosoglutathione. Analytical (algebraic) expressions are provided for the concentrations of the key reactive intermediates, allowing the calculations to be extended readily.
Lim
Chang Hoon
CH
Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Dedon
Peter C
PC
Deen
William M
WM
D005978:Glutathione / Q000378:metabolism; D017665:Hydroxyl Radical; D007700:Kinetics; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D026422:S-Nitrosoglutathione / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D026361:Reactive Nitrogen Species; D009569:Nitric Oxide; D017665:Hydroxyl Radical; D014443:Tyrosine; D026422:S-Nitrosoglutathione; D005978:Glutathione