Hydroxyguanidines inhibit peroxynitrite-induced oxidation.
Hydroxyguanidines (OHGs), including the endogenously formed NG-hydroxy-L-arginine (OH-arg), can react with nitric oxide (NO) and nitrogen oxides (NOx) in vitro. Therefore, we have tested OHGs and related compounds for their ability to scavenge peroxynitrite and to protect against peroxynitrite-induced oxidative processes in cells. Hydroxyguanidine, NG-hydroxy-L-arginine and other N-substituted OHGs, dose-dependently inhibited the in vitro oxidation of dihydrorhodamine (DHR) by peroxynitrite (PN), with similar or better efficacy than glutathione or cysteine. Amidoximes, aminoguanidines and O-substituted OHGs were less effective, and guanidines were without effect. In contrast to their effects on DHR oxidation, OHGs exerted only minimal inhibitory effects on the hydroxylation of benzoate by PN, suggesting that OHGs do not react with the activated isomer of peroxynitrous acid. Selected compounds were tested for protection against PN-induced suppression of mitochondrial respiration and protein oxidation in cultured J774 murine macrophages. Aminoguanidines afforded some protection against the effects of PN, but substituted-phenyl OHGs were considerably more effective. Analysis of the products of the reaction of 4-methoxybenzyl-OHG with PN showed rapid formation of nitrosated derivatives, as well as 4-methoxybenzylcyanamide and a small amount of 4-methoxybenzylurea. Nitric oxide and nitrous oxide were also evolved, but indirectly, arising from the decomposition of one of the nitrosation products. The current results demonstrate that hydroxyguanidines react with PN to protect cells against PN-mediated injury and may be more effective than the endogenous antioxidants cysteine and glutathione.
Southan
G J
GJ
Intramural Research Support Program, SAIC-Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, MD, USA. gjsouthan@aol.com
Salzman
A L
AL
Szabó
C
C
D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D019817:Benzoic Acid / Q000737:chemistry; D002460:Cell Line; D016166:Free Radical Scavengers; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology*; D006898:Hydroxylamines; D006900:Hydroxylation; D008264:Macrophages / Q000187:drug effects; D009566:Nitrates / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D012235:Rhodamines / Q000737:chemistry
D016166:Free Radical Scavengers; D006146:Guanidines; D006898:Hydroxylamines; D009566:Nitrates; D012235:Rhodamines; C058319:dihydrorhodamine 123; C039642:peroxynitric acid; C068309:N(omega)-hydroxyarginine; C029604:hydroxyguanidine; D019817:Benzoic Acid; D001120:Arginine