The Cytotoxicity of Nitroxyl: Possible Implications for the Pathophysiological Role of NO

Abstract

or superoxide, can generate reactive nitrogen oxide spe-AS was found to be cytotoxic to Chinese hamster V79 cies (RNOS) 2 , which can oxidize nitrate, or nitrosate, lung fibroblast cells over a concentration range of 2-4 mM. The presence of equimolar ferricyanide (Fe(III)-other biomolecules (2, 3). RNOS are proposed to medi-(CN 6 ) 30 ), which converts NO 0 to NO, afforded dramatic ate various toxic and cytotoxic mechanisms. In conprotection against AS-mediated cytotoxicity. Treat-trast, NO can protect cells from damage caused by reacment of V79 cells with L-buthionine sulfoximine to re-tive oxygen species (ROS) (4-6), as a result of different duce intracellular glutathione markedly enhanced AS chemical reactions than those involving RNOS (7-10).cytotoxicity, which suggests that GSH is critical for NO participates in chemical reactions associated cellular protection against the toxicity of NO 0 . Fur-with both oxidative and nitrosative stress which can ther experiments showed that low molecular weight have deleterious consequences in vivo. Studies suggest transition metal complexes associated with the forma-that there exists a balance between NO and two of tion of reactive oxygen species are not involved in AS-the major reactive nitrogen oxide species, dinitrogen mediated cytotoxicity since metal chelators had no ef-trioxide (N 2 O 3 ) and peroxynitrite (ONOO 0 ) (11-13) fect. However, under aerobic conditions, AS was more that can determine the toxicological outcome under toxic than under hypoxic conditions, suggesting that oxygen dramatically enhanced AS-mediated cytotoxicity. At a molecular level, AS exposure resulted in DNA 2 Abbreviations used: RNOS, reactive nitrogen oxide species; AS, double strand breaks in whole cells, and this effect was Angelis's salt; DETAPAC, diethylenetriaminepentaacetic acid; DF, desferrioxime; TPH, tempol-H; NADPH, b-nicotinamide adenine dinucleotide phosphate; PBS, phosphate-buffered saline; GSH, intra-1 To whom correspondence and reprint requests should be ad-cellular glutathione; ER, enhancement ratio; ESR, electron spin resonance. dressed. Fax: (301) 480-2238. 66

A mosquito 2-Cys peroxiredoxin protects against nitrosative and oxidative stresses associated with malaria parasite infection

“…However, the chemistries of HNO and PN differ, and some studies have noted that toxicities of these compounds derive from different reactive intermediates [53]. For example, HNO has a high affinity for GSH [54]; exposure of cells to millimolar concentrations of AS can dramatically reduce intracellular GSH through the production of GSNHOH [51,53]. As such, Prxs may function to protect cells through direct recycling of oxidized thiols to maintain cellular homeostasis [55] in mosquito cells.…”

“…Nitroxyl (HNO/NO − ) induces double-and single-strand DNA breaks and base oxidation [51]. It is widely accepted that HNO and singlet oxygen can react to form PN [52].…”

“…Whereas we suspect that this RNOS is toxic to developing parasites, midgut nitroxyl may also be associated with rapid activation of ingested human latent transforming growth factor-β1, which regulates parasite development in A. stephensi [17]. As such, AsPrx-4783 seems to protect mosquito cells against an RNOS that likely participates directly in parasite killing and indirectly in the regulation of parasite killing.Nitroxyl (HNO/NO − ) induces double-and single-strand DNA breaks and base oxidation [51]. It is widely accepted that HNO and singlet oxygen can react to form PN [52].…”

Microbial carbohydrate depolymerization by antigen-presenting cells: Deamination prior to presentation by the MHCII pathway

“…To date, the interaction between nitroxyl and carbohydrates has not been explored, although nitroxyl is reportedly more toxic to (or reactive with) cells than is NO itself (14). In vitro, nitroxyl can be generated by protonation of Angeli's salt (sodium trioxodinitrate) (15).…”

Bioanalytical profile of the l-arginine/nitric oxide pathway and its evaluation by capillary electrophoresis

“…However stoichiometry of entire process may vary depending on the enzyme type, status, and redox conditions. It may involve either two-electron or one-electron oxidation in the terminal reactions resulting distinct nitroxy products [62,63]. Subsequent monooxygenation is catalyzed by an axially symmetrical homodimmeric NOS complex in which each subunit collaborates with five essential cofactors -prosthetic groups: FAD, FMN, iron coordinated haem, (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4) and Ca 2+ -calmodulin [64,65].…”