Cellular antioxidant and pro-oxidant actions of nitric oxide.
We describe a biphasic action of nitric oxide (NO) in its effects on oxidative killing of isolated cells: low concentrations protect against oxidative killing, while higher doses enhance killing, and these two effects occur by distinct mechanisms. While low doses of NO (from (Z)-1-[N-(3-ammonio propyl)-N-(n-propyl)-amino]-diazen-1-ium-1,2(2) diolate [PAPA/NO] or S-nitroso-N-acetyl-L-penicillamine [SNAP] prevent killing of rat hepatocytes by t-butylhydroperoxide (tBH), further increasing doses result in increased killing. Similar effects occur with rat hepatoma cells treated with PAPA/NO and tBH or H2O2. Increased killing with higher concentrations of NO donor is due to both NO and tBH, because NO donor alone is without effect. Glutathione (GSH) is not involved in either of these actions. Based on measurements of thiobarbituric acid-reactive substances (TBARS) and effects of lipid radical scavenger (DPPD) and deferoxamine, the protective effect, but not the enhancing effect, involves peroxidative chemistry. Fructose has no effect on tBH killing alone but provides substantial protection against killing by higher concentrations of NO plus tBH, suggesting that the enhancing effect involves mitochondrial dysfunction. Hepatocytes, when stimulated to produce NO endogenously, become resistant to tBH killing, indicative of the presence of an NO-triggered antioxidant defensive mechanism. The finding that the protective effects of low concentrations of NO and the harmful effects of high concentrations of NO are fundamentally different in nature suggest that therapeutic interventions could be designed, which selectively prevent its pro-oxidant activity at high concentrations, thus converting NO from a "Janus-faced" modulator of oxidant injury into a "pure" protectant.
Joshi
M S
MS
Department of Surgery, Louisiana State University Medical Center, New Orleans 70112, USA.
Ponthier
J L
JL
Lancaster
J R
JR
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology; D002478:Cells, Cultured; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008099:Liver / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009573:Nitrites / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
C111679:1-(N-(3-ammoniopropyl)-N-(n-propyl)amino)diazen-1-ium-1,2-diolate; D000975:Antioxidants; D001384:Azetidines; D016166:Free Radical Scavengers; D020030:Nitric Oxide Donors; D009573:Nitrites; D016877:Oxidants; C110881:S-nitro-N-acetylpenicillamine; D017392:Thiobarbituric Acid Reactive Substances; D009569:Nitric Oxide; D020122:tert-Butylhydroperoxide; D006861:Hydrogen Peroxide; D005978:Glutathione; D010396:Penicillamine