| Peroxynitrite-mediated DNA strand breakage activates poly-adenosine diphosphate ribosyl synthetase and causes cellular energy depletion in macrophages stimulated with bacterial lipopolysaccharide. | |
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MedLine Citation:
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PMID: 8598485 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The inducible isoform of nitric oxide (NO) synthase produces large quantities of NO, a cytotoxic free radical. Recent studies show that treatment with exogenous NO produces DNA strand breaks, activating the nuclear repair enzyme poly(ADP)ribosyltransferase (PARS), which results in ADP ribosylation, NAD+ consumption, and exhaustion of intracellular energy stores. Here we have characterized the cytotoxic effect of endogenous NO and peroxynitrite, a reactive oxidant formed from NO and superoxide. Immunostimulation of J774.2 macrophages with endotoxin resulted in the generation of superoxide (within 1 h) and NO (after 8 h). NO production paralleled an increase in peroxynitrite formation and DNA strand breakage, and a decrease in intracellular NAD+ content and mitochondrial respiration. Inhibition of NO synthase by NG-methyl-L-arginine or S-methyl-isothiourea or inhibition of PARS activity by 3-aminobenzamide or nicotinamide prevented the decrease in mitochondrial respiration and the depletion of NAD+. A similar pattern of free radical formation and cytotoxicity was observed in peritoneal macrophages from endotoxemic rats (formation of NO, superoxide, peroxynitrite, and DNA strand breaks). In vivo treatment with 3-aminobenzamide preserved mitochondrial respiration, NAD+, and ATP. Our data suggest that inflammatory cell injury involved DNA strand breakage and PARS, triggering an energy-consuming, futile repair cycle leading to cellular energy depletion. The active species responsible for the development of DNA strand breaks is peroxynitrite, rather than NO, since exogenous peroxynitrite, but not NO, induces DNA strand breaks. Inhibition of PARS may improve cellular energy homeostasis in patho-physiologic conditions associated with peroxynitrite generation. |
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Authors:
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B Zingarelli; M O'Connor; H Wong; A L Salzman; C Szabó |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 156 ISSN: 0022-1767 ISO Abbreviation: J. Immunol. Publication Date: 1996 Jan |
Date Detail:
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Created Date: 1996-04-23 Completed Date: 1996-04-23 Revised Date: 2005-11-17 |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 350-8 Citation Subset: AIM; IM |
Affiliation:
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Division of Critical Care, Children's Hospital Medical Center, Cincinnati, OH 45229, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Diphosphate Ribose
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biosynthesis Animals Cell Line DNA Damage / immunology* Energy Metabolism / drug effects* Enzyme Activation / drug effects Hydrogen Peroxide / metabolism Lipopolysaccharides / pharmacology Macrophage Activation / drug effects* Macrophages, Peritoneal / drug effects, enzymology*, metabolism Male Nitrates / metabolism, pharmacology* Nitric Oxide / biosynthesis Nitric Oxide Synthase / antagonists & inhibitors, physiology Oxidation-Reduction RNA Ligase (ATP) / antagonists & inhibitors, drug effects* Rats Rats, Wistar Rhodamines / metabolism Superoxides / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Lipopolysaccharides; 0/Nitrates; 0/Rhodamines; 10102-43-9/Nitric Oxide; 11062-77-4/Superoxides; 20762-30-5/Adenosine Diphosphate Ribose; 26404-66-0/peroxynitric acid; 7722-84-1/Hydrogen Peroxide; EC 1.14.13.39/Nitric Oxide Synthase; EC 6.5.1.3/RNA Ligase (ATP) |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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