Journal
NITRIC OXIDE-BIOLOGY AND CHEMISTRY
Volume 14, Issue 2, Pages 109-121Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.niox.2005.11.001
Keywords
peroxynitrite; guanine; 8-oxoguanine; 8-nitroguanine; dehydroguanidinohydantoin; 2,4,6-trioxo- [1,3,5]triazinane-1-carboxamidine; spiroiminodihydantoin; 4-hydroxy-2,5-dioxo-imidazolidine-4-carboxylic acid; nitric oxide; DNA damage; oxidative damage
Categories
Funding
- NCI NIH HHS [CA 26731] Funding Source: Medline
- NHGRI NIH HHS [5F31-HG00144] Funding Source: Medline
- NIEHS NIH HHS [ES02109-24] Funding Source: Medline
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Peroxynitrite induces DNA base damage predominantly at guanine (G) and 8-oxoguanine (8-oxoG) nucleobases via oxidation reactions. Nitration products are also observed, consistent with the generation of radical intermediates that can recombine with the NO2 formed during peroxynitrite degradation. The neutral G radical, G, reacts with NO2 to yield 8-nitroguanine (8-nitroG) and 5-nitro-4-guanidinohydantoin (NI), while for 8-oxoG we have proposed a reactive guanidinylidene radical intermediate. The products generated during peroxynitrite-mediated 8-oxoG oxidation depend oil oxidant flux.. with dehydroguanidinolivdantoin (DGh), 2,4,6-trioxo[1,3,5]triazinane-1-carboxarnidine (CAC) and NO2-DGh predominating at high fluxes and spiroiminodihydantoin (Sp), guanidinollydantoin (Gh) and 4-hydroxy-2,5-dioxo-imidazolidine-4-carboxylic acid (HICA) predominating at low fluxes. Both product sets are observed at intermediate fluxes. It is therefore important in model systems to ensure that the relative concentrations are well controlled to minimize competing reactions that may not be relevant in vivo. Increasingly sophisticated systems for modeling peroxynitrite production in vivo are being developed and these should help with predicting the products most likely to be formed in vivo. Together with the emerging information on the genotoxic and mutational characteristics of the individual oxidation products, it may be found that the extent of tissue damage, mutational spectra and, hence, cancer risk may change as a function of peroxynitrite fluxes as different product combinations predominate. (c) 2005 Elsevier Inc. All rights reserved.
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