By Reactive Nitrogen Species

N2O3 formed by a third order reaction, can deaminate DNA bases yielding uracil from cytosine, xanthine from guanine, methyl cytosine from thymine and hypoxanthine from adenine [ 56 ]. Furthermore, it can react with secondary amines to yield carcinogenic N-nitrosoamines, which can damage DNA by alkylation, [57]. 

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It has already been mentioned earlier that similar to LOXs, prostaglandin H synthases can be activated or inhibited by reactive nitrogen species. Nitric oxide may exhibit the inhibitory [58,65,86,101 104] or stimulatory effects [105 110] on PGHSs. Inhibitory effects depend on the ability of nitric oxide to reduce the ferric enzyme to the inactive ferrous form, competition... 

Deleterious protein cross-linking can also be induced by reactive nitrogen species (RNS) such as peroxynitrite ONOO formed by the reaction of superoxide with nitric oxide (NO). The cross-links are formed between tyrosine residues following nitration by peroxynitrite (Sitte, 2003). Carnosine appears to play roles not only in NO generation but also in protection against excess NO production by inducible nitric oxide synthetase (NOS), thereby preventing ONOO-mediated protein modification (Fontana et ah, 2002). Evidence for a carnosine-NO adduct has also been published (Nicoletti et al., 2007). 

As an example, acetaminophen (APAP) in overdose has been used by several groups to identify hepatotoxicity biomarkers in mice. APAP-induced hepatotoxicity is characterized by hepatic centrilobular necrosis and hepatitis. APAP biotransformation by Phase I enzymes leads to the formation of the reactive metabolite N-acetyl-p-benzoquinone (NAPQI), which can deplete glutathione and form adducts with hepatic proteins (see Section 15.2). Protein adduction primes the hepatocytes for cytokines released by activated macrophages (Kupffer cells) and/or destructive insults by reactive nitrogen species. Although necrosis is recognized as the mode of cell death in APAP overdose, the precise mechanisms are still being elucidated [152]. 

Eu JP, Xu L, Stamler JS, Meissner G. 1999. Regulation of ryanodine receptors by reactive nitrogen species. Biochem Pharmacol 57 1079-84. 

M. Dong et al., Development of enzymatic probes of oxidative and nitrosative DNA damage caused by reactive nitrogen species. Mutat. Res. 594, 120-134 (2006)... 

Yamakura F, Ikeda K. Modification of tryptophan and tryptophan residues in proteins by reactive nitrogen species. Nitric Oxide 2006 14 152-161. 

Ohshima, H. (2003) Genetic and epigenetic damage induced by reactive nitrogen species implications in carcinogenesis. Toxicol. Lett., 140-141, 99-104. 

Van der Vliet, Eiserich JP, O Neill A, Halliwell B. Cross C E. Tyrosine modification by reactive, nitrogen species a closer look. Arch Biochem Biophys 1995 319 341-9. 

Pennathur, S., C. Beigt, B. Shao, J. Byun, S. Y. Kassim, P. Singh, P. S. Green et al. 2004. Human atherosclerotic intima and blood of patients with established coronary artery disease contain high density lipoprotein damaged by reactive nitrogen species,... 

Glutathione S-transferases are susceptible to inactivation by reactive nitrogen species. Treatment of isolated glutathione S-transferases or rat liver homogenates with either peroxynitrite, the myeloper-oxidase/hydrogen peroxide/nitrite system, or tetra-nitromethane, resulted in loss of glutathione S-transferase activity with a concomitant increase in the formation of protein-associated 3-nitrotyrosine (Wong et al. 2001). 

Ohshima R, Sawa T, Akaike T (2006) 8-Nitroguanine, a product of nitrative DNA damage caused by reactive nitrogen species formation, occurrence, and implications in inflammation and carcinogenesis. Antioxid Redox Signal 8 1033-1045... 

Figure 4. y-Tocopherol plays a unique role in preventing damage caused by reactive nitrogen species see text for details. 

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