8-Nitroguanine,a Product of Nitrative DNA Damage Caused by Reactive Nitrogen Species: Formation,Occurrence,and Implications in Inflammation and Carcinogenesis

The authors review studies on 8-nitroguanine (8-NO₂-G) formed by reactions of guanine, guanosine, and 2´- deoxyguanosine, either free or in DNA or RNAwith reactive nitrogen species (RNS) generated from peroxynitrite, the myeloperoxidase-H₂O₂-nitrite system, and others. Use of antibodies against 8-NO₂-G has revealed increased formation of 8-NO₂-G in various pathological conditions, including RNA virus-induced pneumonia in mice, intrahepatic bile ducts of hamsters infected with the liver fluke Opisthorchis viverrini, and gastric mucosa of patients with Helicobacter pylori-induced gastritis. Immunoreactivity has been found in the cytosol as well as in the nucleus of inflammatory cells and epithelial cells in inflamed tissues, but not in normal tissues. 8- NO₂-G in DNA is potentially mutagenic, yielding G:C to T:A transversion, possibly through its rapid depurination to form an apurinic site and/or miscoding with adenine. 8-NO₂-G in RNA may interfere with RNA functions and metabolism. Nitrated guanine nucleosides and nucleotides in the nucleotide pool may contribute to oxidative stress via production of superoxide mediated by various reductases and may disturb or modulate directly various important enzymes such as GTP-binding proteins and cGMP-dependent enzymes. Further studies are warranted to establish the roles of 8-NO₂-G in various pathophysiological conditions and inflammation-associated cancer.