Minireview Reactive nitrogen species in the chemical biology of inflammation Peter C. Dedon a, * and Steven R. Tannenbaum b, * a Biological Engineering Division, Massachusetts Institute of Technology, NE47-277, 77 Massachusetts Avenue, Cambridge, MA 02139, USA b Biological Engineering Division and Department of Chemistry, Massachusetts Institute of Technology, 56-731, 77 Massachusetts Avenue, Cambridge, MA 02139, USA Received 19 September 2003, and in revised form 3 December 2003 Abstract The preponderance of epidemiological evidence now points to a strong association between chronic inflammation and cancers of several organs, including the gastrointestinal tract, liver, and lungs. The strongest evidence for a mechanistic link here involves the generation of reactive oxygen and nitrogen species by macrophages and neutrophils that respond to cytokines and other signaling processes arising at sites of inflammation. These reactive species cause oxidation, nitration, halogenation, and deamination of biomolecules of all types, including lipids, proteins, carbohydrates, and nucleic acids, with the formation of toxic and mutagenic products. This review, in honor of Bruce Ames, will focus on recent advances in our understanding of the protein and DNA damage caused by reactive nitrogen species produced by macrophages and neutrophils, with emphasis on nitric oxide, nitrous anhydride, peroxynitrite, and nitrogen dioxide radical. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Nitric oxide; Peroxynitrite; Macrophages; Inflammation; Carcinogenesis; DNA damage; Reactive nitrogen species; Reactive oxygen species Epidemiological studies demonstrate an association between chronic inflammation and increased cancer risk [1–4]. Examples include inflammatory bowel disease and colon cancer [5,6], Helicobacter pylori infection and gastric cancer [7,8], and Schistosoma haematobium in- fection and bladder cancer [9,10]. During the process of inflammation, professional phagocytes secrete chemi- cally reactive oxidants, radicals, and electrophilic com- pounds, as shown in Fig. 1, that bring about the elimination of infectious agents [11,12]. These same in- flammatory mediators can also damage surrounding host tissue, leading to DNA adduct formation and so- matic mutations that result in malignant transformation [13,14]. Also, observations in vitro and in cultured cell systems indicate that oxidative stress contributes to cancer risk by a number of mechanisms that are inde- pendent of genotoxicity [15,16]. These include resistance to apoptosis [17,18], cytotoxicity and compensatory hyper-proliferation [19], adaptive changes [20], and en- hanced angiogenesis [21]. This review, in honor of Bruce Ames, addresses the chemical biology of the reactive nitrogen mediators of inflammation, which are physiologically important molecules that also play the role of genotoxins. NO Å biochemistry Since its discovery, nitric oxide (NO Å ) 1 has become one of the most highly studied and important biological molecules. While a complete review of NO Å biochemistry is beyond the scope of the present work, the reader is referred to several useful review articles [22–28] from which we have extracted the following brief summary. There are now known to be several NO Å synthases (NOS; EC 1.13.23) including nNOS (neuronal NOS), eNOS (endothelial NOS), and iNOS (inducible NOS). * Corresponding authors. Fax: 1-617-252-1787 (S.R. Tannenbaum), 1-617-324-7554 (P.C. Dedon). E-mail addresses: pcdedon@mit.edu (P.C. Dedon), srt@mit.edu (S.R. Tannenbaum). 1 Abbreviations used: NO Å , nitric oxide; nNOS, neuronal NOS; eNOS, endothelial NOS; iNOS, inducible NOS; SOD, superoxide dismutase; NO 2 Cl, nitryl chloride. 0003-9861/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.abb.2003.12.017 Archives of Biochemistry and Biophysics 423 (2004) 12–22 ABB www.elsevier.com/locate/yabbi