Carcinogenesis Advance Access published online on March 7, 2007
Carcinogenesis, doi:10.1093/carcin/bgm037
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Lipid peroxidation dominates the chemistry of DNA adduct formation in a mouse model of inflammation
1 Biological Engineering Division
2 Center for Environmental Health Sciences
3 Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA
* Author to whom correspondence should be addressed: Biological Engineering Division, NE47-277, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139; tel: 617-253-8017; fax: 617-324-7554; email: pcdedon{at}mit.edu
In an effort to define the prevalent DNA damage chemistry associated chronic inflammation, we have quantified twelve DNA damage products in tissues from the SJL mouse model of nitric oxide (NO) over-production. Using LC-MS/MS and immunoblot techniques, we analyzed spleen, liver and kidney from RcsX-stimulated and control mice for the level of the following adducts: the DNA oxidation products 8-oxo-7,8-dihydro-2'-deoxyguanosine, guanidinohydantoin, oxazolone, 5-guanidino-4-nitroimidazole, and spiroiminodihydantoin, and M1dG; the nitrosative deamination products 2'-deoxyxanthosine, 2'-deoxyoxanosine, 2'-deoxyinosine, and 2'-deoxyuridine; and the lipid peroxidation-derived adducts 1,N6-etheno-deoxyadenosine and 1,N2-etheno-deoxyguanosine. The levels of 2'-deoxyoxanosine, guanidinohydantoin, oxazolone, 5-guanidino-4-nitroimidazole and spiroiminodihydantoin were all below a detection limit of 
1 lesion per 107 bases. While there were only modest increases in the spleens of RcsX-treated compared to control mice for the nucleobase deamination products (10-30%) and the DNA oxidation products 8-oxo-7,8-dihydro-2'-deoxyguanosine (10%) and M1dG (50%), there were large (3- to 4-fold) increases in the levels of 1,N6-etheno-deoxyadenosine and 1,N2-etheno-deoxyguanosine. Similar results were obtained with the liver and with an organ not considered to be a target for inflammation in the SJL mouse, the kidney. This latter observation suggests that oxidative and nitrosative stresses associated with inflammation can affect tissues at a distance from the activated macrophages responsible for NO over-production during chronic inflammation. These results reveal the complexity of NO chemistry in vivo and suggest an important role for lipids in the pathophysiology of inflammation.
Key Words: DNA damage • inflammation • biomarker • nitric oxide
Present address: Boehringer Ingelheim Pharmaceuticals Inc., Drug Metabolism and Pharmacokinetics, 900 Ridgebury Road, Ridgefield, CT 06877
Present address: Novartis Institutes for BioMedical Research, Models of Disease Center, 250 Massachusetts Ave., Cambridge, MA 02139
Received August 4, 2006; revised January 23, 2007; accepted February 3, 2007.
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