Carcinogenesis Advance Access originally published online on March 7, 2007
Carcinogenesis 2007 28(8):1807-1813; 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, USA
4 Present address: Barclays Global Investors, 45 Freemont Street, San Francisco, CA 94105
5 Present address: Boehringer Ingelheim Pharmaceuticals, Drug Metabolism and Pharmacokinetics, 900 Ridgebury Road, Ridgefield, CT 06877, USA
6 Present address: Novartis Pharma AG, Basel CH-4002, Switzerland
* To whom correspondence should be addressed. 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 12 DNA damage products in tissues from the SJL mouse model of nitric oxide (NO) overproduction. Using liquid chromatography–mass spectrometry/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 (8-oxodG), guanidinohydantoin (Gh), oxazolone (Ox); 5-guanidino-4-nitroimidazole (NitroIm); spiroiminodihydantoin (Sp) and M1dG; the nitrosative deamination products 2'-deoxyxanthosine, 2'-deoxyoxanosine (dO), 2'-deoxyinosine and 2'-deoxyuridine and the lipid peroxidation-derived adducts 1,N6-etheno-deoxyadenosine and 1,N2-etheno-deoxyguanosine. The levels of dO, Gh, Ox, NitroIm and Sp were all below a detection limit of 
1 lesion per 107 bases. Whereas there were only modest increases in the spleens of RcsX-treated compared with control mice for the nucleobase deamination products (10–30%) and the DNA oxidation products 8-oxodG (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 overproduction during chronic inflammation. These results reveal the complexity of NO chemistry in vivo and support an important role for lipids in the pathophysiology of inflammation.
Abbreviations: dI, 2'-deoxyinosine; dO, 2'-deoxyoxanosine; dU, 2'-deoxyuridine; dX, 2'-deoxyxanthosine; 
dA, 1,N6-etheno-2'-deoxyadenosine; dC, 3,N4-etheno-2'-deoxycytidine; dG, 1,N2-etheno-2'-deoxyguanosine; Gh, guanidinohydantoin or N(1)-(ß-D-erythro-pentofuranosyl)-5-guanidinohydantoin; HPLC, high performance liquid chromatography; LC, liquid chromatography; MS, mass spectrometry/meter; MS/MS, tandem or triple quadrupole mass spectrometry; NitroIm, 5-guanidino-4-nitroimidazole; NO, nitric oxide; 8-oxodG, 8-oxo-7,8-dihydro-2'-deoxyguanosine; Ox, oxazolone; ONOOCO
, nitrosoperoxycarbonate; ONOO–, peroxynitrite; PBS, phosphate-buffered saline; Sp, spiroiminodihydantoin
Received August 4, 2006; revised January 23, 2007; accepted February 3, 2007.
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