Lipid peroxidation dominates the chemistry of DNA adduct formation in a mouse model of inflammation.
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 M(1)dG; the nitrosative deamination products 2'-deoxyxanthosine, 2'-deoxyoxanosine (dO), 2'-deoxyinosine and 2'-deoxyuridine and the lipid peroxidation-derived adducts 1,N(6)-etheno-deoxyadenosine and 1,N(2)-etheno-deoxyguanosine. The levels of dO, Gh, Ox, NitroIm and Sp were all below a detection limit of approximately 1 lesion per 10(7) 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 M(1)dG (50%), there were large (3- to 4-fold) increases in the levels of 1,N(6)-etheno-deoxyadenosine and 1,N(2)-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.
Pang
Bo
B
Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, MA, USA.
Zhou
Xinfeng
X
Yu
Hongbin
H
Dong
Min
M
Taghizadeh
Koli
K
Wishnok
John S
JS
Tannenbaum
Steven R
SR
Dedon
Peter C
PC
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002460:Cell Line; D018736:DNA Adducts / Q000096:biosynthesis* / Q000737:chemistry; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000737:chemistry; D004195:Disease Models, Animal; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000235:genetics*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism
D018736:DNA Adducts; D009569:Nitric Oxide; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine