One possible mechanism linking
inflammation with
cancer involves the generation of reactive
oxygen,
nitrogen, and
halogen species by activated macrophages and neutrophils infiltrating sites of
infection or tissue damage, with these chemical mediators causing damage that ultimately leads to cell death and mutation. To determine the most biologically deleterious chemistries of
inflammation, we previously assessed products across the spectrum of DNA damage arising in inflamed tissues in the SJL mouse model
nitric oxide overproduction ( Pang et al. ( 2007 )
Carcinogenesis 28 , 1807 - 1813 ). Among the anticipated DNA damage chemistries, we observed significant changes only in lipid peroxidation-derived etheno adducts. We have now developed an
isotope-dilution, liquid chromatography-coupled, tandem quadrupole mass spectrometric method to quantify representative species across the spectrum of
RNA damage products predicted to arise at sites of
inflammation, including nucleobase deamination (
xanthosine and
inosine), oxidation (8-oxoguanosine), and alkylation (1,N(6)-ethenoadenosine). Application of the method to the liver, spleen, and kidney from the SJL mouse model revealed generally higher levels of oxidative background
RNA damage than was observed in
DNA in control mice. However, compared to control mice, RcsX treatment to induce
nitric oxide overproduction resulted in significant increases only in
inosine and only in the spleen. Further, the
nitric oxide synthase inhibitor, N-methylarginine, did not significantly affect the levels of
inosine in control and RcsX-treated mice. The differences between
DNA and
RNA damage in the same animal model of
inflammation point to possible influences from DNA repair, RcsX-induced alterations in
adenosine deaminase activity, and differential accessibility of
DNA and
RNA to reactive
oxygen and
nitrogen species as determinants of
nucleic acid damage during
inflammation.