Detection of Lipid Peroxidation-Induced DNA Adducts Caused by 4-Oxo-2(E)-nonenal and 4-Oxo-2(E)-hexenal in Human Autopsy Tissues

DNA adducts are produced both exogenously and endogenously via exposure to various DNA-damaging agents. Two lipid peroxidation (LPO) products, 4-oxo-2(E)-nonenal (4-ONE) and 4-oxo-2(E)-hexenal (4-OHE), induce substituted etheno-DNA adducts in cells and chemically treated animals, but the adduct levels in humans have never been reported. It is important to investigate the occurrence of 4-ONE- and 4-ONE-derived DNA adducts in humans to further understand their potential impact on human health. In this study, we conducted DNA adductome analysis of several human specimens of pulmonary DNA as well as various LPO-induced DNA adducts in 68 human autopsy tissues, including colon, heart, kidney, liver, lung, pancreas, small intestine, and spleen, by liquid chromatography tandem mass spectrometry. In the adductome analysis, DNA adducts derived from 4-ONE and 4-OHE, namely, heptanone-etheno2'-deoxycytidine (H epsilon dC), heptanone-etheno-2'-deoxyadenosine (H epsilon dA), and butanone-etheno-2'-deoxycytidine (B epsilon dC), were identified as major adducts in one human pulmonary DNA. Quantitative analysis revealed 4-ONE-derived H epsilon AC, H epsilon dA, and heptanone-etheno-2'-deoxyguanosine (HEdG) to be ubiquitous in various human tissues at median values of 10, 15, and 8.6 adducts per 108 bases, respectively. More importantly, an extremely high level (more than 100 per 108 bases) of these DNA adducts was observed in several cases. The level of 4-OHE-derived B epsilon dC was highly correlated with that of H epsilon dC (R-2 = 0.94), although B epsilon dC was present at about a 7-fold lower concentration than H epsilon dC. These results suggest that 4-ONE- and 4-OHE-derived DNA adducts are likely to be significant DNA adducts in human tissues, with potential for deleterious effects on human health.