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

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• 作者：Pei-Hsin Chou ; Shinji Kageyama ; Shun Matsuda ; Keishi Kanemoto ; Yoshiaki Sasada ; Megumi Oka ; Kazuya Shinmura ; Hiroki Mori ; Kazuaki Kawai ; Hiroshi Kasai ; Haruhiko Sugimura ; Tomonari Matsuda
• 刊名：Chemical Research in Toxicology
• 出版年：2010
• 出版时间：September 20, 2010
• 年：2010
• 卷：23
• 期：9
• 页码：1442-1448
• 全文大小：358K
• 年卷期：v.23,no.9(September 20, 2010)
• ISSN：1520-5010

文摘

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-OHE-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-etheno-2′-deoxycytidine (HεdC), heptanone-etheno-2′-deoxyadenosine (HεdA), and butanone-etheno-2′-deoxycytidine (BεdC), were identified as major adducts in one human pulmonary DNA. Quantitative analysis revealed 4-ONE-derived HεdC, HεdA, and heptanone-etheno-2′-deoxyguanosine (HεdG) 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 BεdC was highly correlated with that of HεdC (R² = 0.94), although BεdC was present at about a 7-fold lower concentration than HεdC. 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.