Detection of lipid peroxidation-induced DNA adducts caused by 4-Oxo-2(E)-nonenal and 4-Oxo-2(E)-hexenal in human autopsy tissues

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

研究成果: Article同行評審

57 引文 斯高帕斯(Scopus)

摘要

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

原文English
頁(從 - 到)1442-1448
頁數7
期刊Chemical Research in Toxicology
23
發行號9
DOIs
出版狀態Published - 2010 9月 20

All Science Journal Classification (ASJC) codes

  • 毒理學

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