Detection of Lipid Peroxidation-Induced DNA Adducts Caused by 4-Oxo-2(E)-nonenal and 4-Oxo-2(E)-hexenal in Human Autopsy Tissues
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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DOI：
10.1021/tx100047d
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发表时间：
2010-09-01
影响因子：
4.1
通讯作者：
Matsuda, Tomonari
中科院分区：
文献类型：
--
作者：
Chou, Pei-Hsin;Kageyama, Shinji;Matsuda, Tomonari
DNA加合物通过暴露于各种DNA损伤剂而外源性和内源性地产生。两种脂质过氧化（LPO）产物，4-氧代-2（E）-壬烯醛（4-ONE）和4-氧代-2（E）-己烯醛（4-OHE），在细胞和化学处理的动物中诱导取代的乙烯基-DNA加合物，但在人体中的加合物水平从未报道过。重要的是要调查4-ONE和4-ONE衍生的DNA加合物在人体中的发生情况，以进一步了解它们对人类健康的潜在影响。在这项研究中，我们进行了几个人的肺DNA标本的DNA加合物分析，以及各种LPO诱导的DNA加合物在68人尸检组织，包括结肠，心脏，肾脏，肝脏，肺，胰腺，小肠和脾脏，液相色谱串联质谱。在内收体分析中，从4-ONE和4-OHE衍生的DNA加合物，即庚酮-乙烯基-2 '-脱氧胞苷（H β dC）、庚酮-乙烯基-2'-脱氧腺苷（H β dA）和丁酮-乙烯基-2 '-脱氧胞苷（B β dC）被鉴定为一个人肺DNA中的主要加合物。定量分析显示，4-ONE衍生的H β AC、H β dA和庚酮-乙烯基-2 '-脱氧鸟苷（HEdG）在各种人体组织中普遍存在，中位数分别为每108个碱基10、15和8.6个加合物。更重要的是，在几种情况下观察到极高水平（每108个碱基中超过100个）的这些DNA加合物。4-OHE衍生的B β dC的水平与H β dC的水平高度相关（R-2 = 0.94），尽管B β dC的浓度比H β dC低约7倍。这些结果表明，4-ONE和4-OHE衍生的DNA加合物可能是人体组织中的重要DNA加合物，对人体健康具有潜在的有害影响。
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.