Immunohistochemical detection of 1,N6-ethenodeoxyadenosine in nuclei of human liver affected by diseases predisposing to hepato-carcinogenesis
Immunohistochemical detection of 1,N6-ethenodeoxyadenosine in nuclei of human liver affected by diseases predisposing to hepato-carcinogenesis
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DOI：
10.1093/carcin/bgh089
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发表时间：
2004-06-01
期刊：
影响因子：
4.7
通讯作者：
Nair, J
中科院分区：
文献类型：
--
作者：
Frank, A;Seitz, HK;Nair, J
氧化应激增加和脂质过氧化（LPO）与多阶段致癌作用有关。近期研究表明，LPO衍生的活性羟基烯醛可在体内形成诱变性的外环乙烯基 - DNA加合物。在金属贮积病患者的肝脏以及家族性腺瘤性息肉病患者的结肠腺瘤中发现此类DNA损伤增加。我们现在对从一组被诊断患有肝炎、脂肪肝、纤维化和肝硬化、原发性血色素沉着症以及威尔逊病的患者获取的人类肝脏样本中1,N - 6 - 乙烯基脱氧腺苷（εdA）的水平进行了研究。使用免疫组织化学方法，通过成像软件测量随机选取的细胞核的相对平均像素强度；对阳性染色的细胞核（任意平均像素强度大于或等于0.5）进行计数。εdA的患病率（%）由阳性染色细胞核数量与计数的细胞总数之比计算得出。与正常肝脏（3.1%）相比，酒精性脂肪肝（15%）和纤维化患者（50%）样本中的患病率百分比（均值）显著更高，但在（由各种因素引起的）肝炎样本中并非如此（6.2%）。酒精性纤维化中的患病率百分比与威尔逊病（50.7%）和血色素沉着症（33%）患者的肝脏中一样高。这是首次证明在因酗酒导致的人类肝脏疾病中εdA增加。我们得出结论，通过对肝脏活检细胞核中错编码的乙烯基 - DNA加合物进行评估，肝脏DNA过度损伤可能是由酒精诱导的氧化应激和LPO引起的。在易患癌症的肝脏疾病（脂肪肝、肝硬化/纤维化）中，这种损伤可能是迈向恶性肿瘤的驱动力。
Increased oxidative stress and lipid peroxidation (LPO) are implicated in multistage carcinogenesis. Recent studies have shown that LPO-derived reactive hydroxyalkenals can form promutagenic exocyclic etheno-DNA adducts in vivo. Such DNA damage was found to be increased in the liver of patients with metal storage diseases and in colon adenomas of familial adenomatous polyposis patients. We now have investigated the levels of 1,N-6-ethenodeoxyadenosine (epsilondA) in human liver samples obtained from a group of patients diagnosed with hepatitis, fatty liver, fibrosis and cirrhosis, primary hemochromatosis and Wilson's disease. Using an immunohistochemical method, the relative mean pixel intensity of randomly selected nuclei was measured by imaging software; positively stained cell nuclei (arbitrary mean pixel intensity greater than or equal to0.5) were counted. Prevalence of epsilondA (%) was calculated from the ratio of a number of positively stained cell nuclei over a total number of cells counted. When compared with normal livers (3.1%), the percent prevalence (means) was significantly higher in specimens of alcoholic fatty liver (15%) and fibrosis patients (50%) but not in samples with hepatitis (induced by various factors) (6.2%). The percent prevalence in alcohol fibrosis was as high as in the liver from Wilson's disease (50.7%) and hemochromatosis (33%) patients. This is the first demonstration of increased epsilondA in human liver diseases due to alcohol abuse. We conclude that excessive hepatic DNA damage, as assessed by miscoding etheno-DNA adduct in the nuclei of liver biopsies, is probably caused by alcohol-induced oxidative stress and LPO. In cancer-prone liver diseases (fatty liver, cirrhosis/fibrosis) such damage may act as a driving force towards malignancy.