Increased p53 mutation load in nontumorous human liver of Wilson disease and hemochromatosis:: Oxyradical overload diseases
Increased p53 mutation load in nontumorous human liver of Wilson disease and hemochromatosis:: Oxyradical overload diseases
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DOI：
10.1073/pnas.220416097
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发表时间：
2000-11-07
影响因子：
11.1
通讯作者：
Harris, CC
中科院分区：
文献类型：
--
作者：
Hussain, SP;Raja, K;Harris, CC
血色沉着症和肝豆状核变性(WD)分别以肝脏铁和铜的过度沉积为特征，会产生氧化应激并增加患肝癌的风险。由于人类非肿瘤组织中P53突变等位基因的频率可能是氧自由基损伤的生物标志物，并识别出癌症风险增加的个体，我们已经确定了WD和血色沉着症患者非肿瘤肝组织中P53突变等位基因的频率。与正常对照组相比，WD患者肝组织中第249位密码子G：C到T：A易位频率(P<；0.001)和第250位密码子C：C到A：T易位频率(P<；0.001和P<；0.005)和第249位G：C到T：A易位频率也较高(P<；0.05)。60%的WD和28%的血色沉着症患者肝脏中诱导型一氧化氮合酶的表达也较高，这表明一氧化氮是氧化应激增加的来源之一。在WD和血色沉着症患者的肝脏中，有高水平的乙烯-DNA加合物，它是由氧自由基诱导的脂质过氧化反应形成的。因此，我们将野生型p53 TK-6淋巴母细胞系暴露于4-羟基壬烯醛。一种参与脂质过氧化的不饱和醛，并观察到P53密码子249(ACC到AGT)的G到T转换率增加。这些结果与血色素沉着症和WD中铁和铜超载产生氧/氮物种和不饱和醛导致p53肿瘤抑制基因突变的假设是一致的。
Hemochromatosis and Wilson disease (WD), characterized by the excess hepatic deposition of iron and copper, respectively, produce oxidative stress and increase the risk of liver cancer. Because the frequency of p53 mutated alleles in nontumorous human tissue may be a biomarker of oxyradical damage and identify individuals at increased cancer risk, we have determined the frequency of p53 mutated alleles in nontumorous liver tissue from WD and hemochromatosis patients. When compared with the liver samples from normal controls, higher frequencies of G:C to T:A transversions at codon 249 (P < 0.001) and C:G to A:T transversions and C:C to T:A transitions at codon 250 (P < 0.001 and P < 0.005) were found in liver tissue from WD cases, and a higher frequency of G:C to T:A transversions at codon 249 (P < 0.05) also was found in liver tissue from hemochromatosis cases. Sixty percent of the WD and 28% of hemochromatosis cases also showed a higher expression of inducible nitric oxide synthase in the liver, which suggests nitric oxide as a source of increased oxidative stress. A high level of etheno-DNA adducts, formed from oxyradical-induced lipid peroxidation, in liver from WD and hemochromatosis patients has been reported previously. Therefore, we exposed a wild-type p53 TK-6 lymphoblastoid cell line to 4-hydroxynonenal. an unsaturated aldehyde involved in lipid peroxidation, and observed an increase in G to T transversions at p53 codon 249 (ACC to AGT). These results are consistent with the hypothesis that the generation of oxygen/ nitrogen species and unsaturated aldehydes from iron and copper overload in hemochromatosis and WD causes mutations in the p53 tumor suppressor gene.