Hardie L J, Briggs J A, Davidson L A, Allan J M, King R F, Williams G I, Wild C P
Molecular Epidemiology Unit, School of Medicine, University of Leeds and Institute of Pathology, Algernon Firth Building, Leeds LS2 9JT, UK.
Carcinogenesis. 2000 Feb;21(2):167-72. doi: 10.1093/carcin/21.2.167.
Polymorphic genes for the peroxide scavenger glutathione peroxidase I (GPX1) and 8-hydroxydeoxyguanosine (8-OHdG) DNA glycosylase/apurinic (AP) lyase (hOGG1) map to loci on chromosome 3p which are subject to frequent loss of heterozygosity (LOH) in lung tumours. Levels of the pro-mutagenic, oxidative DNA lesion 8-OHdG, were measured in 37 paired normal and tumorous lung specimens using HPLC with electrochemical detection. Lung tumours were also analysed for 3p LOH by fluorescent PCR with Genescan analysis. No significant difference was observed between 8-OHdG levels in tumour [7.7 +/- 6.7 (mean +/- SE) 8-OHdG/10(6) 2'-deoxyguanosine (dG)] and normal (8.1 +/- 8.8 8-OHdG/10(6) dG) lung tissue. Adduct levels in normal lung tissue DNA were not associated with constitutive hOGG1 genotype although there was a trend towards lower 8-OHdG levels in individuals possessing the ALA6 GPX1 polymorphism. Lung tumours exhibiting 3p LOH (40%) contained higher levels of 8-OHdG adducts (10.9 +/- 2.6 8-OHdG/10(6) dG) (P = 0.05) and lower GPX1 enzyme activity [45.5 nmol glutathione (GSH)/min/mg] (P = 0.09) when compared with tumours without LOH at these sites (5.55 +/- 0.87 8-OHdG/10(6) dG and 63.6 nmol GSH/min/mg, respectively). In conclusion, tumours with 3p LOH at loci associated with hOGG1 and GPX1 appear to have compromised oxidative defence mechanisms as measured by reduced GPX1 enzyme activity and elevated 8-OHdG levels and this may affect the prognosis of lung cancer patients.
过氧化物清除剂谷胱甘肽过氧化物酶I（GPX1）和8-羟基脱氧鸟苷（8-OHdG）DNA糖基化酶/脱嘌呤（AP）裂解酶（hOGG1）的多态基因定位于3号染色体短臂上的位点，这些位点在肺肿瘤中经常发生杂合性缺失（LOH）。使用高效液相色谱电化学检测法，在37对正常和肿瘤肺标本中测量了促诱变的氧化性DNA损伤8-OHdG的水平。还通过荧光PCR和基因扫描分析对肺肿瘤进行了3p LOH分析。肿瘤（7.7±6.7（平均值±标准误）8-OHdG/10⁶ 2'-脱氧鸟苷（dG））和正常肺组织（8.1±8.8 8-OHdG/10⁶ dG）中的8-OHdG水平未观察到显著差异。正常肺组织DNA中的加合物水平与组成型hOGG1基因型无关，尽管具有ALA6 GPX1多态性的个体中8-OHdG水平有降低的趋势。与这些位点无LOH的肿瘤（分别为5.55±0.87 8-OHdG/10⁶ dG和63.6 nmol谷胱甘肽（GSH）/分钟/毫克）相比，表现出3p LOH的肺肿瘤（40%）含有更高水平的8-OHdG加合物（10.9±2.6 8-OHdG/10⁶ dG）（P = 0.05）和更低的GPX1酶活性[45.5 nmol GSH/分钟/毫克]（P = 0.09）。总之，在与hOGG1和GPX1相关的位点发生3p LOH的肿瘤，通过降低的GPX1酶活性和升高的8-OHdG水平测量，其氧化防御机制似乎受到损害，这可能会影响肺癌患者的预后。
