DNA加合物及其相关修复酶基因多态性在COPD发病中的研究
摘要
慢性阻塞性肺疾病(COPD)是严重危害人民身体健康的常见疾病，其发病率和死亡率在发达国家和发展中国家都呈上升趋势，对于COPD目前还没有确实有效的治疗方法，主要原因还是其发病机制不清楚。吸烟是COPD和肺癌最重要的危险因素，近90％的COPD和肺癌患者为吸烟者。在吸烟致肺癌的研究上，目前的研究发现香烟有毒成分可与细胞的DNA结合形成DNA加合物，DNA加合物可导致基因的突变、缺失和错配等，最终导致肺癌的发生，但DNA加合物是否与吸烟导致COPD发病有关以及哪种DNA加合物与吸烟导致COPD发病有关至今还未有研究。
近年来，越来越多的研究表明氧化应激在COPD发病中起重要作用。香烟烟雾含有大量活性氧(reactive oxygen species，ROS)，其可直接攻击生物大分子DNA，诱发DNA链断裂和多种形式的碱基修饰，进而导致DNA损伤(DNA damage)。在众多DNA氧化损伤中，以鸟嘌呤8位碳原子的氧化最常见，其氧化产物8-羟基脱氧鸟苷(8-hydroxydeoxyguanine，8-OHdG)为DNA经受氧化损伤的代表性产物，如其不能被有效修复，会导致DNA复制过程中G：C→T：A颠换，该颠换在肿瘤形成中发生最早，有研究发现肺癌组织8-OHdG含量高于非肺癌组织，但8-OHdG是否与吸烟导致COPD的发生有关至今还未有研究。
机体存在多种DNA修复途径以维护基因组的稳定，8-羟基鸟嘌呤DNA糖苷酶1(human 8-oxoguanine DNA glycosylase，简称hOGG1)，是碱基切除修复途径中的一个重要成分，该基因产物具有DNA糖苷酶活性，可以特异性切除8-OHdG，从而避免在DNA复制过程中因错配而导致的G：C→T：A颠换突变，在维持基因组稳定上具有举足轻重的作用。有关hOGG1表达与8-OHdG的关系的研究结果不尽一致，而且有研究发现，hOGG1基因具有遗传多态性，其中位于第7外显子第1245位碱基的C／G多态，使其编码326位丝氨酸(Ser)变为半胱氨酸(Cys)，hOGG1-326Cys蛋白修复8-OHdG的活性显著低于hOGG1-326Ser蛋白，提示携带326Cys等位基因的个体有可能修复能力低下或缺陷。X射线修复交叉互补基因(X-ray repair cross complementinggroup 1，XRCC1)是另一个重要的DNA损伤修复基因，在短片修复通路中其与hOGG1直接发生相互作用。迄今为止，人类已经在XRCC1中识别了60多种单核苷酸多态，其中研究主要集中在进化保守的三个编码区，即26304C→T、27466G→A和28152G→A，这三个SNP导致相应氨基酸改变分别为194位密码子Arg→Trp、280位密码子Arg→His和399位密码子Arg→Gln，他们的生物学功能目前并不完全清楚。吸烟虽为COPD最重要的危险因素，但并非所有吸烟者均患COPD，这说明基因易感性在COPD发病中起重要作用。DNA修复基因hOGG1及XRCC1的单核苷酸多态性是否与部分吸烟者易患COPD有关至今还未见报道。
本研究包括两部分，第一部分探讨8-OHdG是否与吸烟导致COPD发生有关，本部分包括两个分题，分题一探讨淋巴细胞8-OHdG含量和肺组织8-OHdG含量的相关性，分题二探讨8-OHdG与吸烟所致COPD发病的关系；第二部分探讨hOGG1和XRCC1基因多态性与吸烟者易患COPD的关系。
第一部分8-OHdG与吸烟导致COPD发生的研究
分题1淋巴细胞8-OHdG含量与肺组织8-OHdG含量的相关性研究
【目的】探讨淋巴细胞8-OHdG含量和肺组织8-OHdG含量之间是否存在相关性。
【方法】采用淋巴细胞和肺手术切除肺组织，分为COPD组和非COPD组，通过高效液相色谱-电化学法检测8例COPD患者和8例非COPD患者淋巴细胞和肺组织8-OHdG含量。
【结果】
(1) COPD组淋巴细胞8-OHdG的含量为7．25±2．29／10~5dG，非COPD组淋巴细胞8-OHdG的含量为3.34±1．94／10~5dG，差异有显著统计学意义(P＜0．05)。
(2) COPD组肺组织的8-OHdG含量为8．15±2．19／10~5dG，非COPD组肺组织8-OHdG含量为3．19±1．51／10~5dG，差异有显著统计学意义(P＜0．05)。
(3) COPD组淋巴细胞8-OHdG含量与肺组织的8-OHdG含量呈明显正相关(r=0．768，P＜0．05)；非COPD组淋巴细胞8-OHdG含量与肺组织的8-OHdG含量呈明显正相关(r=0．787，P＜0．05)。
【结论】COPD患者淋巴细胞和肺组织8-OHdG含量明显高于非COPD患者淋巴细胞和肿组织8-OHdG含量，且淋巴细胞8-OHdG含量与肺组织8-OHdG含量存在明显相关性，提示可以用淋巴细胞8-OHdG研究吸烟导致COPD发病的关系。
分题2 8-OHdG与吸烟所致COPD发病的关系
【目的】探讨8-OHdG在吸烟所致COPD发病中的作用，以及活性氧水平、hOGG1mRNA及hOGG1蛋白表达水平对8-OHdG含量的影响。
【方法】收集140例健康不吸烟者、143例健康吸烟者和129例吸烟COPD者静脉血，分离淋巴细胞，采用高效液相色谱-电化学法检测8-OHdG含量，2'，7'-二乙酰二氯荧光素(DCFH-DA)检测细胞内ROS水平，实时定量PCR(Real-time PCR)检测hOGG1 mRNA表达，Western Blot检测hOGG1蛋白表达。
【结果】
(1)健康吸烟组和吸烟COPD组淋巴细胞8-OHdG含量明显高于健康不吸烟组，差异有显著统计学意义(P＜0．05)，且吸烟COPD组淋巴细胞8-OHdG含量明显高于健康吸烟组，差异亦有显著统计学意义(P＜0．05)。
(2)健康吸烟组和吸烟COPD组淋巴细胞ROS、hOGG1 mRNA及hOGG1蛋白表达均明显高于健康不吸烟组，差异有显著统计学意义(P＜0．05)；吸烟COPD组淋巴细胞ROS水平明显高于健康吸烟组，差异有显著统计学意义(P＜0．05)；吸烟COPD组淋巴细胞hOGG1 mRNA及hOGG1蛋白表达水平明显低于健康吸烟组，差异有显著统计学意义(P＜0．05)。
(3)健康吸烟组及吸烟COPD组淋巴细胞8-OHdG含量与吸烟指数均呈明显正相关(P＜0．05)；三组淋巴细胞8-OHdG含量与淋巴细胞ROS水平均呈明显正相关(P＜0．05)，与hOGG1 mRNA表达水平呈明显负相关(P＜0．05)，与hOGG1蛋白表达水平亦呈明显负相关(P＜0．05)。
(4)健康不吸烟组和健康吸烟组淋巴细胞8-OHdG含量与FEV_1％预计值和FEV_1／FVC均无明显相关性(P＞0．05)；而吸烟COPD组淋巴细胞8-OHdG含量与FEV_1％预计值和FEV_1／FVC呈显著负相关性(r=-0．575、-0．448，P＜0．05)。
【结论】吸烟COPD组淋巴细胞8-OHdG含量明显高于健康不吸烟组与健康吸烟组淋巴细胞8-OHdG含量，提示8-OHdG水平升高与吸烟导致COPD发病有关。
第二部分hOGG1和XRCC1基因多态性与吸烟者易患COPD的关系
【目的】探讨DNA修复基因hOGG1 Ser326Cys和XRCC1 Arg194Trp、Arg280His、Arg399Gln基因多态性与COPD易感性的关系。
【方法】收集201例COPD患者和309例对照，用聚合酶链反应和限制性片段长度多态方法(PCR-RFLP)分析hOGG1第326密码子和XRCC1第194、280及399密码子基因多态性。
【结果】
(1) hOGG1 Ser326Cys基因型携带者和Cys326Cys基因型携带者与Ser326Ser基因型携带者相比，COPD患病风险无明显差异；XRCC1 Gln399Gln基因型携带者与Arg399Arg基因型携带者相比COPD患病风险亦无明显差异；但XRCC1Arg399Gln基因型携带者患COPD风险明显高于Arg399Arg基因型携带者，其校正后相对危险度为1．55(95％CI 1．05-2．29，P＜0．05)。按吸烟特征分层后，携带有hOGG1 Cys326Cys基因型的现在吸烟者患COPD的风险明显高于携带Ser326Ser基因型的现在吸烟者，校正后相对危险度为5．07(95％CI 1．84-13．95，P＜0．05)；携带有XRCC1 Arg399Gln基因型的现在吸烟者患COPD的风险明显高于携带Arg399Arg基因型的现在吸烟者，校正后相对危险度为2．77(95％CI1．52-5．07，P＜0．05)。按照吸烟强度分层后，携带有hOGG1 Cys326Cys基因型的轻吸烟者患COPD的风险明显高于携带Ser／Ser基因型的轻度吸烟者，校正后相对危险度为4．02(95％CI 1．05-16．80，P＜0．05)；携带有XRCC1 Gln399Gln基因型的轻度吸烟者患COPD的风险明显高于携带Arg399Arg基因型的轻度吸烟者，校正后相对危险度为4．48(95％CI 1．35-14．90，P＜0．05)；携带有XRCC1Arg399Gln基因型的重度吸烟者患COPD的风险明显高于携带Arg399Arg基因型的重度吸烟者，校正后相对危险度为2．55(95％CI 1．42-4．58．P＜0．05)。
(2) XRCC1 Trp194Trp基因型携带者与Arg194Arg基因型携带者相比患COPD的风险无明显差异，但经吸烟特征和吸烟强度分层后，在戒烟者层，携带XRCC1Trp194Trp基因型者相较于Arg194Arg基因型者患COPD风险减低，其校正后相对危险度为0．22(95％CI 0．06-0．85，P＜0．05);在轻度吸烟者层，携带XRCC1Arg194Trp基因型和Trp194Trp基因型者相较于Arg194Arg基因型者患COPD风险都减低，其校正后相对危险度分别为0．39(95％CI 0．16-0．94，P＜0．05)和0．24(95％CI 0．07-0．79．P＜0．05)。
(3) XRCC1 Arg280His三种基因型在COPD组的频率与在对照组的频率无明显差异(P＞0．05)，按吸烟特征和吸烟强度分层后，在不吸烟者层、戒烟者层、现在吸烟者层、轻度吸烟者层和重度吸烟者层XRCC1 Arg280His三种基因型在COPD组的频率与在对照组的频率均无明显差异(P＞0．05)。
【结论】hOGG1 326Cys和XRCC1 399Gln明显升高现在吸烟者和轻度吸烟者患COPD的危险度，XRCC1 194Trp与降低戒烟者和轻度吸烟者患COPD的风险有关，XRCC1 280His与COPD患病风险无明显相关性。
Chronic obstructive pulmonary disease (COPD) is a major and increasing cause ofmorbidity and mortality worldwide and its prevalence is still increasing. At the present time,there is no specific and effective treatment for COPD, because the pathogenesis is still notclear. Cigarette smoke is a major risk factor for COPD and lung cancer, and almost 90% ofCOPD and lung cancer patients are smokers. The present study found DNA adducts-thetoxic components combined with DNA, which could cause the gene mutation, deletion andmismatching, caused the lung cancer eventually. However, whether DNA adducts isassociated with COPD and which DNA adducts is associated with COPD is still notstudied.
Now, there is ample evidence that oxidative stress plays a major role in COPD.Cigarette smoke is a rich source of reactive oxygen species (ROS), which can attack DNAand cause DNA damage. Among the various forms of DNA damage induced by oxygenradicals, 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a major form of oxidative DNAdamage and an important marker of cellular oxidative stress. If 8-OHdG is not effectivelyrepaired, it will cause G:C→T:A transversion. Some researches found the 8-OHdG level inlung cancer tissue was higher than non-lung cancer tissue. However, whether 8-OHdG isassociated with COPD is still not studied.
There are many DNA repair pathways to maintain the stabilization of gene. Human8-oxoguanine DNA glycosylase (hOGG1), a major component in the DNA repair pathways,which can excise 8-OHdG specifically and avoid G:C→T:A transversion, plays a majorrole in gene stability. The results about the relationship between the expression of hOGG1and 8-OHdG were inconsistent, In addition, the substitution of cysteine for serine at codon326 (Ser326Cys) was associated with significant reduction in the repair capacity. X-rayrepair cross complementing group 1 (XRCC1), is another major DNA repair gene, whichinteracts with hOGG1 directly. So far, more than 60 single nucleotide polymorphisms werefound. The most studied were 26304C→T、27466G→A and 28152G→A, which caused the corresponding amino acid transition: 194 Arg→Trp、280 Arg→His and 399Arg→Gln.Although smoking is the most important risk factor, not all smokers develop COPD, whichsuggests that there is a genetic susceptibility to the development of COPD. Whether thepolymorphisms of hOGG1 and XRCC1 are associated with COPD is not studied.
The present study consisted of two parts. One part investigated the relationshipbetween 8-OHdG and COPD: section one investigated the association between 8-OHdGlevel in lymphocyte and the 8-OHdG level in lung tissue; section two investigated therelationship among cigarette smoke、8-OHdG and COPD. The other part investigated therelationship between the polymorphisms of hOGG1 and XRCC1 and COPD.
PartⅠStudy on 8-OHdG and COPD related with cigarette smoke
Section 1 The association between 8-OHdG level in lymphocyte and the 8-OHdG levelin lung tissue
【Objective】To investigate the association between 8-OHdG level in lymphocyte and the8-OHdG level in lung tissue.
【Methods】8-OHdG was detected by high press liquid chromatography withelectrochemical detection in peripheral blood lymphocyte and lung tissue of 8 COPD casesand 8 controls.
【Results】
(1) The level of 8-OHdG in lymphocyte was significantly higher in COPD cases(7.25±2.29/10~5dG) than in controls (3.30±1.94/10~5dG), (P＜0.05).
(2) The level of 8-OHdG in lung tissue was significantly higher in COPD cases(8.15±2.19/10~5dG) than in controls (3.19±1.51/10~5dG), (P＜0.05).
(3) In COPD group, the level of 8-OHdG in lymphocyte was positively correlated with thelevel of 8-OHdG in lung tissue (r=0.768, P＜0.05); and in control, the level of 8-OHdGin lymphocyte was also positively correlated with the level of 8-OHdG in lung tissue(r=0.787, P＜0.05).
【Conclusions】The level of 8-OHdG in lymphocyte and lung tissue of COPD cases washigher than the level of 8-OHdG in lymphocyte and lung tissue of controls. And in COPD cases and controls, the level of 8-OHdG in lymphocyte was significantly associated withthe level of 8-OHdG in lung tissue, which suggested that 8-OHdG in lymphocyte could beused to investigate the relationship between cigarette smoke and COPD.
【Keywords】COPD, 8-OHdG, lymphocyte, lung tissueSection 2 The relationship among cigarette smoking、8-OHdG and COPD
【Objective】To investigate the relationship among cigarette smoking、8-OHdG inlymphocyte and COPD and the influence of ROS、hOGG1 mRNA and hOGG1 protein on8-OHdG level.
【Methods】A total 140 healthy non-smokers, 143 healthy smokers and 129 smokers withCOPD were recruited. 8-OHdG was detected by high press liquid chromatography withelectrochemical detection; DCFH-DA was used to detect ROS level; Real-time PCR wasused to detect the expression of hOGG1 mRNA; Western Blot was used to detect theexpression of hOGG1 protein.
【Results】
(1) The level of 8-OHdG in lymphocyte was significantly higher in healthy smokers andsmokers with COPD than in healthy nonsmokers (P＜0.05); and the level of 8-OHdG inlymphocyte was significantly higher in smokers with COPD than in healthy smokers.
(2) The level of ROS、hOGG1 mRNA and hOGG1 protein in lymphocyte was significantlyhigher in healthy smokers and smokers with COPD than in healthy nonsmokers(P＜0.05); the level of ROS in lymphocyte was significantly higher in smokers withCOPD than in healthy smokers (P＜0.05); the expression of hOGG1 mRNA and hOGG1protein in lymphocyte was significantly lower in smokers with COPD than in healthysmokers (P＜0.05).
(3) In healthy smokers and smokers with COPD, the level of 8-OHdG in lymphocyte waspositively correlated with smoking index (P＜0.05); in all three groups, the level of8-OHdG in lymphocyte was positively correlated with ROS level (P＜0.05), andnegatively correlated with the expression of hOGG1 mRNA (P＜0.05) and hOGG1protein (P＜0.05).
(4) In healthy nonsmokers and healthy smokers, the level of 8-OHdG in lymphocyte was not significantly correlated with FEV_1% predicted and FEV_1/FVC (P＞0.05); however,in smokers with COPD, the level of 8-OHdG in lymphocyte was significantlynegatively correlated with FEV_1% predicted and FEV_1/FVC (P＜0.05).
【Conclusions】The level of 8-OHdG in lymphocyte of smokers with COPD was higherthan the level of 8-OHdG in lymphocyte of healthy nonsmokers and healthy smokers,which suggested that the elevation was associated with COPD caused by cigarette smoke.
PartⅡ: The relationship between the polymorphisms of hOGG1 and XRCC1 and therisk of COPD
【Objective】To investigate the relationship between the polymorphisms of hOGG1Ser326Cys、XRCC1 Arg194Trp、Arg280His and Arg399Gln and the risk of COPD.
【Methods】A total 201 COPD cases and 309 controls were recruited, hOGG1 genotypeand XRCC1 genotype were determined by PCR-restriction fragment length polymorphismanalysis.
【Results】
(1) Compared with those with the hOGG1 Ser326Ser genotype, the risk for COPD was notsignificantly different among individuals with Ser326Cys genotype and Cys326Cysgenotype. Compared with those with the XRCC1 Arg399Arg genotype, the risk forCOPD was not significantly different among individuals with Gln399Gln genotype, butthe risk for COPD was significantly elevated among individuals with Arg399Glngenotype (adjusted odds ratios (OR)=1.55, 95% confidence intervals (CI) 1.05-2.29,P＜0.05). After stratifying by smoking status, in current smokers, compared with thosewith the hOGG1 Ser326Ser genotype, the risk for COPD was significantly elevatedamong individuals with Cys326Cys genotype (adjusted OR=5.07, 95% CI 1.84-13.95,P＜0.05); compared with those with the XRCC1 Arg399Arg genotype, the risk forCOPD was significantly elevated among individuals with Arg399Gln genotype(adjusted OR=2.77, 95% CI 1.52-5.07, P＜0.05). After stratifying by smoking exposure,in light smokers, compared with those with the hOGG1 Ser326Ser genotype, the riskfor COPD was significantly elevated among individuals with Cys326Cys genotype (adjusted OR=4.02, 95% CI 1.05-16.80, P＜0.05); compared with those with the XRCC1Arg399Arg genotype, the risk for COPD was significantly elevated among individualswith Gln/Gln genotype (adjusted OR=4.48, 95% CI 1.35-14.90, P＜0.05). In heavysmokers, compared with those with the XRCC1 Arg399Arg genotype, the risk forCOPD was significantly elevated among individuals with Arg399Gln genotype(adjusted OR=2.55, 95% CI 1.42-4.58, P＜0.05).
(2) Cmpared with those with the XRCC1 Arg194Arg genotype, the risk for COPD was notsignificantly different among individuals with Trp194Trp genotype. However, afterstratifying by smoking status, in former smokers, compared with those with the XRCC1Arg194Arg genotype, the risk for COPD was significantly reduced among individualswith Trp194Trp genotype (adjusted OR=0.22, 95% CI 0.06-0.85, P＜0.05); afterstratifying by smoking exposure, in light smokers, compared with those with theXRCC1 Arg194Arg genotype, the risk for COPD was significantly reduced amongindividuals with Arg194Trp genotype and Trp194Trp genotype (adjusted OR=0.39,95% CI 0.16-0.94, P＜0.05; 0.24, 95% CI 0.07-0.79, P＜0.05, respectively).
(3) There was no significant deviation in three XRCC1 Arg280His genotypic frequenciesbetween the COPD patient group and the control group (P＞0.05). And after stratifyingby smoking status and smoking exposure, there was also no significant deviation inthree XRCC1 Arg280His genotypic frequencies between the COPD patient group andthe control group (P＞0.05).
【Conclusions】The risk for COPD is significantly elevated among current/light smokerswith hOGG1 326Cys and XRCC1 399Gln; XRCC1 194Trp genotype is associated with ared uced risk of developing COPD among former and light smokers; XRCC1 280His wasnot significantly associated with the risk of COPD caused by cigarette smoke.
近年来，越来越多的研究表明氧化应激在COPD发病中起重要作用。香烟烟雾含有大量活性氧(reactive oxygen species，ROS)，其可直接攻击生物大分子DNA，诱发DNA链断裂和多种形式的碱基修饰，进而导致DNA损伤(DNA damage)。在众多DNA氧化损伤中，以鸟嘌呤8位碳原子的氧化最常见，其氧化产物8-羟基脱氧鸟苷(8-hydroxydeoxyguanine，8-OHdG)为DNA经受氧化损伤的代表性产物，如其不能被有效修复，会导致DNA复制过程中G：C→T：A颠换，该颠换在肿瘤形成中发生最早，有研究发现肺癌组织8-OHdG含量高于非肺癌组织，但8-OHdG是否与吸烟导致COPD的发生有关至今还未有研究。
机体存在多种DNA修复途径以维护基因组的稳定，8-羟基鸟嘌呤DNA糖苷酶1(human 8-oxoguanine DNA glycosylase，简称hOGG1)，是碱基切除修复途径中的一个重要成分，该基因产物具有DNA糖苷酶活性，可以特异性切除8-OHdG，从而避免在DNA复制过程中因错配而导致的G：C→T：A颠换突变，在维持基因组稳定上具有举足轻重的作用。有关hOGG1表达与8-OHdG的关系的研究结果不尽一致，而且有研究发现，hOGG1基因具有遗传多态性，其中位于第7外显子第1245位碱基的C／G多态，使其编码326位丝氨酸(Ser)变为半胱氨酸(Cys)，hOGG1-326Cys蛋白修复8-OHdG的活性显著低于hOGG1-326Ser蛋白，提示携带326Cys等位基因的个体有可能修复能力低下或缺陷。X射线修复交叉互补基因(X-ray repair cross complementinggroup 1，XRCC1)是另一个重要的DNA损伤修复基因，在短片修复通路中其与hOGG1直接发生相互作用。迄今为止，人类已经在XRCC1中识别了60多种单核苷酸多态，其中研究主要集中在进化保守的三个编码区，即26304C→T、27466G→A和28152G→A，这三个SNP导致相应氨基酸改变分别为194位密码子Arg→Trp、280位密码子Arg→His和399位密码子Arg→Gln，他们的生物学功能目前并不完全清楚。吸烟虽为COPD最重要的危险因素，但并非所有吸烟者均患COPD，这说明基因易感性在COPD发病中起重要作用。DNA修复基因hOGG1及XRCC1的单核苷酸多态性是否与部分吸烟者易患COPD有关至今还未见报道。
本研究包括两部分，第一部分探讨8-OHdG是否与吸烟导致COPD发生有关，本部分包括两个分题，分题一探讨淋巴细胞8-OHdG含量和肺组织8-OHdG含量的相关性，分题二探讨8-OHdG与吸烟所致COPD发病的关系；第二部分探讨hOGG1和XRCC1基因多态性与吸烟者易患COPD的关系。
第一部分8-OHdG与吸烟导致COPD发生的研究
分题1淋巴细胞8-OHdG含量与肺组织8-OHdG含量的相关性研究
【目的】探讨淋巴细胞8-OHdG含量和肺组织8-OHdG含量之间是否存在相关性。
【方法】采用淋巴细胞和肺手术切除肺组织，分为COPD组和非COPD组，通过高效液相色谱-电化学法检测8例COPD患者和8例非COPD患者淋巴细胞和肺组织8-OHdG含量。
【结果】
(1) COPD组淋巴细胞8-OHdG的含量为7．25±2．29／10~5dG，非COPD组淋巴细胞8-OHdG的含量为3.34±1．94／10~5dG，差异有显著统计学意义(P＜0．05)。
(2) COPD组肺组织的8-OHdG含量为8．15±2．19／10~5dG，非COPD组肺组织8-OHdG含量为3．19±1．51／10~5dG，差异有显著统计学意义(P＜0．05)。
(3) COPD组淋巴细胞8-OHdG含量与肺组织的8-OHdG含量呈明显正相关(r=0．768，P＜0．05)；非COPD组淋巴细胞8-OHdG含量与肺组织的8-OHdG含量呈明显正相关(r=0．787，P＜0．05)。
【结论】COPD患者淋巴细胞和肺组织8-OHdG含量明显高于非COPD患者淋巴细胞和肿组织8-OHdG含量，且淋巴细胞8-OHdG含量与肺组织8-OHdG含量存在明显相关性，提示可以用淋巴细胞8-OHdG研究吸烟导致COPD发病的关系。
分题2 8-OHdG与吸烟所致COPD发病的关系
【目的】探讨8-OHdG在吸烟所致COPD发病中的作用，以及活性氧水平、hOGG1mRNA及hOGG1蛋白表达水平对8-OHdG含量的影响。
【方法】收集140例健康不吸烟者、143例健康吸烟者和129例吸烟COPD者静脉血，分离淋巴细胞，采用高效液相色谱-电化学法检测8-OHdG含量，2'，7'-二乙酰二氯荧光素(DCFH-DA)检测细胞内ROS水平，实时定量PCR(Real-time PCR)检测hOGG1 mRNA表达，Western Blot检测hOGG1蛋白表达。
【结果】
(1)健康吸烟组和吸烟COPD组淋巴细胞8-OHdG含量明显高于健康不吸烟组，差异有显著统计学意义(P＜0．05)，且吸烟COPD组淋巴细胞8-OHdG含量明显高于健康吸烟组，差异亦有显著统计学意义(P＜0．05)。
(2)健康吸烟组和吸烟COPD组淋巴细胞ROS、hOGG1 mRNA及hOGG1蛋白表达均明显高于健康不吸烟组，差异有显著统计学意义(P＜0．05)；吸烟COPD组淋巴细胞ROS水平明显高于健康吸烟组，差异有显著统计学意义(P＜0．05)；吸烟COPD组淋巴细胞hOGG1 mRNA及hOGG1蛋白表达水平明显低于健康吸烟组，差异有显著统计学意义(P＜0．05)。
(3)健康吸烟组及吸烟COPD组淋巴细胞8-OHdG含量与吸烟指数均呈明显正相关(P＜0．05)；三组淋巴细胞8-OHdG含量与淋巴细胞ROS水平均呈明显正相关(P＜0．05)，与hOGG1 mRNA表达水平呈明显负相关(P＜0．05)，与hOGG1蛋白表达水平亦呈明显负相关(P＜0．05)。
(4)健康不吸烟组和健康吸烟组淋巴细胞8-OHdG含量与FEV_1％预计值和FEV_1／FVC均无明显相关性(P＞0．05)；而吸烟COPD组淋巴细胞8-OHdG含量与FEV_1％预计值和FEV_1／FVC呈显著负相关性(r=-0．575、-0．448，P＜0．05)。
【结论】吸烟COPD组淋巴细胞8-OHdG含量明显高于健康不吸烟组与健康吸烟组淋巴细胞8-OHdG含量，提示8-OHdG水平升高与吸烟导致COPD发病有关。
第二部分hOGG1和XRCC1基因多态性与吸烟者易患COPD的关系
【目的】探讨DNA修复基因hOGG1 Ser326Cys和XRCC1 Arg194Trp、Arg280His、Arg399Gln基因多态性与COPD易感性的关系。
【方法】收集201例COPD患者和309例对照，用聚合酶链反应和限制性片段长度多态方法(PCR-RFLP)分析hOGG1第326密码子和XRCC1第194、280及399密码子基因多态性。
【结果】
(1) hOGG1 Ser326Cys基因型携带者和Cys326Cys基因型携带者与Ser326Ser基因型携带者相比，COPD患病风险无明显差异；XRCC1 Gln399Gln基因型携带者与Arg399Arg基因型携带者相比COPD患病风险亦无明显差异；但XRCC1Arg399Gln基因型携带者患COPD风险明显高于Arg399Arg基因型携带者，其校正后相对危险度为1．55(95％CI 1．05-2．29，P＜0．05)。按吸烟特征分层后，携带有hOGG1 Cys326Cys基因型的现在吸烟者患COPD的风险明显高于携带Ser326Ser基因型的现在吸烟者，校正后相对危险度为5．07(95％CI 1．84-13．95，P＜0．05)；携带有XRCC1 Arg399Gln基因型的现在吸烟者患COPD的风险明显高于携带Arg399Arg基因型的现在吸烟者，校正后相对危险度为2．77(95％CI1．52-5．07，P＜0．05)。按照吸烟强度分层后，携带有hOGG1 Cys326Cys基因型的轻吸烟者患COPD的风险明显高于携带Ser／Ser基因型的轻度吸烟者，校正后相对危险度为4．02(95％CI 1．05-16．80，P＜0．05)；携带有XRCC1 Gln399Gln基因型的轻度吸烟者患COPD的风险明显高于携带Arg399Arg基因型的轻度吸烟者，校正后相对危险度为4．48(95％CI 1．35-14．90，P＜0．05)；携带有XRCC1Arg399Gln基因型的重度吸烟者患COPD的风险明显高于携带Arg399Arg基因型的重度吸烟者，校正后相对危险度为2．55(95％CI 1．42-4．58．P＜0．05)。
(2) XRCC1 Trp194Trp基因型携带者与Arg194Arg基因型携带者相比患COPD的风险无明显差异，但经吸烟特征和吸烟强度分层后，在戒烟者层，携带XRCC1Trp194Trp基因型者相较于Arg194Arg基因型者患COPD风险减低，其校正后相对危险度为0．22(95％CI 0．06-0．85，P＜0．05);在轻度吸烟者层，携带XRCC1Arg194Trp基因型和Trp194Trp基因型者相较于Arg194Arg基因型者患COPD风险都减低，其校正后相对危险度分别为0．39(95％CI 0．16-0．94，P＜0．05)和0．24(95％CI 0．07-0．79．P＜0．05)。
(3) XRCC1 Arg280His三种基因型在COPD组的频率与在对照组的频率无明显差异(P＞0．05)，按吸烟特征和吸烟强度分层后，在不吸烟者层、戒烟者层、现在吸烟者层、轻度吸烟者层和重度吸烟者层XRCC1 Arg280His三种基因型在COPD组的频率与在对照组的频率均无明显差异(P＞0．05)。
【结论】hOGG1 326Cys和XRCC1 399Gln明显升高现在吸烟者和轻度吸烟者患COPD的危险度，XRCC1 194Trp与降低戒烟者和轻度吸烟者患COPD的风险有关，XRCC1 280His与COPD患病风险无明显相关性。
Chronic obstructive pulmonary disease (COPD) is a major and increasing cause ofmorbidity and mortality worldwide and its prevalence is still increasing. At the present time,there is no specific and effective treatment for COPD, because the pathogenesis is still notclear. Cigarette smoke is a major risk factor for COPD and lung cancer, and almost 90% ofCOPD and lung cancer patients are smokers. The present study found DNA adducts-thetoxic components combined with DNA, which could cause the gene mutation, deletion andmismatching, caused the lung cancer eventually. However, whether DNA adducts isassociated with COPD and which DNA adducts is associated with COPD is still notstudied.
Now, there is ample evidence that oxidative stress plays a major role in COPD.Cigarette smoke is a rich source of reactive oxygen species (ROS), which can attack DNAand cause DNA damage. Among the various forms of DNA damage induced by oxygenradicals, 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a major form of oxidative DNAdamage and an important marker of cellular oxidative stress. If 8-OHdG is not effectivelyrepaired, it will cause G:C→T:A transversion. Some researches found the 8-OHdG level inlung cancer tissue was higher than non-lung cancer tissue. However, whether 8-OHdG isassociated with COPD is still not studied.
There are many DNA repair pathways to maintain the stabilization of gene. Human8-oxoguanine DNA glycosylase (hOGG1), a major component in the DNA repair pathways,which can excise 8-OHdG specifically and avoid G:C→T:A transversion, plays a majorrole in gene stability. The results about the relationship between the expression of hOGG1and 8-OHdG were inconsistent, In addition, the substitution of cysteine for serine at codon326 (Ser326Cys) was associated with significant reduction in the repair capacity. X-rayrepair cross complementing group 1 (XRCC1), is another major DNA repair gene, whichinteracts with hOGG1 directly. So far, more than 60 single nucleotide polymorphisms werefound. The most studied were 26304C→T、27466G→A and 28152G→A, which caused the corresponding amino acid transition: 194 Arg→Trp、280 Arg→His and 399Arg→Gln.Although smoking is the most important risk factor, not all smokers develop COPD, whichsuggests that there is a genetic susceptibility to the development of COPD. Whether thepolymorphisms of hOGG1 and XRCC1 are associated with COPD is not studied.
The present study consisted of two parts. One part investigated the relationshipbetween 8-OHdG and COPD: section one investigated the association between 8-OHdGlevel in lymphocyte and the 8-OHdG level in lung tissue; section two investigated therelationship among cigarette smoke、8-OHdG and COPD. The other part investigated therelationship between the polymorphisms of hOGG1 and XRCC1 and COPD.
PartⅠStudy on 8-OHdG and COPD related with cigarette smoke
Section 1 The association between 8-OHdG level in lymphocyte and the 8-OHdG levelin lung tissue
【Objective】To investigate the association between 8-OHdG level in lymphocyte and the8-OHdG level in lung tissue.
【Methods】8-OHdG was detected by high press liquid chromatography withelectrochemical detection in peripheral blood lymphocyte and lung tissue of 8 COPD casesand 8 controls.
【Results】
(1) The level of 8-OHdG in lymphocyte was significantly higher in COPD cases(7.25±2.29/10~5dG) than in controls (3.30±1.94/10~5dG), (P＜0.05).
(2) The level of 8-OHdG in lung tissue was significantly higher in COPD cases(8.15±2.19/10~5dG) than in controls (3.19±1.51/10~5dG), (P＜0.05).
(3) In COPD group, the level of 8-OHdG in lymphocyte was positively correlated with thelevel of 8-OHdG in lung tissue (r=0.768, P＜0.05); and in control, the level of 8-OHdGin lymphocyte was also positively correlated with the level of 8-OHdG in lung tissue(r=0.787, P＜0.05).
【Conclusions】The level of 8-OHdG in lymphocyte and lung tissue of COPD cases washigher than the level of 8-OHdG in lymphocyte and lung tissue of controls. And in COPD cases and controls, the level of 8-OHdG in lymphocyte was significantly associated withthe level of 8-OHdG in lung tissue, which suggested that 8-OHdG in lymphocyte could beused to investigate the relationship between cigarette smoke and COPD.
【Keywords】COPD, 8-OHdG, lymphocyte, lung tissueSection 2 The relationship among cigarette smoking、8-OHdG and COPD
【Objective】To investigate the relationship among cigarette smoking、8-OHdG inlymphocyte and COPD and the influence of ROS、hOGG1 mRNA and hOGG1 protein on8-OHdG level.
【Methods】A total 140 healthy non-smokers, 143 healthy smokers and 129 smokers withCOPD were recruited. 8-OHdG was detected by high press liquid chromatography withelectrochemical detection; DCFH-DA was used to detect ROS level; Real-time PCR wasused to detect the expression of hOGG1 mRNA; Western Blot was used to detect theexpression of hOGG1 protein.
【Results】
(1) The level of 8-OHdG in lymphocyte was significantly higher in healthy smokers andsmokers with COPD than in healthy nonsmokers (P＜0.05); and the level of 8-OHdG inlymphocyte was significantly higher in smokers with COPD than in healthy smokers.
(2) The level of ROS、hOGG1 mRNA and hOGG1 protein in lymphocyte was significantlyhigher in healthy smokers and smokers with COPD than in healthy nonsmokers(P＜0.05); the level of ROS in lymphocyte was significantly higher in smokers withCOPD than in healthy smokers (P＜0.05); the expression of hOGG1 mRNA and hOGG1protein in lymphocyte was significantly lower in smokers with COPD than in healthysmokers (P＜0.05).
(3) In healthy smokers and smokers with COPD, the level of 8-OHdG in lymphocyte waspositively correlated with smoking index (P＜0.05); in all three groups, the level of8-OHdG in lymphocyte was positively correlated with ROS level (P＜0.05), andnegatively correlated with the expression of hOGG1 mRNA (P＜0.05) and hOGG1protein (P＜0.05).
(4) In healthy nonsmokers and healthy smokers, the level of 8-OHdG in lymphocyte was not significantly correlated with FEV_1% predicted and FEV_1/FVC (P＞0.05); however,in smokers with COPD, the level of 8-OHdG in lymphocyte was significantlynegatively correlated with FEV_1% predicted and FEV_1/FVC (P＜0.05).
【Conclusions】The level of 8-OHdG in lymphocyte of smokers with COPD was higherthan the level of 8-OHdG in lymphocyte of healthy nonsmokers and healthy smokers,which suggested that the elevation was associated with COPD caused by cigarette smoke.
PartⅡ: The relationship between the polymorphisms of hOGG1 and XRCC1 and therisk of COPD
【Objective】To investigate the relationship between the polymorphisms of hOGG1Ser326Cys、XRCC1 Arg194Trp、Arg280His and Arg399Gln and the risk of COPD.
【Methods】A total 201 COPD cases and 309 controls were recruited, hOGG1 genotypeand XRCC1 genotype were determined by PCR-restriction fragment length polymorphismanalysis.
【Results】
(1) Compared with those with the hOGG1 Ser326Ser genotype, the risk for COPD was notsignificantly different among individuals with Ser326Cys genotype and Cys326Cysgenotype. Compared with those with the XRCC1 Arg399Arg genotype, the risk forCOPD was not significantly different among individuals with Gln399Gln genotype, butthe risk for COPD was significantly elevated among individuals with Arg399Glngenotype (adjusted odds ratios (OR)=1.55, 95% confidence intervals (CI) 1.05-2.29,P＜0.05). After stratifying by smoking status, in current smokers, compared with thosewith the hOGG1 Ser326Ser genotype, the risk for COPD was significantly elevatedamong individuals with Cys326Cys genotype (adjusted OR=5.07, 95% CI 1.84-13.95,P＜0.05); compared with those with the XRCC1 Arg399Arg genotype, the risk forCOPD was significantly elevated among individuals with Arg399Gln genotype(adjusted OR=2.77, 95% CI 1.52-5.07, P＜0.05). After stratifying by smoking exposure,in light smokers, compared with those with the hOGG1 Ser326Ser genotype, the riskfor COPD was significantly elevated among individuals with Cys326Cys genotype (adjusted OR=4.02, 95% CI 1.05-16.80, P＜0.05); compared with those with the XRCC1Arg399Arg genotype, the risk for COPD was significantly elevated among individualswith Gln/Gln genotype (adjusted OR=4.48, 95% CI 1.35-14.90, P＜0.05). In heavysmokers, compared with those with the XRCC1 Arg399Arg genotype, the risk forCOPD was significantly elevated among individuals with Arg399Gln genotype(adjusted OR=2.55, 95% CI 1.42-4.58, P＜0.05).
(2) Cmpared with those with the XRCC1 Arg194Arg genotype, the risk for COPD was notsignificantly different among individuals with Trp194Trp genotype. However, afterstratifying by smoking status, in former smokers, compared with those with the XRCC1Arg194Arg genotype, the risk for COPD was significantly reduced among individualswith Trp194Trp genotype (adjusted OR=0.22, 95% CI 0.06-0.85, P＜0.05); afterstratifying by smoking exposure, in light smokers, compared with those with theXRCC1 Arg194Arg genotype, the risk for COPD was significantly reduced amongindividuals with Arg194Trp genotype and Trp194Trp genotype (adjusted OR=0.39,95% CI 0.16-0.94, P＜0.05; 0.24, 95% CI 0.07-0.79, P＜0.05, respectively).
(3) There was no significant deviation in three XRCC1 Arg280His genotypic frequenciesbetween the COPD patient group and the control group (P＞0.05). And after stratifyingby smoking status and smoking exposure, there was also no significant deviation inthree XRCC1 Arg280His genotypic frequencies between the COPD patient group andthe control group (P＞0.05).
【Conclusions】The risk for COPD is significantly elevated among current/light smokerswith hOGG1 326Cys and XRCC1 399Gln; XRCC1 194Trp genotype is associated with ared uced risk of developing COPD among former and light smokers; XRCC1 280His wasnot significantly associated with the risk of COPD caused by cigarette smoke.
引文
1. Fishman AP.One Hundred Years of COPD. Am J Respir Crit Care Med, 2005.
2. Mannino DM, Homa DM, Akinbami LJ, et al. Chronic obstructive pulmonary disease surveillance-United States, 1971-2000. MMWR Surveill Summ, 2002. 51(6): p. 1-16.
3. Barnes PJ, Shapiro SD, and Pauwels RA. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J, 2003. 22(4): p. 672-88.
4. Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet, 2004. 364(9435): p. 709-21.
5. Kasai H. Analysis of a form of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis. Mutat Res, 1997. 387(3): p. 147-63.
6. Floyd RA. The role of 8-hydroxyguanine in carcinogenesis. Carcinogenesis, 1990. 11 (9): p. 1447-50.
7. Saetta M, Di Stefano A, Maestrelli P, et al. Activated T-lymphocytes and macrophages in bronchial mucosa of subjects with chronic bronchitis. Am Rev Respir Dis, 1993. 147(2): p. 301-6.
8. Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med, 2007. 176(6): p. 532-55.
9. Boyum A. Isolation of lymphocytes, granulocytes and macrophages. Scand J Immunol, 1976. S uppl 5: p. 9-15.
10. Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risks Hum, 2004. 83: p. 1-1438.
11. Liu X, Conner H, Kobayashi T, et al. Cigarette smoke extract induces DNA damage but not apoptosis in human bronchial epithelial cells. Am J Respir Cell Mol Biol, 2005. 33(2): p. 121-9.
12. Coleman CN and Harris JR. Current scientific issues related to clinical radiation oncology. Radiat Res, 1998. 150(2): p. 125-33.
13. Vayssier-Taussat M, Camilli T, Aron Y, et al. Effects of tobacco smoke and benzo[a]pyrene on human endothelial cell and monocyte stress responses. Am J Physiol Heart Circ Physiol, 2001. 280(3): p. H1293-300.
14. Bartsch H, Ohshima H, Pignatelli B, et al. Endogenously formed N-nitroso compounds and nitrosating agents in human cancer etiology. Pharmacogenetics, 1992. 2(6): p. 272-7.
15. Mirvish SS. Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC. Cancer Lett, 1995. 93(1): p. 17-48.
16. Asami S, Manabe H, Miyake J, et al. Cigarette smoking induces an increase in oxidative DNA damage, 8-hydroxydeoxyguanosine, in a central site of the human lung. Carcinogenesis, 1997. 18(9): p. 1763-6.
17. Ames BN. Endogenous DNA damage as related to cancer and aging. Mutat Res, 1989. 214(1): p. 41-6.
18. Shigenaga MK and Ames BN. Assays for 8-hydroxy-2'-deoxyguanosine: a biomarker of in vivo oxidative DNA damage. Free Radic Biol Med, 1991. 10(3-4): p. 211-6.
19. Shigenaga MK, Gimeno CJ, and Ames BN. Urinary 8-hydroxy-2'-deoxyguanosine as a biological marker of in vivo oxidative DNA damage. Proc Natl Acad Sci U S A, 1989. 86(24): p. 9697-701.
20. Collins A, Cadet J, Epe B, et al. Problems in the measurement of 8-oxoguanine in human DNA. Report of a workshop, DNA oxidation, held in Aberdeen, UK, 19-21 January, 1997. Carcinogenesis, 1997. 18(9): p. 1833-6.
21. Beckman KB and Ames BN. Oxidative decay of DNA. J Biol Chem, 1997. 272(32): p. 19633-6.
22. MacNee W. Oxidants/antioxidants and COPD. Chest, 2000. 117(5 S uppl 1): p. 303S-17S.
23. MacNee W. Oxidants/antioxidants and chronic obstructive pulmonary disease: pathogenesis to therapy. Novartis Found Symp, 2001. 234: p. 169-85; discussion 185-8.
24. Rahman I, Mulier B, Gilmour PS, et al. Oxidant-mediated lung epithelial cell tolerance: the role of intracellular glutathione and nuclear factor-kappa B. Biochem Pharmacol, 2001. 62(6): p. 787-94.
25. Rahman I and Adcock IM. Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J, 2006. 28(1): p. 219-42.
26. Oudijk EJ, Koenderman LJ. Systemic inflammation in chronic obstructive pulmonary disease. Eur Respir J Suppl, 2003. 46: p. 5s-13s.
27. Hegde V, Wang M, and Deutsch WA. Human ribosomal protein S3 interacts with DNA base excision repair proteins hAPE/Ref-1 and hOGGl. Biochemistry, 2004. 43(44): p. 14211-7.
28. Vodicka P, Kumar R, Stetina R, et al. Markers of individual susceptibility and DNA repair rate in workers exposed to xenobiotics in a tire plant. Environ Mol Mutagen, 2004. 44(4): p. 283-92.
29. Ide H and Kotera M. Human DNA glycosylases involved in the repair of oxidatively damaged DNA. Biol Pharm Bull, 2004. 27(4): p. 480-5.
30. Kuo HW, Chang SF, Wu KY, et al. Chromium (VI) induced oxidative damage to DNA: increase of urinary 8-hydroxydeoxyguanosine concentrations (8-OHdG) among electroplating workers. Occup Environ Med, 2003. 60(8): p. 590-4.
31. Lunec J, Holloway KA, Cooke MS, et al. Urinary 8-oxo-2'-deoxyguanosine: redox regulation of DNA repair in vivo? Free Radic Biol Med, 2002. 33(7): p. 875-85.
32. Cheng KC, Cahill DS, Kasai H, et al. 8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G--T and A--C substitutions. J Biol Chem, 1992. 267(1): p. 166-72.
33. Kuchino Y, Mori F, Kasai H, et al. Misreading of DNA templates containing 8-hydroxydeoxyguanosine at the modified base and at adjacent residues. Nature, 1987. 327(6117): p. 77-9.
34. Friedberg EC. DNA damage and repair. Nature, 2003. 421(6921): p. 436-40.
35. Krokan HE, Nilsen H, Skorpen F, et al. Base excision repair of DNA in mammalian cells. FEBS Lett, 2000. 476(1-2): p. 73-7.
36. Nickoloff JA and Hoekstra MF. DNA damage and repair. In: DNA Repair in Higher Eukaryotes. 1998.
37. Wood RD, Mitchell M, Sgouros J, et al. Human DNA repair genes. Science, 2001. 291(5507): p. 1284-9.
38. de Laat WL, Jaspers NG, and Hoeijmakers JH. Molecular mechanism of nucleotide excision repair. Genes Dev, 1999. 13(7): p. 768-85.
39. Boiteux S and Radicella JP. Base excision repair of 8-hydroxyguanine protects DNA from endogenous oxidative stress. Biochimie, 1999. 81(1-2): p. 59-67.
40. Bruner SD, Norman DP, and Verdine GL. Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA. Nature, 2000. 403(6772): p. 859-66.
41. Chevillard S, Radicella JP, Levalois C, et al. Mutations in OGG1, a gene involved in the repair of oxidative DNA damage, are found in human lung and kidney tumours. Oncogene, 1998. 16(23): p. 3083-6.
42. Hirano T. Repair system of 7, 8-dihydro-8-oxoguanine as a defense line against carcinogenesis. J Radiat Res 2008. 49(4): p. 329-40.
43. Hardie LJ, Briggs JA, Davidson LA, et al. The effect of hOGGl and glutathione peroxidase I genotypes and 3p chromosomal loss on 8-hydroxydeoxyguanosine levels in lung cancer. Carcinogenesis, 2000. 21(2): p. 167-72.
44. Shinmura K, Kasai H, Sasaki A, et al. 8-hydroxyguanine (7,8-dihydro-8-oxoguanine) DNA glycosylase and AP lyase activities of hOGGl protein and their substrate specificity. Mutat Res, 1997. 385(1): p. 75-82.
45. Hazra TK, Hill JW, Izumi T, et al. Multiple DNA glycosylases for repair of 8-oxoguanine and their potential in vivo f unctions. Prog Nucleic Acid Res Mol Biol, 2001. 68: p. 193-205.
46. Wickenden JA, Clarke MC, Rossi AG, et al. Cigarette smoke prevents apoptosis through inhibition of caspase activation and induces necrosis. Am J Respir Cell Mol Biol, 2003. 29(5): p. 562-70.
47. Baglole CJ, Bushinsky SM, Garcia TM, et al. Differential induction of apoptosis by cigarette smoke extract in primary human lung fibroblast strains: implications for emphysema. Am J Physiol Lung Cell Mol Physiol, 2006. 291(1): p. L19-29.
48. Rogers DF. The airway goblet cell. Int J Biochem Cell Biol, 2003. 35(1): p. 126.
49. Andor R. Enhanced expression of fibroblast growth factors and receptor FGFR21 during vascular remodeling in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol, 2002. 27(3): p. 517-525.
50. Saetta M. Airway inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 1999. 160(5 Pt 2): p. S17-20.
51. Burdet L, de Muralt B, Scz Y, et al. Administration of growth hormone to underweight patients with chronic obstructive pulmonary disease. A prospective, randomized, controlled study. Am J Respir Crit Care Med, 1997. 156(6): p. 1800-6.
52. Helbock HJ, Beckman KB, Shigenaga MK, et al. DNA oxidation matters: the HPLC-electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine. Proc Natl Acad Sci U S A, 1998. 95(1): p. 288-93.
53. Miwa M, Matsumaru H, Akimoto Y, et al. Quantitative determination of urinary 8-hydroxy-2'-deoxyguanosine level in healthy Japanese volunteers. Bio factors, 2004. 22(1-4): p. 249-53.
54. Sarafian TA, Magallanes JA, Shau H, et al. Oxidative stress produced by marijuana smoke. An adverse effect enhanced by cannabinoids. Am J Respir Cell Mol Biol, 1999. 20(6): p. 1286-93.
55. Fletcher CM. Letter: Natural history of chronic bronchitis. Br Med J, 1976. 1(6025): p. 1592-3.
56. Lokke A, Lange P, Scharling H, et al. Developing COPD: a 25 year follow up study of the general population. Thorax, 2006. 61(11): p. 935-9.
57. Sandford AJ and Silverman EK. Chronic obstructive pulmonary disease. 1: Susceptibility factors for COPD the genotype-environment interaction. Thorax, 2002. 57(8): p. 736-41.
58. Spitz MR, Wu X, Wang Y, et al. Modulation of nucleotide excision repair capacity by XPD polymorphisms in lung cancer patients. Cancer Res, 2001. 61(4): p. 1354-7.
59. Wei Q, Cheng L, Hong WK, et al. Reduced DNA repair capacity in lung cancer patients. Cancer Res, 1996. 56(18): p. 4103-7.
60. Shen H, Spitz MR, Qiao Y, et al. Smoking, DNA repair capacity and risk of nonsmall cell lung cancer. Int J Cancer, 2003. 107(1): p. 84-8.
61. Pryor WA. Cigarette smoke radicals and the role of free radicals in chemical carcinogenicity. Environ Health Perspect, 1997. 105 Suppl 4: p. 875-82.
62. Mohrenweiser HW, Wilson DM, and Jones IM. Challenges and complexities in estimating both the functional impact and the disease risk associated with the extensive genetic variation in human DNA repair genes. Mutat Res, 2003. 526(1-2): p. 93-125.
63. Lindahl T and Wood RD. Quality control by DNA repair. Science, 1999. 286(5446): p. 1897-905.
64. Kohno T, Shinmura K, Tosaka M, et al. Genetic polymorphisms and alternative splicing of the hOGGl gene, that is involved in the repair of 8-hydroxyguanine in damaged DNA. Oncogene, 1998. 16(25): p. 3219-25.
65. Thompson L. and West MG. XRCC1 keeps DNA from getting stranded. Mutat Res,2000. 459(1): p. 1-18.
66. David-Beabes GL and London SJ. Genetic polymorphism of XRCC1 and lung cancer risk among African-Americans and Caucasians. Lung Cancer, 2001. 34(3): p. 333-9.
67. Le Marchand L, Donlon T, Lum-Jones A, et al. Association of the hOGGl Ser326Cys polymorphism with lung cancer risk. Cancer Epidemiol Biomarkers Prev, 2002. 11(4): p. 409-12.
68. Park J, Chen L, Tockman MS, et al. The human 8-oxoguanine DNA N-glycosylase 1 (hOGGl) DNA repair enzyme and its association with lung cancer risk. Pharmacogenetics, 2004. 14(2): p. 103-9.
69. Park JY, Lee SY, Jeon HS, et al. Polymorphism of the DNA repair gene XRCC1 and risk of primary lung cancer. Cancer Epidemiol Biomarkers Prev, 2002. 11(1): p. 23-7.
70. Sugimura H, Kohno T, Wakai K, et al. hOGGl Ser326Cys polymorphism and lung cancer susceptibility. Cancer Epidemiol Biomarkers Prev, 1999. 8(8): p. 669-74.
71. Zhou W, Liu G, Miller DP, et al. Polymorphisms in the DNA repair genes XRCC1 and ERCC2, smoking, and lung cancer risk. Cancer Epidemiol Biomarkers Prev, 2003. 12(4): p. 359-65.
72. Pauwels RA, Buist AS, Calverley PM, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med, 2001. 163(5): p. 1256-76.
73. Sandford AJ and Pare PD. Genetic risk factors for chronic obstructive pulmonary disease. Clin Chest Med, 2000. 21(4): p. 633-43.
74. Janssen K, Schlink K, Gotte W, et al. DNA repair activity of 8-oxoguanine DNA glycosylase 1 (OGG1) in human lymphocytes is not dependent on genetic polymorphism Ser326/Cys326. Mutat Res, 2001. 486(3): p. 207-16.
75. Dherin C, Radicella JP, Dizdaroglu M, et al. Excision of oxidatively damaged DNA bases by the human alpha-hOGGl protein and the polymorphic alpha-hOGGl(Ser326Cys) protein which is frequently found in human populations. Nucleic Acids Res, 1999. 27(20): p. 4001-7.
76. Caldecott KW. XRCC1 and DNA strand break repair. DNA Repair (Amst), 2003. 2(9): p. 955-69.
77. Caldecott KW. Mammalian DNA single-strand break repair: an X-ra(y)ted affair. Bioessays, 2001. 23(5): p. 447-55.
78. Whitehouse CJ, Taylor RM, Thistlethwaite A, et al. XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell, 2001. 104(1): p. 107-17.
79. Wang Y, Spitz MR, Zhu Y, et al. From genotype to phenotype: correlating XRCC1 polymorphisms with mutagen sensitivity. DNA Repair (Amst), 2003. 2(8): p. 901-8.
80. Fan J, Otterlei M, Wong HK, et al. XRCC1 co-localizes and physically interacts with PCNA. Nucleic Acids Res, 2004. 32(7): p. 2193-201.
81. Takanami T, Nakamura J, Kubota Y, et al. The Arg280His polymorphism in X-ray repair cross-complementing gene 1 impairs DNA repair ability. Mutat Res, 2005. 582(1-2): p. 135-45.
82. Matullo G, Guarrera S, Carturan S, et al. DNA repair gene polymorphisms, bulky DNA adducts in white blood cells and bladder cancer in a case-control study. Int J Cancer, 2001. 92(4): p. 562-7.
83. Abdel-Rahman SZ, Soliman AS, Bondy ML, et al. Inheritance of the 194Trp and the 399Gln variant alleles of the DNA repair gene XRCC1 are associated with increased risk of early-onset colorectal carcinoma in Egypt. Cancer Lett, 2000. 159(1): p. 79-86.
84. Divine KK, Gilliland FD, Crowell RE, et al. The XRCCl 399 glutamine allele is a risk factor for adenocarcinoma of the lung. Mutat Res, 2001. 461(4): p. 273-8.
85. Duell EJ, Wiencke JK, Cheng TJ, et al. Polymorphisms in the DNA repair genes XRCCl and ERCC2 and biomarkers of DNA damage in human blood monon uclear cells. Carcinogenesis, 2000. 21(5): p. 965-71.
86. Lunn RM, Langlois RG, Hsieh LL, et al. XRCCl polymorphisms: effects on aflatoxin Bl-DNA adducts and glycophorin A variant frequency. Cancer Res, 1999. 59(11): p. 2557-61.
87. Hung RJ, Hall J, Brennan P, et al. Genetic polymorphisms in the base excision repair pathway and cancer risk: a Huge review. Am J Epidemiol, 2005. 162(10): p. 925-42.
88. Seedhouse C, Bainton R, Lewis M, et al. The genotype distribution of the XRCCl gene indicates a role for base excision repair in the development of therapy-related acute myeloblastic leukemia. Blood, 2002. 100(10): p. 3761-6.
89. Takezaki T, Gao CM, Wu JZ, et al. hOGGl Ser(326)Cys polymorphism and modification by environmental factors of stomach cancer risk in Chinese. Int J Cancer, 2002. 99(4): p. 624-7.
90. Elahi A, Zheng Z, Park J, et al. The human OGG1 DNA repair enzyme and its association with orolaryngeal cancer risk. Carcinogenesis, 2002. 23(7): p. 1229-34.
91. Kelley MR, Cheng L, Foster R, et al. Elevated and altered expression of the multifunctional DNA base excision repair and redox enzyme Apel/ref-1 in prostate cancer. Clin Cancer Res, 2001. 7(4): p. 824-30.
92. Marullo G, Palli D, Peluso M, et al. XRCCl, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy s ubjects. Carcinogenesis, 2001. 22(9): p. 1437-45.
93. Ishida T, Takashima R, Fukayama M, et al. New DNA polymorphisms of human MMH/OGG1 gene: prevalence of one polymorphism among lung-adenocarcinoma patients in Japanese. Int J Cancer, 1999. 80(1): p. 18-21.
1. Mannino DM. Epidemiology and global impact of chronic obstructive pulmonary disease. Semin Respir Crit Care Med, 2005. 26(2): p. 204-10.
2. Bartsch H, Ohshima H, Pignatelli B, et al. Endogenously formed N-nitroso compounds and nitrosating agents in human cancer etiology. Pharmacogenetics, 1992. 2(6): p. 272-7.
3. Mirvish SS. Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC. Cancer Lett, 1995. 93(1): p. 17-48.
4. Thompson AB, Bohling T, Heires A, et al. Lower respiratory tractiron burden is increased in association with cigarette smoking. J Lab Clin Med, 1991. 117(6): p. 493-9.
5. Karadag F, Cildag O, Altinisik M, et al. Trace elements as a component of oxidative stress in COPD. Respirology, 2004. 9(1): p. 33-7.
6. Kharitonov SA and Barnes PJ. Exhaled markers of inflammation. Curr Opin Allergy Clin Immunol, 2001. 1(3): p. 217-24.
7. Nishikawa M, Kakemizu N, Ito T, et al. Superoxide mediates cigarette smoke-induced infiltration of neutrophils into the airways through nuclear factor-kappa B activation and IL-8 mRNA expression in guinea pigs in vivo. Am J Respir Cell Mol Biol, 1999. 20(2): p. 189-98.
8. Wouters EF, Creutzberg EC and Schols AM. Systemic effects in COPD. Chest, 2002. 121(5 S uppl):p. 127S-130S.
9. Engelen MP, Schols AM, Does JD, et al. Skeletal muscle weakness is associated with wasting of extremity fat-free mass but not with airflow obstruction in patients with chronic obstructive pulmonary disease. Am J Clin Nutr, 2000. 71(3): p. 733-8.
10. Li YP, Atkins CM, Sweatt JD, et al. Mitochondria mediate tumor necrosis factor-alpha/NF-kappa B signaling in skeletal muscle myotubes. Antioxid Redox Signal, 1999. 1(1): p. 97-104.
11. Langen RC, Van Der Velden JL, Schols AM, et al. Tumor necrosis factor-alpha inhibits myogenic differentiation through MyoD protein destabilization. Faseb J, 2004. 18(2): p. 227-37.
12. Thierens H, Vral A, and De Ridder L. A cytogenetic study of radiological workers: effect of age, smoking and radiation burden on the micronucleus frequency. Mutat Res, 1996. 360(2): p. 75-82.
13. Coleman CN and Harris JR. Current scientific issues related to clinical radiation oncology. Radiat Res, 1998. 150(2): p. 125-33.
14. Vayssier-Taussat M, Camilli T, Aron Y, et al. Effects of tobacco smoke and benzo[a]pyrene on human endothelial cell and monocyte stress responses. Am J Physiol Heart Circ Physiol, 2001. 280(3): p. H1293-300.
15. Kasai H. Analysis of a form of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis. Mutat Res, 1997. 387(3): p. 147-63.
16. Hegde V, Wang M, and Deutsch WA. Human ribosomal protein S3 interacts with DNA base excision repair proteins hAPE/Ref-1 and hOGGl. Biochemistry, 2004. 43(44): p. 14211-7.
17. Vodicka P, Kumar R, Stetina R, et al. Markers of individual susceptibility and DNA repair rate in workers exposed to xenobiotics in a tire plant. Environ Mol Mutagen, 2004. 44(4): p. 283-92.
18. Ide H and Kotera M. Human DNA glycosylases involved in the repair of oxidatively damaged DNA. Biol Pharm Bull, 2004. 27(4): p. 480-5.
19. Ames BN. Endogenous DNA damage as related to cancer and aging. Mutat Res, 1989. 214(1): p. 41-6.
20. Shigenaga MK and Ames BN. Assays for 8-hydroxy-2'-deoxyguanosine: a biomarker of in vivo oxidative DNA damage. Free Radic Biol Med, 1991. 10(3-4): p. 211-6.
21. Halliwell B and Aruoma OI. DNA damage by oxygen-derived species. Its mechanism and measurement in mammalian systems. FEBS Lett, 1991. 281(1-2): p. 9-19.
22. Loft S HDP, Mikkelsen L, Risom L. Biomarkers of oxidative damage to DNA and repair. Biochem Soc Trans, 2008. 36(pt 5): p. 1071-6.
23. Wood RD, Mitchell M, Sgouros J, et al. Human DNA repair genes. Science, 2001. 291(5507): p. 1284-9.
24. de Laat WL, Jaspers NG, and Hoeijmakers JH. Molecular mechanism of nucleotide excision repair. Genes Dev, 1999. 13(7): p. 768-85.
25. Spitz MR, Wu X, Wang Y, et al. Modulation of nucleotide excision repair capacity by XPD polymorphisms in lung cancer patients. Cancer Res, 2001. 61(4): p. 1354-7.
26. Goode EL, Ulrich CM and Potter JD. Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomarkers Prev, 2002. 11(12): p. 1513-30.
27. Rosenquist TA, Zharkov DO and Grollman AP. Cloning and characterization of a mammalian 8-oxoguanine DNA glycosylase. Proc Natl Acad Sci USA, 1997. 94(14): p. 7429-34.
28. Audebert M, Charbonnier JB, Boiteux S, et al. Mitochondrial targeting of human 8-oxoguanine DNA glycosylase hOGGl is impaired by a somatic mutation found in kidney cancer. DNA Repair (Amst), 2002. 1(7): p. 497-505.
29. Shinmura K, Kasai H, Sasaki A, et al. 8-hydroxyguanine (7,8-dihydro-8-oxoguanine) DNA glycosylase and AP lyase activities of hOGGl protein and their substrate specificity. Mutat Res, 1997. 385(1): p. 75-82.
30. Takezaki T, Gao CM, Wu JZ, et al. hOGGl Ser(326)Cys polymorphism and modification by environmental factors of stomach cancer risk in Chinese. Int J Cancer, 2002. 99(4): p. 624-7.
31. Ishida T, Takashima R, Fukayama M, et al. New DNA polymorphisms of human MMH/OGG1 gene: prevalence of one polymorphism among lung-adenocarcinoma patients in Japanese. Int J Cancer, 1999. 80(1): p. 18-21.
32. Kohno T, Shinmura K, Tosaka M, et al. Genetic polymorphisms and alternative splicing of the hOGGl gene, that is involved in the repair of 8-hydroxyg uanine in damaged DNA. Oncogene, 1998. 16(25): p. 3219-25.
33. Dhenaut A, Boiteux S and Radicella JP. Characterization of the hOGGl promoter and its expression during the cell cycle. Mutat Res, 2000. 461(2): p. 109-18.
34. Le Marchand L, Donlon T, Lum-Jones A, et al. Association of the hOGGl Ser326Cys polymorphism with lung cancer risk. Cancer Epidemiol Biomarkers Prev, 2002. 11(4): p. 409-12.
35. Paz-Elizur T, Krupsky M, Blumenstein S, et al. DNA repair activity for oxidative damage and risk of lung cancer. J Natl Cancer Inst, 2003. 95(17): p. 1312-9.
36. Sugimura H, Kohno T, Wakai K, et al. hOGGl Ser326Cys polymorphism and lung cancer susceptibility. Cancer Epidemiol Biomarkers Prev, 1999. 8(8): p. 669-74.
37. Marsin S, Vidal AE, Sossou M, et al. Role of XRCC1 in the coordination and stimulation of oxidative DNA damage repair initiated by the DNA glycosylase hOGGl. J Biol Chem, 2003. 278(45): p. 44068-74.
38. Dherin C, Radicella JP, Dizdaroglu M, et al. Excision of oxidatively damaged DNA bases by the human alpha-hOGGl protein and the polymorphic alpha-hOGGl(Ser326Cys) protein which is frequently found in human populations. N ucleic Acids Res, 1999. 27(20): p. 4001-7.
39. Vidal AE, Boiteux S, Hickson ID, et al. XRCC1 coordinates the initial and late stages of DNA abasic site repair through protein-protein interactions. Embo J, 2001. 20(22): p. 6530-9.
40. Kubota Y, Nash RA, Klungland A, et al. Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 protein. Embo J, 1996. 15(23): p. 6662-70.
41. Caldecott KW. XRCC1 and DNA strand break repair. DNA Repair (Amst), 2003. 2(9): p. 955-69.
42. Caldecott KW, McKeown CK, Tucker JD, et al. An interaction between the mammalian DNA repair protein XRCC1 and DNA ligase III. Mol Cell Biol, 1994. 14(1): p. 68-76.
43. Fan J, Otterlei M, Wong HK, et al. XRCC1 co-localizes and physically interacts with PCNA. Nucleic Acids Res, 2004. 32(7): p. 2193-201.
44. Masson M, Niedergang C, Schreiber V, et al. XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage. Mol Cell Biol, 1998. 18(6): p. 3563-71.
45. Whitehouse CJ, Taylor RM, Thistlethwaite A, et al. XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell, 2001. 104(1): p. 107-17.
46. Wang Y, Spitz MR, Zhu Y, et al. From genotype to phenotype: correlating XRCCl polymorphisms with mutagen sensitivity. DNA Repair (Amst), 2003. 2(8): p. 901-8.
47. Takanami T, Nakamura J, Kubota Y, et al. The Arg280His polymorphism in X-ray repair cross-complementing gene 1 impairs DNA repair ability. Mutat Res, 2005. 582(1-2): p. 135-45.
48. Shen H, Spitz MR, Qiao Y, et al. Smoking, DNA repair capacity and risk of nonsmall cell lung cancer. Int J Cancer, 2003. 107(1): p. 84-8.
49. Lunn RM, Langlois RG, Hsieh LL, et al. XRCCl polymorphisms: effects on aflatoxin Bl-DNA adducts and glycophorin A variant frequency. Cancer Res, 1999. 59(11): p. 2557-61.
50. Matullo G, Guarrera S, Carturan S, et al. DNA repair gene polymorphisms, bulky DNA adducts in white blood cells and bladder cancer in a case-control study. Int J Cancer, 2001. 92(4): p. 562-7.
51. Matullo G, Palli D, Peluso M, et al. XRCCl, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects. Carcinogenesis, 2001. 22(9): p. 1437-45.
52. Abdel-Rahman SZ and El-Zein RA. The 399Gln polymorphism in the DNA repair gene XRCCl modulates the genotoxic response induced in human lymphocytes by the tobacco-specific nitrosamine NNK. Cancer Lett, 2000. 159(1): p. 63-71.
2. Mannino DM, Homa DM, Akinbami LJ, et al. Chronic obstructive pulmonary disease surveillance-United States, 1971-2000. MMWR Surveill Summ, 2002. 51(6): p. 1-16.
3. Barnes PJ, Shapiro SD, and Pauwels RA. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J, 2003. 22(4): p. 672-88.
4. Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet, 2004. 364(9435): p. 709-21.
5. Kasai H. Analysis of a form of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis. Mutat Res, 1997. 387(3): p. 147-63.
6. Floyd RA. The role of 8-hydroxyguanine in carcinogenesis. Carcinogenesis, 1990. 11 (9): p. 1447-50.
7. Saetta M, Di Stefano A, Maestrelli P, et al. Activated T-lymphocytes and macrophages in bronchial mucosa of subjects with chronic bronchitis. Am Rev Respir Dis, 1993. 147(2): p. 301-6.
8. Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med, 2007. 176(6): p. 532-55.
9. Boyum A. Isolation of lymphocytes, granulocytes and macrophages. Scand J Immunol, 1976. S uppl 5: p. 9-15.
10. Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risks Hum, 2004. 83: p. 1-1438.
11. Liu X, Conner H, Kobayashi T, et al. Cigarette smoke extract induces DNA damage but not apoptosis in human bronchial epithelial cells. Am J Respir Cell Mol Biol, 2005. 33(2): p. 121-9.
12. Coleman CN and Harris JR. Current scientific issues related to clinical radiation oncology. Radiat Res, 1998. 150(2): p. 125-33.
13. Vayssier-Taussat M, Camilli T, Aron Y, et al. Effects of tobacco smoke and benzo[a]pyrene on human endothelial cell and monocyte stress responses. Am J Physiol Heart Circ Physiol, 2001. 280(3): p. H1293-300.
14. Bartsch H, Ohshima H, Pignatelli B, et al. Endogenously formed N-nitroso compounds and nitrosating agents in human cancer etiology. Pharmacogenetics, 1992. 2(6): p. 272-7.
15. Mirvish SS. Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC. Cancer Lett, 1995. 93(1): p. 17-48.
16. Asami S, Manabe H, Miyake J, et al. Cigarette smoking induces an increase in oxidative DNA damage, 8-hydroxydeoxyguanosine, in a central site of the human lung. Carcinogenesis, 1997. 18(9): p. 1763-6.
17. Ames BN. Endogenous DNA damage as related to cancer and aging. Mutat Res, 1989. 214(1): p. 41-6.
18. Shigenaga MK and Ames BN. Assays for 8-hydroxy-2'-deoxyguanosine: a biomarker of in vivo oxidative DNA damage. Free Radic Biol Med, 1991. 10(3-4): p. 211-6.
19. Shigenaga MK, Gimeno CJ, and Ames BN. Urinary 8-hydroxy-2'-deoxyguanosine as a biological marker of in vivo oxidative DNA damage. Proc Natl Acad Sci U S A, 1989. 86(24): p. 9697-701.
20. Collins A, Cadet J, Epe B, et al. Problems in the measurement of 8-oxoguanine in human DNA. Report of a workshop, DNA oxidation, held in Aberdeen, UK, 19-21 January, 1997. Carcinogenesis, 1997. 18(9): p. 1833-6.
21. Beckman KB and Ames BN. Oxidative decay of DNA. J Biol Chem, 1997. 272(32): p. 19633-6.
22. MacNee W. Oxidants/antioxidants and COPD. Chest, 2000. 117(5 S uppl 1): p. 303S-17S.
23. MacNee W. Oxidants/antioxidants and chronic obstructive pulmonary disease: pathogenesis to therapy. Novartis Found Symp, 2001. 234: p. 169-85; discussion 185-8.
24. Rahman I, Mulier B, Gilmour PS, et al. Oxidant-mediated lung epithelial cell tolerance: the role of intracellular glutathione and nuclear factor-kappa B. Biochem Pharmacol, 2001. 62(6): p. 787-94.
25. Rahman I and Adcock IM. Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J, 2006. 28(1): p. 219-42.
26. Oudijk EJ, Koenderman LJ. Systemic inflammation in chronic obstructive pulmonary disease. Eur Respir J Suppl, 2003. 46: p. 5s-13s.
27. Hegde V, Wang M, and Deutsch WA. Human ribosomal protein S3 interacts with DNA base excision repair proteins hAPE/Ref-1 and hOGGl. Biochemistry, 2004. 43(44): p. 14211-7.
28. Vodicka P, Kumar R, Stetina R, et al. Markers of individual susceptibility and DNA repair rate in workers exposed to xenobiotics in a tire plant. Environ Mol Mutagen, 2004. 44(4): p. 283-92.
29. Ide H and Kotera M. Human DNA glycosylases involved in the repair of oxidatively damaged DNA. Biol Pharm Bull, 2004. 27(4): p. 480-5.
30. Kuo HW, Chang SF, Wu KY, et al. Chromium (VI) induced oxidative damage to DNA: increase of urinary 8-hydroxydeoxyguanosine concentrations (8-OHdG) among electroplating workers. Occup Environ Med, 2003. 60(8): p. 590-4.
31. Lunec J, Holloway KA, Cooke MS, et al. Urinary 8-oxo-2'-deoxyguanosine: redox regulation of DNA repair in vivo? Free Radic Biol Med, 2002. 33(7): p. 875-85.
32. Cheng KC, Cahill DS, Kasai H, et al. 8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G--T and A--C substitutions. J Biol Chem, 1992. 267(1): p. 166-72.
33. Kuchino Y, Mori F, Kasai H, et al. Misreading of DNA templates containing 8-hydroxydeoxyguanosine at the modified base and at adjacent residues. Nature, 1987. 327(6117): p. 77-9.
34. Friedberg EC. DNA damage and repair. Nature, 2003. 421(6921): p. 436-40.
35. Krokan HE, Nilsen H, Skorpen F, et al. Base excision repair of DNA in mammalian cells. FEBS Lett, 2000. 476(1-2): p. 73-7.
36. Nickoloff JA and Hoekstra MF. DNA damage and repair. In: DNA Repair in Higher Eukaryotes. 1998.
37. Wood RD, Mitchell M, Sgouros J, et al. Human DNA repair genes. Science, 2001. 291(5507): p. 1284-9.
38. de Laat WL, Jaspers NG, and Hoeijmakers JH. Molecular mechanism of nucleotide excision repair. Genes Dev, 1999. 13(7): p. 768-85.
39. Boiteux S and Radicella JP. Base excision repair of 8-hydroxyguanine protects DNA from endogenous oxidative stress. Biochimie, 1999. 81(1-2): p. 59-67.
40. Bruner SD, Norman DP, and Verdine GL. Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA. Nature, 2000. 403(6772): p. 859-66.
41. Chevillard S, Radicella JP, Levalois C, et al. Mutations in OGG1, a gene involved in the repair of oxidative DNA damage, are found in human lung and kidney tumours. Oncogene, 1998. 16(23): p. 3083-6.
42. Hirano T. Repair system of 7, 8-dihydro-8-oxoguanine as a defense line against carcinogenesis. J Radiat Res 2008. 49(4): p. 329-40.
43. Hardie LJ, Briggs JA, Davidson LA, et al. The effect of hOGGl and glutathione peroxidase I genotypes and 3p chromosomal loss on 8-hydroxydeoxyguanosine levels in lung cancer. Carcinogenesis, 2000. 21(2): p. 167-72.
44. Shinmura K, Kasai H, Sasaki A, et al. 8-hydroxyguanine (7,8-dihydro-8-oxoguanine) DNA glycosylase and AP lyase activities of hOGGl protein and their substrate specificity. Mutat Res, 1997. 385(1): p. 75-82.
45. Hazra TK, Hill JW, Izumi T, et al. Multiple DNA glycosylases for repair of 8-oxoguanine and their potential in vivo f unctions. Prog Nucleic Acid Res Mol Biol, 2001. 68: p. 193-205.
46. Wickenden JA, Clarke MC, Rossi AG, et al. Cigarette smoke prevents apoptosis through inhibition of caspase activation and induces necrosis. Am J Respir Cell Mol Biol, 2003. 29(5): p. 562-70.
47. Baglole CJ, Bushinsky SM, Garcia TM, et al. Differential induction of apoptosis by cigarette smoke extract in primary human lung fibroblast strains: implications for emphysema. Am J Physiol Lung Cell Mol Physiol, 2006. 291(1): p. L19-29.
48. Rogers DF. The airway goblet cell. Int J Biochem Cell Biol, 2003. 35(1): p. 126.
49. Andor R. Enhanced expression of fibroblast growth factors and receptor FGFR21 during vascular remodeling in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol, 2002. 27(3): p. 517-525.
50. Saetta M. Airway inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 1999. 160(5 Pt 2): p. S17-20.
51. Burdet L, de Muralt B, Scz Y, et al. Administration of growth hormone to underweight patients with chronic obstructive pulmonary disease. A prospective, randomized, controlled study. Am J Respir Crit Care Med, 1997. 156(6): p. 1800-6.
52. Helbock HJ, Beckman KB, Shigenaga MK, et al. DNA oxidation matters: the HPLC-electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine. Proc Natl Acad Sci U S A, 1998. 95(1): p. 288-93.
53. Miwa M, Matsumaru H, Akimoto Y, et al. Quantitative determination of urinary 8-hydroxy-2'-deoxyguanosine level in healthy Japanese volunteers. Bio factors, 2004. 22(1-4): p. 249-53.
54. Sarafian TA, Magallanes JA, Shau H, et al. Oxidative stress produced by marijuana smoke. An adverse effect enhanced by cannabinoids. Am J Respir Cell Mol Biol, 1999. 20(6): p. 1286-93.
55. Fletcher CM. Letter: Natural history of chronic bronchitis. Br Med J, 1976. 1(6025): p. 1592-3.
56. Lokke A, Lange P, Scharling H, et al. Developing COPD: a 25 year follow up study of the general population. Thorax, 2006. 61(11): p. 935-9.
57. Sandford AJ and Silverman EK. Chronic obstructive pulmonary disease. 1: Susceptibility factors for COPD the genotype-environment interaction. Thorax, 2002. 57(8): p. 736-41.
58. Spitz MR, Wu X, Wang Y, et al. Modulation of nucleotide excision repair capacity by XPD polymorphisms in lung cancer patients. Cancer Res, 2001. 61(4): p. 1354-7.
59. Wei Q, Cheng L, Hong WK, et al. Reduced DNA repair capacity in lung cancer patients. Cancer Res, 1996. 56(18): p. 4103-7.
60. Shen H, Spitz MR, Qiao Y, et al. Smoking, DNA repair capacity and risk of nonsmall cell lung cancer. Int J Cancer, 2003. 107(1): p. 84-8.
61. Pryor WA. Cigarette smoke radicals and the role of free radicals in chemical carcinogenicity. Environ Health Perspect, 1997. 105 Suppl 4: p. 875-82.
62. Mohrenweiser HW, Wilson DM, and Jones IM. Challenges and complexities in estimating both the functional impact and the disease risk associated with the extensive genetic variation in human DNA repair genes. Mutat Res, 2003. 526(1-2): p. 93-125.
63. Lindahl T and Wood RD. Quality control by DNA repair. Science, 1999. 286(5446): p. 1897-905.
64. Kohno T, Shinmura K, Tosaka M, et al. Genetic polymorphisms and alternative splicing of the hOGGl gene, that is involved in the repair of 8-hydroxyguanine in damaged DNA. Oncogene, 1998. 16(25): p. 3219-25.
65. Thompson L. and West MG. XRCC1 keeps DNA from getting stranded. Mutat Res,2000. 459(1): p. 1-18.
66. David-Beabes GL and London SJ. Genetic polymorphism of XRCC1 and lung cancer risk among African-Americans and Caucasians. Lung Cancer, 2001. 34(3): p. 333-9.
67. Le Marchand L, Donlon T, Lum-Jones A, et al. Association of the hOGGl Ser326Cys polymorphism with lung cancer risk. Cancer Epidemiol Biomarkers Prev, 2002. 11(4): p. 409-12.
68. Park J, Chen L, Tockman MS, et al. The human 8-oxoguanine DNA N-glycosylase 1 (hOGGl) DNA repair enzyme and its association with lung cancer risk. Pharmacogenetics, 2004. 14(2): p. 103-9.
69. Park JY, Lee SY, Jeon HS, et al. Polymorphism of the DNA repair gene XRCC1 and risk of primary lung cancer. Cancer Epidemiol Biomarkers Prev, 2002. 11(1): p. 23-7.
70. Sugimura H, Kohno T, Wakai K, et al. hOGGl Ser326Cys polymorphism and lung cancer susceptibility. Cancer Epidemiol Biomarkers Prev, 1999. 8(8): p. 669-74.
71. Zhou W, Liu G, Miller DP, et al. Polymorphisms in the DNA repair genes XRCC1 and ERCC2, smoking, and lung cancer risk. Cancer Epidemiol Biomarkers Prev, 2003. 12(4): p. 359-65.
72. Pauwels RA, Buist AS, Calverley PM, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med, 2001. 163(5): p. 1256-76.
73. Sandford AJ and Pare PD. Genetic risk factors for chronic obstructive pulmonary disease. Clin Chest Med, 2000. 21(4): p. 633-43.
74. Janssen K, Schlink K, Gotte W, et al. DNA repair activity of 8-oxoguanine DNA glycosylase 1 (OGG1) in human lymphocytes is not dependent on genetic polymorphism Ser326/Cys326. Mutat Res, 2001. 486(3): p. 207-16.
75. Dherin C, Radicella JP, Dizdaroglu M, et al. Excision of oxidatively damaged DNA bases by the human alpha-hOGGl protein and the polymorphic alpha-hOGGl(Ser326Cys) protein which is frequently found in human populations. Nucleic Acids Res, 1999. 27(20): p. 4001-7.
76. Caldecott KW. XRCC1 and DNA strand break repair. DNA Repair (Amst), 2003. 2(9): p. 955-69.
77. Caldecott KW. Mammalian DNA single-strand break repair: an X-ra(y)ted affair. Bioessays, 2001. 23(5): p. 447-55.
78. Whitehouse CJ, Taylor RM, Thistlethwaite A, et al. XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell, 2001. 104(1): p. 107-17.
79. Wang Y, Spitz MR, Zhu Y, et al. From genotype to phenotype: correlating XRCC1 polymorphisms with mutagen sensitivity. DNA Repair (Amst), 2003. 2(8): p. 901-8.
80. Fan J, Otterlei M, Wong HK, et al. XRCC1 co-localizes and physically interacts with PCNA. Nucleic Acids Res, 2004. 32(7): p. 2193-201.
81. Takanami T, Nakamura J, Kubota Y, et al. The Arg280His polymorphism in X-ray repair cross-complementing gene 1 impairs DNA repair ability. Mutat Res, 2005. 582(1-2): p. 135-45.
82. Matullo G, Guarrera S, Carturan S, et al. DNA repair gene polymorphisms, bulky DNA adducts in white blood cells and bladder cancer in a case-control study. Int J Cancer, 2001. 92(4): p. 562-7.
83. Abdel-Rahman SZ, Soliman AS, Bondy ML, et al. Inheritance of the 194Trp and the 399Gln variant alleles of the DNA repair gene XRCC1 are associated with increased risk of early-onset colorectal carcinoma in Egypt. Cancer Lett, 2000. 159(1): p. 79-86.
84. Divine KK, Gilliland FD, Crowell RE, et al. The XRCCl 399 glutamine allele is a risk factor for adenocarcinoma of the lung. Mutat Res, 2001. 461(4): p. 273-8.
85. Duell EJ, Wiencke JK, Cheng TJ, et al. Polymorphisms in the DNA repair genes XRCCl and ERCC2 and biomarkers of DNA damage in human blood monon uclear cells. Carcinogenesis, 2000. 21(5): p. 965-71.
86. Lunn RM, Langlois RG, Hsieh LL, et al. XRCCl polymorphisms: effects on aflatoxin Bl-DNA adducts and glycophorin A variant frequency. Cancer Res, 1999. 59(11): p. 2557-61.
87. Hung RJ, Hall J, Brennan P, et al. Genetic polymorphisms in the base excision repair pathway and cancer risk: a Huge review. Am J Epidemiol, 2005. 162(10): p. 925-42.
88. Seedhouse C, Bainton R, Lewis M, et al. The genotype distribution of the XRCCl gene indicates a role for base excision repair in the development of therapy-related acute myeloblastic leukemia. Blood, 2002. 100(10): p. 3761-6.
89. Takezaki T, Gao CM, Wu JZ, et al. hOGGl Ser(326)Cys polymorphism and modification by environmental factors of stomach cancer risk in Chinese. Int J Cancer, 2002. 99(4): p. 624-7.
90. Elahi A, Zheng Z, Park J, et al. The human OGG1 DNA repair enzyme and its association with orolaryngeal cancer risk. Carcinogenesis, 2002. 23(7): p. 1229-34.
91. Kelley MR, Cheng L, Foster R, et al. Elevated and altered expression of the multifunctional DNA base excision repair and redox enzyme Apel/ref-1 in prostate cancer. Clin Cancer Res, 2001. 7(4): p. 824-30.
92. Marullo G, Palli D, Peluso M, et al. XRCCl, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy s ubjects. Carcinogenesis, 2001. 22(9): p. 1437-45.
93. Ishida T, Takashima R, Fukayama M, et al. New DNA polymorphisms of human MMH/OGG1 gene: prevalence of one polymorphism among lung-adenocarcinoma patients in Japanese. Int J Cancer, 1999. 80(1): p. 18-21.
1. Mannino DM. Epidemiology and global impact of chronic obstructive pulmonary disease. Semin Respir Crit Care Med, 2005. 26(2): p. 204-10.
2. Bartsch H, Ohshima H, Pignatelli B, et al. Endogenously formed N-nitroso compounds and nitrosating agents in human cancer etiology. Pharmacogenetics, 1992. 2(6): p. 272-7.
3. Mirvish SS. Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC. Cancer Lett, 1995. 93(1): p. 17-48.
4. Thompson AB, Bohling T, Heires A, et al. Lower respiratory tractiron burden is increased in association with cigarette smoking. J Lab Clin Med, 1991. 117(6): p. 493-9.
5. Karadag F, Cildag O, Altinisik M, et al. Trace elements as a component of oxidative stress in COPD. Respirology, 2004. 9(1): p. 33-7.
6. Kharitonov SA and Barnes PJ. Exhaled markers of inflammation. Curr Opin Allergy Clin Immunol, 2001. 1(3): p. 217-24.
7. Nishikawa M, Kakemizu N, Ito T, et al. Superoxide mediates cigarette smoke-induced infiltration of neutrophils into the airways through nuclear factor-kappa B activation and IL-8 mRNA expression in guinea pigs in vivo. Am J Respir Cell Mol Biol, 1999. 20(2): p. 189-98.
8. Wouters EF, Creutzberg EC and Schols AM. Systemic effects in COPD. Chest, 2002. 121(5 S uppl):p. 127S-130S.
9. Engelen MP, Schols AM, Does JD, et al. Skeletal muscle weakness is associated with wasting of extremity fat-free mass but not with airflow obstruction in patients with chronic obstructive pulmonary disease. Am J Clin Nutr, 2000. 71(3): p. 733-8.
10. Li YP, Atkins CM, Sweatt JD, et al. Mitochondria mediate tumor necrosis factor-alpha/NF-kappa B signaling in skeletal muscle myotubes. Antioxid Redox Signal, 1999. 1(1): p. 97-104.
11. Langen RC, Van Der Velden JL, Schols AM, et al. Tumor necrosis factor-alpha inhibits myogenic differentiation through MyoD protein destabilization. Faseb J, 2004. 18(2): p. 227-37.
12. Thierens H, Vral A, and De Ridder L. A cytogenetic study of radiological workers: effect of age, smoking and radiation burden on the micronucleus frequency. Mutat Res, 1996. 360(2): p. 75-82.
13. Coleman CN and Harris JR. Current scientific issues related to clinical radiation oncology. Radiat Res, 1998. 150(2): p. 125-33.
14. Vayssier-Taussat M, Camilli T, Aron Y, et al. Effects of tobacco smoke and benzo[a]pyrene on human endothelial cell and monocyte stress responses. Am J Physiol Heart Circ Physiol, 2001. 280(3): p. H1293-300.
15. Kasai H. Analysis of a form of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis. Mutat Res, 1997. 387(3): p. 147-63.
16. Hegde V, Wang M, and Deutsch WA. Human ribosomal protein S3 interacts with DNA base excision repair proteins hAPE/Ref-1 and hOGGl. Biochemistry, 2004. 43(44): p. 14211-7.
17. Vodicka P, Kumar R, Stetina R, et al. Markers of individual susceptibility and DNA repair rate in workers exposed to xenobiotics in a tire plant. Environ Mol Mutagen, 2004. 44(4): p. 283-92.
18. Ide H and Kotera M. Human DNA glycosylases involved in the repair of oxidatively damaged DNA. Biol Pharm Bull, 2004. 27(4): p. 480-5.
19. Ames BN. Endogenous DNA damage as related to cancer and aging. Mutat Res, 1989. 214(1): p. 41-6.
20. Shigenaga MK and Ames BN. Assays for 8-hydroxy-2'-deoxyguanosine: a biomarker of in vivo oxidative DNA damage. Free Radic Biol Med, 1991. 10(3-4): p. 211-6.
21. Halliwell B and Aruoma OI. DNA damage by oxygen-derived species. Its mechanism and measurement in mammalian systems. FEBS Lett, 1991. 281(1-2): p. 9-19.
22. Loft S HDP, Mikkelsen L, Risom L. Biomarkers of oxidative damage to DNA and repair. Biochem Soc Trans, 2008. 36(pt 5): p. 1071-6.
23. Wood RD, Mitchell M, Sgouros J, et al. Human DNA repair genes. Science, 2001. 291(5507): p. 1284-9.
24. de Laat WL, Jaspers NG, and Hoeijmakers JH. Molecular mechanism of nucleotide excision repair. Genes Dev, 1999. 13(7): p. 768-85.
25. Spitz MR, Wu X, Wang Y, et al. Modulation of nucleotide excision repair capacity by XPD polymorphisms in lung cancer patients. Cancer Res, 2001. 61(4): p. 1354-7.
26. Goode EL, Ulrich CM and Potter JD. Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomarkers Prev, 2002. 11(12): p. 1513-30.
27. Rosenquist TA, Zharkov DO and Grollman AP. Cloning and characterization of a mammalian 8-oxoguanine DNA glycosylase. Proc Natl Acad Sci USA, 1997. 94(14): p. 7429-34.
28. Audebert M, Charbonnier JB, Boiteux S, et al. Mitochondrial targeting of human 8-oxoguanine DNA glycosylase hOGGl is impaired by a somatic mutation found in kidney cancer. DNA Repair (Amst), 2002. 1(7): p. 497-505.
29. Shinmura K, Kasai H, Sasaki A, et al. 8-hydroxyguanine (7,8-dihydro-8-oxoguanine) DNA glycosylase and AP lyase activities of hOGGl protein and their substrate specificity. Mutat Res, 1997. 385(1): p. 75-82.
30. Takezaki T, Gao CM, Wu JZ, et al. hOGGl Ser(326)Cys polymorphism and modification by environmental factors of stomach cancer risk in Chinese. Int J Cancer, 2002. 99(4): p. 624-7.
31. Ishida T, Takashima R, Fukayama M, et al. New DNA polymorphisms of human MMH/OGG1 gene: prevalence of one polymorphism among lung-adenocarcinoma patients in Japanese. Int J Cancer, 1999. 80(1): p. 18-21.
32. Kohno T, Shinmura K, Tosaka M, et al. Genetic polymorphisms and alternative splicing of the hOGGl gene, that is involved in the repair of 8-hydroxyg uanine in damaged DNA. Oncogene, 1998. 16(25): p. 3219-25.
33. Dhenaut A, Boiteux S and Radicella JP. Characterization of the hOGGl promoter and its expression during the cell cycle. Mutat Res, 2000. 461(2): p. 109-18.
34. Le Marchand L, Donlon T, Lum-Jones A, et al. Association of the hOGGl Ser326Cys polymorphism with lung cancer risk. Cancer Epidemiol Biomarkers Prev, 2002. 11(4): p. 409-12.
35. Paz-Elizur T, Krupsky M, Blumenstein S, et al. DNA repair activity for oxidative damage and risk of lung cancer. J Natl Cancer Inst, 2003. 95(17): p. 1312-9.
36. Sugimura H, Kohno T, Wakai K, et al. hOGGl Ser326Cys polymorphism and lung cancer susceptibility. Cancer Epidemiol Biomarkers Prev, 1999. 8(8): p. 669-74.
37. Marsin S, Vidal AE, Sossou M, et al. Role of XRCC1 in the coordination and stimulation of oxidative DNA damage repair initiated by the DNA glycosylase hOGGl. J Biol Chem, 2003. 278(45): p. 44068-74.
38. Dherin C, Radicella JP, Dizdaroglu M, et al. Excision of oxidatively damaged DNA bases by the human alpha-hOGGl protein and the polymorphic alpha-hOGGl(Ser326Cys) protein which is frequently found in human populations. N ucleic Acids Res, 1999. 27(20): p. 4001-7.
39. Vidal AE, Boiteux S, Hickson ID, et al. XRCC1 coordinates the initial and late stages of DNA abasic site repair through protein-protein interactions. Embo J, 2001. 20(22): p. 6530-9.
40. Kubota Y, Nash RA, Klungland A, et al. Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 protein. Embo J, 1996. 15(23): p. 6662-70.
41. Caldecott KW. XRCC1 and DNA strand break repair. DNA Repair (Amst), 2003. 2(9): p. 955-69.
42. Caldecott KW, McKeown CK, Tucker JD, et al. An interaction between the mammalian DNA repair protein XRCC1 and DNA ligase III. Mol Cell Biol, 1994. 14(1): p. 68-76.
43. Fan J, Otterlei M, Wong HK, et al. XRCC1 co-localizes and physically interacts with PCNA. Nucleic Acids Res, 2004. 32(7): p. 2193-201.
44. Masson M, Niedergang C, Schreiber V, et al. XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage. Mol Cell Biol, 1998. 18(6): p. 3563-71.
45. Whitehouse CJ, Taylor RM, Thistlethwaite A, et al. XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell, 2001. 104(1): p. 107-17.
46. Wang Y, Spitz MR, Zhu Y, et al. From genotype to phenotype: correlating XRCCl polymorphisms with mutagen sensitivity. DNA Repair (Amst), 2003. 2(8): p. 901-8.
47. Takanami T, Nakamura J, Kubota Y, et al. The Arg280His polymorphism in X-ray repair cross-complementing gene 1 impairs DNA repair ability. Mutat Res, 2005. 582(1-2): p. 135-45.
48. Shen H, Spitz MR, Qiao Y, et al. Smoking, DNA repair capacity and risk of nonsmall cell lung cancer. Int J Cancer, 2003. 107(1): p. 84-8.
49. Lunn RM, Langlois RG, Hsieh LL, et al. XRCCl polymorphisms: effects on aflatoxin Bl-DNA adducts and glycophorin A variant frequency. Cancer Res, 1999. 59(11): p. 2557-61.
50. Matullo G, Guarrera S, Carturan S, et al. DNA repair gene polymorphisms, bulky DNA adducts in white blood cells and bladder cancer in a case-control study. Int J Cancer, 2001. 92(4): p. 562-7.
51. Matullo G, Palli D, Peluso M, et al. XRCCl, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects. Carcinogenesis, 2001. 22(9): p. 1437-45.
52. Abdel-Rahman SZ and El-Zein RA. The 399Gln polymorphism in the DNA repair gene XRCCl modulates the genotoxic response induced in human lymphocytes by the tobacco-specific nitrosamine NNK. Cancer Lett, 2000. 159(1): p. 63-71.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |