细胞色素P4501A1和谷胱甘肽硫转移酶M1基因多态与肺癌易感性关系研究
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摘要
肺癌(Lung Cancer，LC)是世界上最常见的六大恶性肿瘤之一，占所有肿瘤发病率的19％，死亡率的29％，我国肺癌的死亡率已跃居第一位。肿瘤流行病学研究证实：吸烟是肺癌发生最重要的原因，吸烟人群患肺癌的相对危险性比不吸烟人群高20倍之多，但只有少于20％吸烟者有患肺癌的危险性，显然机体对烟草烟雾中致癌物的敏感性有很大个体差异。近年来的研究发现，肺癌的发生是环境暴露与遗传因素复杂交互作用的结果，外源性致癌物的代谢、DNA损伤与修复、细胞周期调控、细胞死亡与分化以及机体免疫监控等方面存在的基因多态现象，对个体肺癌易感性差异有显著影响。在外源性致癌物的代谢活化、DNA损伤与修复这两个环节中，药物代谢酶CYPs和GSTs最具代表性。研究发现，CYP1A1和GSTM1基因多态与肺癌的易感性密切相关。CYP1 A1多态在CYP1 A1基因的3′非编码区聚腺苷酸下游264bp处，由碱基T→C变异导致酶活性增高。GSTM1有缺陷型和功能型两种多态，缺陷型产生大量无活性酶，导致机体解毒能力下降。
我们假设，在河南地区人群中CYP1A1 m1基因突变所造成的酶活性增高及GSTM1表达缺陷，将会通过干扰正常烟草致癌物的代谢和清除过程而影响机体患肺癌的危险性或易感性。本课题对该地区人群进行回顾性“病例—对照”研究，分析此二种基因多态与支气管肺癌癌变的关系，来探讨其在肺癌诊断方面的价值，并为高危人群的筛选和防治提供有意义的信息和手段。
材料和方法：
实验组包括103例肺癌患者，所有病例均来自河南籍汉族人群，于2003年3～8月间在郑州大学第一、二附属医院气管镜室检查，经纤维支气管镜活检和／或刷检和／或灌洗液脱落细胞病理学检查确诊，为首次确诊病例，
郑州大学20(只年硕士研究生毕业论文细胞色素P450 IAI和谷耽甘肚硫转移酶Ml基因多态与肺癌易感性关系研究
并经综合临床分析，排除有其它恶性肿瘤病史者。正常对照组共138例，
随机选自该地区志愿参与健康体检的人群，与病例组年龄性别相匹配。所
有入选者均经详细问卷调查，以查明其疾病史并排除有肿瘤病史者。
DNA提取试剂采用美国Gentra公司的产品，以盐析法从支气管肺泡
灌洗液或血凝块残留液中提取基因组DNA，采用PcR法及基于PcR基础
上的限制性片段多态检测法(PCR一RFLP)，对各基因型进行检验和区分。
采用回顾性“病例一对照”试验设计，所得的对照组数据采用Fisher Exact
扩检验进行验证，确定其各基因型分布是否符合Hardy一weinberg平衡;危
险度计算采用非条件性逻辑斯谛回归模型(Uneonditional logistic
regression models)分别对年龄、性别进行校正后计算比数比(odds Ratios，
OR)及95%可信区间(Confidential Intervals，Cl);以上计算均由SPSS10.0
(USA)统计软件进行分析，检验显著性水准均采用a=0.05。
结果:
1.CYPIAI的wl野生型、ml突变型等位基因频率在对照组分别为
72%和28%，在肺癌组分别为57%和43%，ml突变型等位基因频率在病例
组明显高于对照组，两组间分布经扩检验差别显著;GsTMI的缺陷型基
因(D)频率在对照组、肺癌组分别为44%和61%，其比例在病例组明
显高于对照组，经扩检验差别显著。
2.对于CYPIAI，其各基因型的分布频率在对照组分别为A型
(wl/wl)52.9%、B型(ml/wl)39.1%、C型(ml/ml)8%，在肺癌
组分别为A型(wl/wl)26.2%、B型(mr/wl)62.1%、C型(ml/ml)
n.7%，两组间分布经扩检验差别显著。GsTMI缺陷型(D)和功能型(F)
基因分布频率在对照组分别为44.2%、55.8%，在肺癌组分别为61.2%、
38.8%，两组间基因型的分布经扩检验差别显著。
各基因型在对照组的分布均符合群体遗传学Hardy一weinberg平衡
(GSTMI，P== 0.291;CYPIAI，P=0.280)，表明研究对象的选择无群体遗
传学偏差。
3.我们将CYP IAI(wl/wl)野生纯合型基因(A型)作为参考组，
考查杂合型(B型)和纯合突变型(C型)患肺癌的危险度。与参考组基
因型相比，B基因型患肺癌的危险度升高3.190倍(95%Cl，1.782一5.713)，
郑州大学2仪抖年硕士研究生毕业论文细胞色素P450 IAI和谷脱甘肤硫转移酶Ml基因多态与肺癌易感性关系研究
C基因型患肺癌的危险度升高2.607倍(95%Cl，x.O18一6.674)，二者合计
患肺癌的危险度升高3.161倍(95%，Cl，1.821一5.489)，三者经统计学分
析差别显著。
4.与GSTMI(F)型基因相比，GSTMI(D)型基因携带者患肺癌
的危险度升高2.085倍(95%Cl，1.225~3.551)，具有显著性统计学意义。
5，将兼有GSTMI(F)和CYPIAI(A)型基因的携带者作为参考组，
考查各类GSTMI与CYPIAI基因型组合(Combination)携带者患肺癌的
危险度。相对于参考组，GSTMI(D)与CYPIAI(A)型基因型组合携
带者患肺癌的危险度升高1.338倍(95%Cl，0.537一3.319)，差异无显著性;
GSTMI(F)与CYPIAI(B或C)基因型组合携带者患肺癌的危险度升高
2.127倍(95%Cl，0.929一4.827);GSTMI(D)与CYPIAI(B)型基因
型组合携带者患肺癌的危险度最高，升高6.456倍(95%Cl，2.740~15.210)，
经统计学分析差别显著;GSTMI(F)与CYPIAI(B)基因型组合携带者
患肺癌的危险度升高2.163倍(95%Cl，0.982一5.040)，无统计?
Lung cancer (LC) is one of the six most common malignant diseases in the world . Lung cancer accounts for 19% of all cancer and 29% of all death. It is the commonest cause of cancer death to human in China. It has the highest mortality rate, too. Epidemiological study have shown that tobacco smoking is the most important etiological factor in the development of this cancer, and the risk is at least 20 times higher in long-term smoker compare nonsmokers. but only less than 20% persons risk to get the cancer. Obvoursely, there is a big deference to individuals' susceptibility of this cancer. Recently, account of study shown there is a growing realization that the development of most cancers results from a complex interaction of both environmental and genetic factor. It is an important factor to lung cancer susceptibility of genetic polymorphism in the bioactivation of procarcinogens and detoxification of carcinogens. In the two fuction, CYPs and GSTs is the most important metabolize enzymes. The common polymor
phism at the CYP1A1 gene nucleotide position 264 (T-C) and cause activity of the enzyme arise. Faction and deletion are the two polymorphisms for GSTM1 gene. The individual in deletion polymorphism produce a lot of enzyme without any normal function , and for this null allele are less efficient at conjugating and detoxifying specific substrate intermediates of carcinogens. The cancer risk were affected by polymorphic CYPs and GSTs together.
We hypothesized that, with the mutation of CYP1A1 and GSTM1 gene, alterations of enzymes activities of CYP1A1 and GSTM1 caused by existing of genetic polymorphisms would raise the risk of lung carcinogenesis through disturbing bioactivation of procarcinogens and detoxification of carcinogens. And also may these polymorphisms contribute to the genetic basis of highly
distinguished and concordant geographical distribution of lung cancer in Henan Chinese people. To test our hypothesis, a retrospective case-control study was conducted to explore the associations, and then to provide informative evidences and useful methods for high-risk population screening, diagnosis and treatment. Materials and Methods:
One hundred and three cases with lung cancer were recruited from the first and second affiliated hospital of Zhengzhou university, which were histopathologically confirmed from March to August in 2003. All cases were Chinese people from Henan areas and were investigated to exclude other simultaneous malignancies. One hundred and thirty-eight subjects with matched age and sex frequencies were randomly selected as control group from the same region in the field surveys between March and August in 2003.
Genomic DNA was extracted from remnant liquid of blood clot or bronchoalveolar larage fluid (BALF) using protocols provided by Gentra Puregene DNA purification kit. Polymerase chain reaction (PCR) and PCR based restriction fragment length polymorphisms (PCR-RFLP) detection were applied to analyze genotypes of the polymorphisms. Retrospective case-control study was conducted and Fisher Exact x 2 test was adopted to check the accordance with Hardy-Weinberg equilibrium in the control group. For risk estimation, the risk was evaluated in terms of age-sex adjusted odds ratios (OR) and 95% confidence intervals (CD by unconditional logistic regression model. All of the statistical analyses were calculated by SPSS 10.0
(USA) statistical software. (p<0.05 was regarded as significant) Results:
1. For CYP1A1, the allele frequencies of ml were 28% and 43% in control and LC groups, respectively. For GSTM1, the allele frequencies of deletion were 44.2% and 61.2% in control and LC groups, respectively.
2. The frequencies of CYP1A1 genotypes distribution were 52.3%, 39.1% and 8% for CYPlAlwl/wl ( A) , CYPlAlwl/ml (B) and CYP1A1 ml/ml
( C ) in controls, respectively; For cases, the frequencies of CYP1 Al A, B, C, were 26.2%, 62.1% and 11.7% in individuals with LC, respectively. For GSTM1, frequencies of deletion were 44.2%. in controls, in cases with LC, fr
我们假设，在河南地区人群中CYP1A1 m1基因突变所造成的酶活性增高及GSTM1表达缺陷，将会通过干扰正常烟草致癌物的代谢和清除过程而影响机体患肺癌的危险性或易感性。本课题对该地区人群进行回顾性“病例—对照”研究，分析此二种基因多态与支气管肺癌癌变的关系，来探讨其在肺癌诊断方面的价值，并为高危人群的筛选和防治提供有意义的信息和手段。
材料和方法：
实验组包括103例肺癌患者，所有病例均来自河南籍汉族人群，于2003年3～8月间在郑州大学第一、二附属医院气管镜室检查，经纤维支气管镜活检和／或刷检和／或灌洗液脱落细胞病理学检查确诊，为首次确诊病例，
郑州大学20(只年硕士研究生毕业论文细胞色素P450 IAI和谷耽甘肚硫转移酶Ml基因多态与肺癌易感性关系研究
并经综合临床分析，排除有其它恶性肿瘤病史者。正常对照组共138例，
随机选自该地区志愿参与健康体检的人群，与病例组年龄性别相匹配。所
有入选者均经详细问卷调查，以查明其疾病史并排除有肿瘤病史者。
DNA提取试剂采用美国Gentra公司的产品，以盐析法从支气管肺泡
灌洗液或血凝块残留液中提取基因组DNA，采用PcR法及基于PcR基础
上的限制性片段多态检测法(PCR一RFLP)，对各基因型进行检验和区分。
采用回顾性“病例一对照”试验设计，所得的对照组数据采用Fisher Exact
扩检验进行验证，确定其各基因型分布是否符合Hardy一weinberg平衡;危
险度计算采用非条件性逻辑斯谛回归模型(Uneonditional logistic
regression models)分别对年龄、性别进行校正后计算比数比(odds Ratios，
OR)及95%可信区间(Confidential Intervals，Cl);以上计算均由SPSS10.0
(USA)统计软件进行分析，检验显著性水准均采用a=0.05。
结果:
1.CYPIAI的wl野生型、ml突变型等位基因频率在对照组分别为
72%和28%，在肺癌组分别为57%和43%，ml突变型等位基因频率在病例
组明显高于对照组，两组间分布经扩检验差别显著;GsTMI的缺陷型基
因(D)频率在对照组、肺癌组分别为44%和61%，其比例在病例组明
显高于对照组，经扩检验差别显著。
2.对于CYPIAI，其各基因型的分布频率在对照组分别为A型
(wl/wl)52.9%、B型(ml/wl)39.1%、C型(ml/ml)8%，在肺癌
组分别为A型(wl/wl)26.2%、B型(mr/wl)62.1%、C型(ml/ml)
n.7%，两组间分布经扩检验差别显著。GsTMI缺陷型(D)和功能型(F)
基因分布频率在对照组分别为44.2%、55.8%，在肺癌组分别为61.2%、
38.8%，两组间基因型的分布经扩检验差别显著。
各基因型在对照组的分布均符合群体遗传学Hardy一weinberg平衡
(GSTMI，P== 0.291;CYPIAI，P=0.280)，表明研究对象的选择无群体遗
传学偏差。
3.我们将CYP IAI(wl/wl)野生纯合型基因(A型)作为参考组，
考查杂合型(B型)和纯合突变型(C型)患肺癌的危险度。与参考组基
因型相比，B基因型患肺癌的危险度升高3.190倍(95%Cl，1.782一5.713)，
郑州大学2仪抖年硕士研究生毕业论文细胞色素P450 IAI和谷脱甘肤硫转移酶Ml基因多态与肺癌易感性关系研究
C基因型患肺癌的危险度升高2.607倍(95%Cl，x.O18一6.674)，二者合计
患肺癌的危险度升高3.161倍(95%，Cl，1.821一5.489)，三者经统计学分
析差别显著。
4.与GSTMI(F)型基因相比，GSTMI(D)型基因携带者患肺癌
的危险度升高2.085倍(95%Cl，1.225~3.551)，具有显著性统计学意义。
5，将兼有GSTMI(F)和CYPIAI(A)型基因的携带者作为参考组，
考查各类GSTMI与CYPIAI基因型组合(Combination)携带者患肺癌的
危险度。相对于参考组，GSTMI(D)与CYPIAI(A)型基因型组合携
带者患肺癌的危险度升高1.338倍(95%Cl，0.537一3.319)，差异无显著性;
GSTMI(F)与CYPIAI(B或C)基因型组合携带者患肺癌的危险度升高
2.127倍(95%Cl，0.929一4.827);GSTMI(D)与CYPIAI(B)型基因
型组合携带者患肺癌的危险度最高，升高6.456倍(95%Cl，2.740~15.210)，
经统计学分析差别显著;GSTMI(F)与CYPIAI(B)基因型组合携带者
患肺癌的危险度升高2.163倍(95%Cl，0.982一5.040)，无统计?
Lung cancer (LC) is one of the six most common malignant diseases in the world . Lung cancer accounts for 19% of all cancer and 29% of all death. It is the commonest cause of cancer death to human in China. It has the highest mortality rate, too. Epidemiological study have shown that tobacco smoking is the most important etiological factor in the development of this cancer, and the risk is at least 20 times higher in long-term smoker compare nonsmokers. but only less than 20% persons risk to get the cancer. Obvoursely, there is a big deference to individuals' susceptibility of this cancer. Recently, account of study shown there is a growing realization that the development of most cancers results from a complex interaction of both environmental and genetic factor. It is an important factor to lung cancer susceptibility of genetic polymorphism in the bioactivation of procarcinogens and detoxification of carcinogens. In the two fuction, CYPs and GSTs is the most important metabolize enzymes. The common polymor
phism at the CYP1A1 gene nucleotide position 264 (T-C) and cause activity of the enzyme arise. Faction and deletion are the two polymorphisms for GSTM1 gene. The individual in deletion polymorphism produce a lot of enzyme without any normal function , and for this null allele are less efficient at conjugating and detoxifying specific substrate intermediates of carcinogens. The cancer risk were affected by polymorphic CYPs and GSTs together.
We hypothesized that, with the mutation of CYP1A1 and GSTM1 gene, alterations of enzymes activities of CYP1A1 and GSTM1 caused by existing of genetic polymorphisms would raise the risk of lung carcinogenesis through disturbing bioactivation of procarcinogens and detoxification of carcinogens. And also may these polymorphisms contribute to the genetic basis of highly
distinguished and concordant geographical distribution of lung cancer in Henan Chinese people. To test our hypothesis, a retrospective case-control study was conducted to explore the associations, and then to provide informative evidences and useful methods for high-risk population screening, diagnosis and treatment. Materials and Methods:
One hundred and three cases with lung cancer were recruited from the first and second affiliated hospital of Zhengzhou university, which were histopathologically confirmed from March to August in 2003. All cases were Chinese people from Henan areas and were investigated to exclude other simultaneous malignancies. One hundred and thirty-eight subjects with matched age and sex frequencies were randomly selected as control group from the same region in the field surveys between March and August in 2003.
Genomic DNA was extracted from remnant liquid of blood clot or bronchoalveolar larage fluid (BALF) using protocols provided by Gentra Puregene DNA purification kit. Polymerase chain reaction (PCR) and PCR based restriction fragment length polymorphisms (PCR-RFLP) detection were applied to analyze genotypes of the polymorphisms. Retrospective case-control study was conducted and Fisher Exact x 2 test was adopted to check the accordance with Hardy-Weinberg equilibrium in the control group. For risk estimation, the risk was evaluated in terms of age-sex adjusted odds ratios (OR) and 95% confidence intervals (CD by unconditional logistic regression model. All of the statistical analyses were calculated by SPSS 10.0
(USA) statistical software. (p<0.05 was regarded as significant) Results:
1. For CYP1A1, the allele frequencies of ml were 28% and 43% in control and LC groups, respectively. For GSTM1, the allele frequencies of deletion were 44.2% and 61.2% in control and LC groups, respectively.
2. The frequencies of CYP1A1 genotypes distribution were 52.3%, 39.1% and 8% for CYPlAlwl/wl ( A) , CYPlAlwl/ml (B) and CYP1A1 ml/ml
( C ) in controls, respectively; For cases, the frequencies of CYP1 Al A, B, C, were 26.2%, 62.1% and 11.7% in individuals with LC, respectively. For GSTM1, frequencies of deletion were 44.2%. in controls, in cases with LC, fr
引文
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19．程家蓉 关赛芳 王学勤等 人口腔细胞P450、GST基因多态性研究 肿瘤 2002，22(3)：242～245
20. Nang Song, Wen Tan, Deyin, et al. CYP1A1 polymorphism and risk of lung cancer in relation to tobacco smoking: a case-control study in china [J] Carcinogenesis 2001, 22 (1) : 11-16,
21．瞿永华 石于波 钟礼杰等 华人 GSTM1，CYP1A1 2E1和APOE等等位基因的基因型 肿瘤 1998，18(1)：17～20
22．支气管肺泡灌洗液细胞学检测技术规范(草案) 中华医学会呼吸病学分会制定 中华结核和呼吸杂志 2002，25(7)：390-341
23．胡毅玲 高扬 张桥等 细胞色素P450 1A1、2D6和谷胱甘肽硫转移酶基因多态性与肺癌易感性的研究 肿瘤 1998，18(7)：269～271
24．章龙珍 王绪 郝兴芝等，CYP1A1、GSTM1基因多态性与肺癌易感性的研究 中国肿瘤临床 29：(8)536-540，2002
25．张吉凯 胡毅玲 胡巢凤等 谷胱甘肽硫转移酶M1和T1基因多态与肺癌易感性关系的研究 中国病理生理杂志 2002，18(4)：352～355
26．邬洪梁 陈迈群 周四保等．湖南土家族、苗族人群 GSTM1 基因多态性研究 湖南医学 2001，18(1)：17～19
27. Mariko Murataa,b, Masatoshi Watanabea, Mikio Yamanakaa, et al. Genetic polymorphisms in cytochrome P450 (CYP) 1A1, CYP1A2, CYP2E1, glutathione S-transferase (GST) M1 and GSTT1 and susceptibility to prostate cancer in the Japanese population [J] Cancer Letters (2001) 165 : 171-177
28. Nakachi K, I mai K, Hayashi S , et al. Polymorphisms of the CYP1A1 and glutathione S transferases genes associated with susceptibility to lung cancer inralation to cigarette dose in a Japanese population [J].Cancer Res, 1993, 53 (13) :2994-2999.
29. Hayashis S, Watanabe J,Kawajiri K. High susceptibility to lung cancer analyzed in terms of P450 1A1 and mu-class glutathione S-transferase genes. [J] Jpn J Cancer Res, 1992, 83:866
30. Loc Le Marchand, Lskahmi Sivaraman, Lisa Pierce, et al. Assications of CYP1A1, GSTM1, and CYP2E1 polymorphisms wish lung cancer suggest cell type specificities to tobacco caocinogens [J] Cancer Research 58:4858-4863,Nov. 1998
31. Blanca Laffon, Beatriz Pe'rez-Cadah, Eduardo Pa'saro, et al.
32. Individual sensitivity to DNA damage induced by styrene in vitro: influence of cytochrome P450, epoxide hydrolase and glutathione S-transferase genotypes [J] Toxicology (2003) 186: 131--141
33. Valle Nazar-Stewart, Thomas L. Vaughan, Patricia Stapleton, et al. A population-based study of glutathione S-transferase M1, T1 and P1
genotypes and risk for lung cancer [J] Lung Cancer 40 (2003) 247-258
34. Mark J. Rotha, Sanford M. Dawseya, Guo-Qing Wang, et al. Association between GSTM1~*0 and squamous dysplasia of the esophagus in the high risk region of Linxian, [J] China Cancer Letters 156 (2000) 73-81
35. Matthias Hahna, Gunnar Hagedornb, Eberhard Kuhlischc, et al. Genetic polymorphisms of drug-metabolizing enzymes and suscep- tibility to oral cavity cancer [J] Oral Oncology 38 (2002) 486- 490
36．瞿永华 石于波 钟礼杰等 非吸烟女性肺病癌患者细胞色素P4501A1和GSTM1的基因型 肿瘤 1998，18(2)：80～83
37. Hirvoen A, Husgafvel-Pursiainen K,Karjalainen A, et al. Pointmut-ational Mspl and ile-val polymorphism closely linked in the CYP 1A1 gene: lack of association with susceptibility to lung cancer in a finish study population. [J] Cancer Epidemiol Biomarkers Prev, 1992, 1:485
38. Carolyn M. Dresler, Cori Fratelli, James Babb, et al. Gender differences in genetic susceptibility for lung cancer [J] Lung Cancer 30 : (2000) 153-160
39．赵鲁抗 陈枢青 余国伟等 细胞色素P450 2C19基因多态与肺癌易感性的关系 中华结核与呼吸杂志 1999．11 22(11)：682～683
40．曹云霞 庄广伦 多囊卵巢综合征与CYP基因多态的关联性研究 现代妇产科进展 8(4)：305～308 1999．4
41．高杨，张桥 GSTM1和CYP2D6基因多态性与肺癌敏感性的关系 中国公共卫生 1999 15(6)：488-490
42．许林，陈森清，马国建等 中国人CYP1A1和GSTM1基因多态性及其对个体肺癌易感性的联合效应 中华医学遗传学杂志 18(2)：125-127 April 2001，Vol．18，No．2
43. L dia Maria da Fonte de Amorima, Ana Rossinib, Gulnar Azeve- do Silva Mendonc et al. CYP1A1, GSTM1, and GSTT1 polymorphism -s and breast cancer risk in Brazilian women [J] Cancer Letters 181: (2002) 179-186
44. Y.-W. Cheng, C.-Y. Chen, P. Lin, et al. DNA adduct level in lung tissue may act as a risk biomarker of lung cancer. [J] European Journal of Cancer
36 (2000) 1381±1388
45. T.T. Sreelekha, K. Ramadas, M. Pandey, et al. Genetic polymor- phism of CYP1A1, GSTM1 and GSTT1 genes in Indian oral cancer [J] Oral Oncology37 (2001) 593-598
46. Drakoulis N, Cascorbi I, Brockmoller J, et al. polymorphism in the human CYP1A1 gene as susceptibility factors Exon-7 mutation (4889 A to G) , and a T to C mutation in the 3'-flanking region. [J] Clin. Invest., 1994, 72:240
47. Emanuela Taioli, Daniela Mari, Claudio Franceschi, et al. Polymorphisms of Drug-Metabolizing Enzymes in Healthy Nonagenarians and Centenarians: Difference at GSTT1 Locus [J] Biochemical and Biophysical Research Communications 280:1389-1392 (2001)
48. J.J. Yim, G.G.Yoo, C.-T. Lee, et al. Lack of association between glutathione S-transferase P1 polymorphism and COPD in Koreans [J] Lung (2002) 180:119-125
49. Paolo Vineis . The relationship between polymorphisms of xenobio -tic metabolizing enzymes and susceptibility to cancer [J] Toxicology 181-182: (2002) 457-462
50. M. Adonis, V. Martnez, R. Riquelme, Susceptibility and expo- sure biomarkers in people exposed to PAHs from diesel exhaust. [J] Toxicology Letters 144: (2003) 3-15
51. Hitoshi Ishikawa, Hidetaka Yamamoto, Ying Tian, et al. Evidence of association of the CYP2E1 genetic polymorphism with micronuclei frequency in human peripheral blood [J] Mutation Research 546: (2004) 45-53
52. Przygodzki R M, Bennett W P, Guinee D G,et al. p53 mutation spec-trum in relation to GSTM1, CYP1A1 and CYP2E1 in surgically treat-ed patients with non small cell lung cancer [J]. Pharmacogenet- ics, 1998, 8 (6) : 503-511.
53. A.G. Casson, FRCSC, Z. Zheng, MD, D. Chiasson, BSc, et al.
Associations between genetic polymorphisms of Phase Ⅰ and Ⅱ
54. metabolizing enzymes, p53 and susceptibility to esophageal adeno carcinoma Cancer Detection and Prevention 27: (2003) 139-146
55. Hou S M, Ryberg D, Falt S, et al. GSTM1 and NAT2 polymorphi- sms in operable and non operable lung cancer patients [J]. Carcino- genesis, 2000, 21 (1) :49-54.
56. Hengstler J G, Arand M, Herrero M E, et al. Polymorphisms of N-acetyl transferases, glutathione S transferases, microsomal epoxide hydrolase and sulfotransferases: influence on cancer susceptibility [J.] Recent Results Cancer Res, 1998, 154 (1) :47-85.
57. Mollrup S, Ryber D, Hewer A, et al. Sex differences in lung CYP 1A1 expression and DNA adduct levels among lung cancer patients [J]. Cancer Res., 1999, 59 (14) : 3317-3320.
58. Senqing Chena, Kaixian Xuea, Lin Xub, et al. Polymorphisms of the CYP1A1 and GSTM1 genes in relation to individual susceptibility to lung carcinoma in Chinese population [J] Mutation Research Genomics 458: (2001) 41-47
59. Hou S M, Ryberg D, Falt S, et al. GSTM1 and NAT2 polymorphis- ms in operable and non operable lung cancer patients [J]. Carcinogen- esis, 2000, 21 (1) :49-54.
60. Rainer Tuominen, Margareta Warholm, Lennart Mo ller, et al. Constitutive CYP1B1 mRNA expression in human blood mononuclear cells in relation to gender, genotype, and environmental factors [J] Environmental Research 93: (2003) 138 - 148
61. K. Mace, E.D. Bowman, P. Vautravers, et al. Characterisation of Xenobiotic-metabolising Enzyme Expression in Human Bronchial Mucosa and Peripheral Lung Tissues [J] European Journal of Cancer, Vol. 34, No. 6, pp. 914-920, 1998
62. L. Quinfonesa, F. Berthoub, N. Varela, et al. Ethnic susceptibility to lung cancer: differences in CYP2E1, CYP1A1 and GSTM1 genetic
polymorphisms between French Caucasian and Chilean populations [J] Cancer Letters 141 (1999) 167-171
63. Kawjiri K, Eguchi H, Nakachi K, et al. Association of CYP1A1 germline Polymorphisms with mutation of p53 gene in lung cancer [J]. Cancer Res., 1996,56 (1) : 72-76.
2．曾益新 吕有勇 朱明华等 肿瘤学．北京人民卫生出版社 1999 10-13
3．冷曙光，宋文佳 肺癌易感性与外源性化学物代谢酶基因多态性的关系 国外医学卫生学分册 2001 28：(1) 38-45
4．顾艳斐，赖百塘，张树才 代谢酶基因多态性与肺癌易感性关系的研究进展 中国肺癌杂志 5 (2)：2002 4 149-151
5．朱文昌，陈清 肺癌易感性相关基因研究进展 肿瘤防治杂志 8：(5)452-455 Oct．2001．Vol．8 No．5
6. Alexandrov K., Rojas M., Geneste O. et al. An improved fluoro- metric assay for dosimetry of benzo[a]pyrene diol-epoxide-DNA adducts and in smoker's lung: comparison with total bulky adducts and aryl hydrocarbon hydroxylase activity. Cancer Res., 52:6248- 6253, 1992.
7. Margarita Rojas, Ingolf Cascorbi, Kroum Alexandrov, et al. Modulation of benzo[a]pyrene diolepoxide-DNA adduct levels in human white blood cells byCYP1A1, GSTM1 and GSTT1 polymorphism Carcinogenesis 21(1): 35-41, 2000.
8. Rojas M, Cassorbil, Alexandrov K. Modulation of benzo[a] pyrendiol epoxide DNA adduct levels in human white blood cells by CYP1A1 GSTM1 and GSTT1 Polymorphisms [J]. Carcinogenesis, 2000, 21 (1) : 35-41.
9. P. Apostoli, G. Neri, D. Lucas, et al. Influence of genetic polymorphisms of CYP1A1 and GSTM1 on the urinary levels of 1-hydroxypyrene [J] Toxicology Letters 144: (2003) 27-34
10. McClellan R. O. Tobacco-specific N-nitrosamines Recent Adv. [J] Crit Toxicol., 26:119-253,1996
11. Hecht S. S. DNA adduct formation from tobacco-specific N-nitrosamines. [J] Mutat. Res., 424: 127-142, 1999.
12. Hecht S. S. Tobacco smoke carcinogens and lung cancer. [J] Natl. Cancer Inst., 91:1194-1210, 1999.
13. Donghui Li, Pervez F. Firozi, Weiqing Zhang, et al. DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer [J] Mutation Research 513 : (2002) 37-48
14. Kriek E., Rojas M., Alexandrov K. et al. Polycyclic aromatic hydrocarbon-DNA adducts in humans: relevance as biomarker for exposure and cancer risk. Mutat. Res., 400: 215-231, 1998.
15. Joo Paulo Teixeira, Jorge Gaspar, Gabriela Martinho, et al. Aromatic DNA adduct levels in coke oven workers: correlation with polymorphisms in genes, GSTM1, GSTT1 andCYP1A1 [J] Mutation Research 517 (2002) 147-155
16. Nair. J., Barbin A., Velic I., Bartsh H. Eheno DNA-base adducts from endogenous reactive species. [J] Mutat Res., 424:59-69, 1999
17. Butiewicz D, Cole K J, Phillips D H, et al. GSTM1, GSTP1, CYP1A1 and CYP2D6 Polymorphisms in lung cancer patients from an environmentally polluted region of Poland: correlation with lung DNA adduct levels [J]. Eur. J. Cancer Prev, 1999,8 (4) : 315-323.
18. R.S.Houlston Glutathione S-Transferase M1 Status and Lung cancer risk [J] Cancer Epidemiology Biomarkers & prevention 8: 675-682, August 1999
19．程家蓉 关赛芳 王学勤等 人口腔细胞P450、GST基因多态性研究 肿瘤 2002，22(3)：242～245
20. Nang Song, Wen Tan, Deyin, et al. CYP1A1 polymorphism and risk of lung cancer in relation to tobacco smoking: a case-control study in china [J] Carcinogenesis 2001, 22 (1) : 11-16,
21．瞿永华 石于波 钟礼杰等 华人 GSTM1，CYP1A1 2E1和APOE等等位基因的基因型 肿瘤 1998，18(1)：17～20
22．支气管肺泡灌洗液细胞学检测技术规范(草案) 中华医学会呼吸病学分会制定 中华结核和呼吸杂志 2002，25(7)：390-341
23．胡毅玲 高扬 张桥等 细胞色素P450 1A1、2D6和谷胱甘肽硫转移酶基因多态性与肺癌易感性的研究 肿瘤 1998，18(7)：269～271
24．章龙珍 王绪 郝兴芝等，CYP1A1、GSTM1基因多态性与肺癌易感性的研究 中国肿瘤临床 29：(8)536-540，2002
25．张吉凯 胡毅玲 胡巢凤等 谷胱甘肽硫转移酶M1和T1基因多态与肺癌易感性关系的研究 中国病理生理杂志 2002，18(4)：352～355
26．邬洪梁 陈迈群 周四保等．湖南土家族、苗族人群 GSTM1 基因多态性研究 湖南医学 2001，18(1)：17～19
27. Mariko Murataa,b, Masatoshi Watanabea, Mikio Yamanakaa, et al. Genetic polymorphisms in cytochrome P450 (CYP) 1A1, CYP1A2, CYP2E1, glutathione S-transferase (GST) M1 and GSTT1 and susceptibility to prostate cancer in the Japanese population [J] Cancer Letters (2001) 165 : 171-177
28. Nakachi K, I mai K, Hayashi S , et al. Polymorphisms of the CYP1A1 and glutathione S transferases genes associated with susceptibility to lung cancer inralation to cigarette dose in a Japanese population [J].Cancer Res, 1993, 53 (13) :2994-2999.
29. Hayashis S, Watanabe J,Kawajiri K. High susceptibility to lung cancer analyzed in terms of P450 1A1 and mu-class glutathione S-transferase genes. [J] Jpn J Cancer Res, 1992, 83:866
30. Loc Le Marchand, Lskahmi Sivaraman, Lisa Pierce, et al. Assications of CYP1A1, GSTM1, and CYP2E1 polymorphisms wish lung cancer suggest cell type specificities to tobacco caocinogens [J] Cancer Research 58:4858-4863,Nov. 1998
31. Blanca Laffon, Beatriz Pe'rez-Cadah, Eduardo Pa'saro, et al.
32. Individual sensitivity to DNA damage induced by styrene in vitro: influence of cytochrome P450, epoxide hydrolase and glutathione S-transferase genotypes [J] Toxicology (2003) 186: 131--141
33. Valle Nazar-Stewart, Thomas L. Vaughan, Patricia Stapleton, et al. A population-based study of glutathione S-transferase M1, T1 and P1
genotypes and risk for lung cancer [J] Lung Cancer 40 (2003) 247-258
34. Mark J. Rotha, Sanford M. Dawseya, Guo-Qing Wang, et al. Association between GSTM1~*0 and squamous dysplasia of the esophagus in the high risk region of Linxian, [J] China Cancer Letters 156 (2000) 73-81
35. Matthias Hahna, Gunnar Hagedornb, Eberhard Kuhlischc, et al. Genetic polymorphisms of drug-metabolizing enzymes and suscep- tibility to oral cavity cancer [J] Oral Oncology 38 (2002) 486- 490
36．瞿永华 石于波 钟礼杰等 非吸烟女性肺病癌患者细胞色素P4501A1和GSTM1的基因型 肿瘤 1998，18(2)：80～83
37. Hirvoen A, Husgafvel-Pursiainen K,Karjalainen A, et al. Pointmut-ational Mspl and ile-val polymorphism closely linked in the CYP 1A1 gene: lack of association with susceptibility to lung cancer in a finish study population. [J] Cancer Epidemiol Biomarkers Prev, 1992, 1:485
38. Carolyn M. Dresler, Cori Fratelli, James Babb, et al. Gender differences in genetic susceptibility for lung cancer [J] Lung Cancer 30 : (2000) 153-160
39．赵鲁抗 陈枢青 余国伟等 细胞色素P450 2C19基因多态与肺癌易感性的关系 中华结核与呼吸杂志 1999．11 22(11)：682～683
40．曹云霞 庄广伦 多囊卵巢综合征与CYP基因多态的关联性研究 现代妇产科进展 8(4)：305～308 1999．4
41．高杨，张桥 GSTM1和CYP2D6基因多态性与肺癌敏感性的关系 中国公共卫生 1999 15(6)：488-490
42．许林，陈森清，马国建等 中国人CYP1A1和GSTM1基因多态性及其对个体肺癌易感性的联合效应 中华医学遗传学杂志 18(2)：125-127 April 2001，Vol．18，No．2
43. L dia Maria da Fonte de Amorima, Ana Rossinib, Gulnar Azeve- do Silva Mendonc et al. CYP1A1, GSTM1, and GSTT1 polymorphism -s and breast cancer risk in Brazilian women [J] Cancer Letters 181: (2002) 179-186
44. Y.-W. Cheng, C.-Y. Chen, P. Lin, et al. DNA adduct level in lung tissue may act as a risk biomarker of lung cancer. [J] European Journal of Cancer
36 (2000) 1381±1388
45. T.T. Sreelekha, K. Ramadas, M. Pandey, et al. Genetic polymor- phism of CYP1A1, GSTM1 and GSTT1 genes in Indian oral cancer [J] Oral Oncology37 (2001) 593-598
46. Drakoulis N, Cascorbi I, Brockmoller J, et al. polymorphism in the human CYP1A1 gene as susceptibility factors Exon-7 mutation (4889 A to G) , and a T to C mutation in the 3'-flanking region. [J] Clin. Invest., 1994, 72:240
47. Emanuela Taioli, Daniela Mari, Claudio Franceschi, et al. Polymorphisms of Drug-Metabolizing Enzymes in Healthy Nonagenarians and Centenarians: Difference at GSTT1 Locus [J] Biochemical and Biophysical Research Communications 280:1389-1392 (2001)
48. J.J. Yim, G.G.Yoo, C.-T. Lee, et al. Lack of association between glutathione S-transferase P1 polymorphism and COPD in Koreans [J] Lung (2002) 180:119-125
49. Paolo Vineis . The relationship between polymorphisms of xenobio -tic metabolizing enzymes and susceptibility to cancer [J] Toxicology 181-182: (2002) 457-462
50. M. Adonis, V. Martnez, R. Riquelme, Susceptibility and expo- sure biomarkers in people exposed to PAHs from diesel exhaust. [J] Toxicology Letters 144: (2003) 3-15
51. Hitoshi Ishikawa, Hidetaka Yamamoto, Ying Tian, et al. Evidence of association of the CYP2E1 genetic polymorphism with micronuclei frequency in human peripheral blood [J] Mutation Research 546: (2004) 45-53
52. Przygodzki R M, Bennett W P, Guinee D G,et al. p53 mutation spec-trum in relation to GSTM1, CYP1A1 and CYP2E1 in surgically treat-ed patients with non small cell lung cancer [J]. Pharmacogenet- ics, 1998, 8 (6) : 503-511.
53. A.G. Casson, FRCSC, Z. Zheng, MD, D. Chiasson, BSc, et al.
Associations between genetic polymorphisms of Phase Ⅰ and Ⅱ
54. metabolizing enzymes, p53 and susceptibility to esophageal adeno carcinoma Cancer Detection and Prevention 27: (2003) 139-146
55. Hou S M, Ryberg D, Falt S, et al. GSTM1 and NAT2 polymorphi- sms in operable and non operable lung cancer patients [J]. Carcino- genesis, 2000, 21 (1) :49-54.
56. Hengstler J G, Arand M, Herrero M E, et al. Polymorphisms of N-acetyl transferases, glutathione S transferases, microsomal epoxide hydrolase and sulfotransferases: influence on cancer susceptibility [J.] Recent Results Cancer Res, 1998, 154 (1) :47-85.
57. Mollrup S, Ryber D, Hewer A, et al. Sex differences in lung CYP 1A1 expression and DNA adduct levels among lung cancer patients [J]. Cancer Res., 1999, 59 (14) : 3317-3320.
58. Senqing Chena, Kaixian Xuea, Lin Xub, et al. Polymorphisms of the CYP1A1 and GSTM1 genes in relation to individual susceptibility to lung carcinoma in Chinese population [J] Mutation Research Genomics 458: (2001) 41-47
59. Hou S M, Ryberg D, Falt S, et al. GSTM1 and NAT2 polymorphis- ms in operable and non operable lung cancer patients [J]. Carcinogen- esis, 2000, 21 (1) :49-54.
60. Rainer Tuominen, Margareta Warholm, Lennart Mo ller, et al. Constitutive CYP1B1 mRNA expression in human blood mononuclear cells in relation to gender, genotype, and environmental factors [J] Environmental Research 93: (2003) 138 - 148
61. K. Mace, E.D. Bowman, P. Vautravers, et al. Characterisation of Xenobiotic-metabolising Enzyme Expression in Human Bronchial Mucosa and Peripheral Lung Tissues [J] European Journal of Cancer, Vol. 34, No. 6, pp. 914-920, 1998
62. L. Quinfonesa, F. Berthoub, N. Varela, et al. Ethnic susceptibility to lung cancer: differences in CYP2E1, CYP1A1 and GSTM1 genetic
polymorphisms between French Caucasian and Chilean populations [J] Cancer Letters 141 (1999) 167-171
63. Kawjiri K, Eguchi H, Nakachi K, et al. Association of CYP1A1 germline Polymorphisms with mutation of p53 gene in lung cancer [J]. Cancer Res., 1996,56 (1) : 72-76.