CYP2A6、CYP1B1和GSTT1基因多态性与人肺癌遗传易感性关系研究
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摘要
背景与目的 肺癌是发病率和死亡率增长最快,对人类健康和生命威胁最大的恶性肿瘤。肺癌已成为我国恶性肿瘤死因的首位。吸烟、职业暴露、环境污染等被认为是肺癌的危险因素。尽管绝大多数肺癌的发生与这些因素相关,但是仅有15%的吸烟者最终发生肺癌,有不足10%的肺癌患者则从不吸烟,而且生活在同一污染环境中的人群仅有小部分发生肺癌。产生这一结果的原因与人群或/和个体肿瘤易感性有关,即不同人群或/和个体对环境致癌物致癌的易患性不同。与肿瘤遗传易感性相关的基因主要有有两大类,即Ⅰ相与Ⅱ相代谢酶基因。这些基因均存在着遗传多态性,它们的产物往往具有不同的生物学活性,从而表现为机体对同一化学致癌物的易感性不同。
本研究首次通过病例-对照PCR-RFLP的方法研究CYP2A6、CYPlBl和GSTTl基因多态性与中国四川汉族人群患肺癌的易感性的关系,并
Background and Objective Lung cancer is the most common malignant tumor which its incidence and mortality are increasing rapidness, and threaten the health and life of human furthest. Lung cancer is the first killer of cancer-related deaths both in men and women in the world. Cigarette smoking, various occupational exposures and carcinogens in heavily polluted air are the risk factors to lung cancer. Although it is well recognized that most of lung cancer are attributable to these factors, only 15% of all smokers develop lung cancer and under 10% of all diagnosed lung cancer are among never smokers. Genetic susceptibility is one of primary hypotheses used to explain why a minority of smokers develop lung cancer. Genetic polymorphism in metabolic enzyme gene, which are involved in the
metabolism of environmental carcinogens, have been thought to be related to the susceptibility of lung cancer. There are two kinds of genes related to tumor susceptibility, namely phase I and phase II metabolic enzyme genes. All the metabolic enzyme genes have polymorphisms, and their products have different biologic activity, therefore the body have different susceptibility to cancer in different people or different individuals.Up to now, we have not seen any reports on the relationship between the genetic polymorphisms of CYP2A6, CYP1B1 and GSTT1 gene and lung cancer susceptibility of the Chinese Han Nationality population in Sichuan province in the world. Our study is the first one using case-control and restriction fragment length polymorphism ( PCR-RFLP) method to investigate the distribution and characteristics of CYP2A6, CYP1B1 and GSTT1 genetic polymorphisms, and the relationship between genetic polymorphisms of CYP2A6, CYP1B1 and GSTT1 gene and lung cancer susceptibility in Chinese Han Nationality population of Sichuan province in China. The key aim of this study are as follows:(1) to evaluate the potential role of separate single CYP2A6, CYP1B1 and GSTT1 genetic polymorphisms on lung cancer susceptibility; (2) to evaluate the potential role of the combination of CYP2A6, CYP1B1 and GSTT1 genetic polymorphisms on lung cancer susceptibility; (3) the interactions between genetic polymorphisms and smoking on lung cancer susceptibility. The results of this study firstly showed in the world as follows: 1 .The frequency of CYP2A6wt and CYP2A6del genotype was 96.0% and 4.0% in lung cancer group, and 87.5% and 12.5% in control group respectively. A highly significant difference was found between the two
groups ft2=7.184, /*=0.007).2.The results of Binary Logistic Regression showed that the people who carried with CYP2A6wt genotype had a 3.756 fold increased risk of lung cancer than those who carried with CYP2A6del genotype(95%CI=1.387~ 10.171, P=0.009).3.The people who carried with CYP2A6wt genotype had a 7.511 fold increased risk of SCC than those who carried with CYP2A6del genotype (95 %CI=1.601—35.230, P=0.011).4.The smokers who carried with CYP2A6wt genotype had a 28.879 fold increased risk of lung cancer than those who carried with CYP2A6del genotype(95%CI=3.537~235.763, P=0.002).5.The smokers who carried with CYP2A6wt genotype had a 10.307 fold increased risk of lung cancer than the nonsmokers who carried with CYP2A6wt genotype (95 %CI=5.199~20.434, P=0.000).6.The heavy smokers(YP^20) who carried with CYP2A6wt genotype had a 23.100 fold increased risk of lung cancer than those who carried with CYP2A6del genotype (95%CI=2.680~199.142, i>=0.004).7.The frequency of CYP1B1(C/C) and CYP1B1(G/C+G/G) genotypes was 67.3% and 32.7% in lung cancer group, and 71.9% and 28.3% in control group respectively. No significant difference was found between the two groups (x2=0.683, i>=0.409).8.No significant difference was found between the people who carried with CYP1B1(G/C+G/G) genotype and those people who carried with CYPlBl(C/C)genotype(OR=1.514, 95%CI=0.883~2.596, P=0.l32).9.No significant difference were found among polymorphisms of
CYP1B1 Val432Leu and the SCC(OR=2.012, 95 % Cl=0.957 - 4.234, P=0.065), AD(OR=1 474, 95%CI=0.727~2.988, P=0.282) and Other type lung cancer risk (OR-1.830, 95%CI=0.646—5.178, P=0.255).lO.The smokers who carried with CYP1B1(G/C+G/G) genotype had a 2.521 fold increased risk of lung cancer than those who carried with CYP1B1(C/C) genotype(95%CI=1.046~6.080, P=0.039).11.The smokers who carried with CYP1B1(C/C) genotype had a 5.764 fold increased risk of lung cancer than the nonsmokers who carried with CYP1B1(C/C) genotype (95%CI=2.690~12.350,P=0.000); The smokers who carried with CYP1B1(G/C+G/G) genotype had a 12.093 fold increased risk of lung cancer than the nonsmokers who carried with CYP1B1(G/C+G/G) genotype (95 %CI=3.713~39.388,P=0.000).12.The heavy smokers(YP^20) who carried with CYP1B1(G/C+G/G) genotype had a 4.762 fold increased risk of lung cancer than those who carried with CYP1B1(C/C) genotype (95 %CI= 1.300—17.444, /M).O18).13.The frequency of GSTT1(+) and GSTTl(-) genotype was 45.3% and 54.7% in lung cancer group, and 61.8% and 38.2% in control group respectively. A highly significant difference was found between the two groups (x2=8.274, P=0.004).14.The people who carried with GSTTl(-) genotype had a 1.715 fold increased risk of lung cancer than those who carried with GSTT1(+) genotype (95%CI= 1.038-2.853, P=0.038).15.The people who carried with GSTTl(-) genotype had a 2.565 (95% CI= 1.323-4.975, P=0.005) fold increased risk of SCC and 2.149 (95%CI = 0.365—2.863, ^=0.966) fold increased risk of AD than those who
carried with GSTT1(+) genotype.16.The smokers who carried with GSTTl(-) genotype had a 4.088 fold increased risk of lung cancer than those who carried with GSTT1(+) genotype (95%CI= 1.977—8.454, i>=0.000).17.The smokers who carried with GSTTl(-) genotype had a 58.518 fold increased risk of lung cancer than the nonsmokers who carried with GSTTl(-) genotype (95%CI= 12.868-266.119, />=0.000).18.The light smokers(YP<20) who carried with GSTTl(-) genotype had a 3.294 fold increased risk of lung cancer than those who carried with GSTT1(+) genotype(95 % CI = 1.022 -10.619, P =■ 0.046). The heavy smokers(YP$:20) who carried with GSTTl(-) genotype had a 4.296 fold increased risk of lung cancer than those who carried with GSTT1(+) genotype(95%CI= 1.649-11.190, P=0.003).19.The individuals who carried with combination of CYP2A6wt/GSTTl(+) and CYP2A6wt/GSTTl(-) genotypes had a 4.444(95%CI=1.240~ 15.926, P=0.022) and 11.782(95%CI = 2.955-46.985, P=0.000) fold increased risk of lung cancer than those who carried with combination of CYP2A6del /GSTT1(+) genotype respectively.2O.The smokers who carried with combination of CYP2A6wt/GSTTl(+) and CYP2A6wt/GSTTl(-) genotypes had a 13.739 (95%CI=1.396—98.737, P=0.023) fold and 46.255(95%CI =5.314-402.584, P=0.00l) fold increased risk of lung cancer than those carried with combination of CYP2A6del/GSTTl(+) genotype respectively.21.The individuals who carried with combination of CYP1B1 (C/C)/GSTT1(-) and CYP1B1(G/C+G/G)/GSTT1(-) genotypes had a
1.915(95%CI=1.023-3.584, P=0.042) and 2.328(95%CI =1.146-4.728, P=0.019) fold increased risk of lung cancer than those who carried with combination of CYP1B1(C/C)/GSTT1(+) genotype respectively.22.The smokers who carried with combination of CYP1B1(C/C)/ GSTTl(-) and CYP1B1(G/C+G/G)/GSTT1(-) genotypes had a 4.592 (95%CI=2.024 — 10.415, /M).000) and 6.612 (95%CI=2.110-20.724, P=0.001) fold increased risk of lung cancer than those who carried with combination of CYP1B1(C/C)/GSTT1(+) genotype respectively.23 .The individuals who carried with combination of CYP2A6wt/ CYP1B1 (C/C) and CYP2A6wt/CYPlBl(G/C+G/G) genotypes had a 4.568 (95%CI=1.417—14.722, P=0.011) and 6.058 (95%CI=1.714-21.407, />=0.005) fold increased risk of lung cancer than those who carried with combination of CYP1B1(C/C)/GSTT1(+) genotype respectively.Conclusion: (1) CYP2A6wt genotype remarkably increases lung cancer susceptibility of Sichuan Han Nationality population in China, especially increases SCC susceptibility. In addition, a close interaction was existed between CYP2A6wt and smoking in the oncogenesis of lung cancer. (2) CYP1B1(G/C+G/G) genotype remarkably increases lung cancer susceptibility in the smokers of Sichuan Han Nationality population in China. Moreover, a close interaction was existed between CYP1B1(G/C+G/G) genotype and smoking in the oncogenesis of lung cancer. (3) GSTTl(-) genotype remarkably increases SCC and AD susceptibility of Sichuan Han Nationality population in China, especially increases lung cancer susceptibility in smokers. Moreover, there is a close interaction between GSTTl(-) genotype and smoking in the oncogenesis of lung cancer. (4) The
combination of CYP2A6wt/GSTTl(+) , CYP2A6wt/GSTTl(-) > CYP1B1(C/C)/ GSTTl(-) and CYP1B1(G/C+G/G)/GSTT1(-) genotypes remarkably increases lung cancer susceptibility of Sichuan Han Nationality population in China respectively, especially increases lung cancer susceptibility in smokers. Moreover, there are close interactions between these genotypes and smoking in the oncogenesis of lung cancer. (5)The individuals who carried with combination of CYP2A6wt/CYPlBl(C/C) and CYP2A6wt/CYPlBl(G/C+G/G) genotypes remarkably increase lung cancer susceptibility of Sichuan Han Nationality population in China respectively. (6) CYP2A6wt genotype is the strongest genotype in increasing lung cancer risk of Sichuan Han Nationality population in China in our study, the GSTTl(-) genotype take second place, and the role of CYP1B1(G/C+G/G) genotype is unclear.
本研究首次通过病例-对照PCR-RFLP的方法研究CYP2A6、CYPlBl和GSTTl基因多态性与中国四川汉族人群患肺癌的易感性的关系,并
Background and Objective Lung cancer is the most common malignant tumor which its incidence and mortality are increasing rapidness, and threaten the health and life of human furthest. Lung cancer is the first killer of cancer-related deaths both in men and women in the world. Cigarette smoking, various occupational exposures and carcinogens in heavily polluted air are the risk factors to lung cancer. Although it is well recognized that most of lung cancer are attributable to these factors, only 15% of all smokers develop lung cancer and under 10% of all diagnosed lung cancer are among never smokers. Genetic susceptibility is one of primary hypotheses used to explain why a minority of smokers develop lung cancer. Genetic polymorphism in metabolic enzyme gene, which are involved in the
metabolism of environmental carcinogens, have been thought to be related to the susceptibility of lung cancer. There are two kinds of genes related to tumor susceptibility, namely phase I and phase II metabolic enzyme genes. All the metabolic enzyme genes have polymorphisms, and their products have different biologic activity, therefore the body have different susceptibility to cancer in different people or different individuals.Up to now, we have not seen any reports on the relationship between the genetic polymorphisms of CYP2A6, CYP1B1 and GSTT1 gene and lung cancer susceptibility of the Chinese Han Nationality population in Sichuan province in the world. Our study is the first one using case-control and restriction fragment length polymorphism ( PCR-RFLP) method to investigate the distribution and characteristics of CYP2A6, CYP1B1 and GSTT1 genetic polymorphisms, and the relationship between genetic polymorphisms of CYP2A6, CYP1B1 and GSTT1 gene and lung cancer susceptibility in Chinese Han Nationality population of Sichuan province in China. The key aim of this study are as follows:(1) to evaluate the potential role of separate single CYP2A6, CYP1B1 and GSTT1 genetic polymorphisms on lung cancer susceptibility; (2) to evaluate the potential role of the combination of CYP2A6, CYP1B1 and GSTT1 genetic polymorphisms on lung cancer susceptibility; (3) the interactions between genetic polymorphisms and smoking on lung cancer susceptibility. The results of this study firstly showed in the world as follows: 1 .The frequency of CYP2A6wt and CYP2A6del genotype was 96.0% and 4.0% in lung cancer group, and 87.5% and 12.5% in control group respectively. A highly significant difference was found between the two
groups ft2=7.184, /*=0.007).2.The results of Binary Logistic Regression showed that the people who carried with CYP2A6wt genotype had a 3.756 fold increased risk of lung cancer than those who carried with CYP2A6del genotype(95%CI=1.387~ 10.171, P=0.009).3.The people who carried with CYP2A6wt genotype had a 7.511 fold increased risk of SCC than those who carried with CYP2A6del genotype (95 %CI=1.601—35.230, P=0.011).4.The smokers who carried with CYP2A6wt genotype had a 28.879 fold increased risk of lung cancer than those who carried with CYP2A6del genotype(95%CI=3.537~235.763, P=0.002).5.The smokers who carried with CYP2A6wt genotype had a 10.307 fold increased risk of lung cancer than the nonsmokers who carried with CYP2A6wt genotype (95 %CI=5.199~20.434, P=0.000).6.The heavy smokers(YP^20) who carried with CYP2A6wt genotype had a 23.100 fold increased risk of lung cancer than those who carried with CYP2A6del genotype (95%CI=2.680~199.142, i>=0.004).7.The frequency of CYP1B1(C/C) and CYP1B1(G/C+G/G) genotypes was 67.3% and 32.7% in lung cancer group, and 71.9% and 28.3% in control group respectively. No significant difference was found between the two groups (x2=0.683, i>=0.409).8.No significant difference was found between the people who carried with CYP1B1(G/C+G/G) genotype and those people who carried with CYPlBl(C/C)genotype(OR=1.514, 95%CI=0.883~2.596, P=0.l32).9.No significant difference were found among polymorphisms of
CYP1B1 Val432Leu and the SCC(OR=2.012, 95 % Cl=0.957 - 4.234, P=0.065), AD(OR=1 474, 95%CI=0.727~2.988, P=0.282) and Other type lung cancer risk (OR-1.830, 95%CI=0.646—5.178, P=0.255).lO.The smokers who carried with CYP1B1(G/C+G/G) genotype had a 2.521 fold increased risk of lung cancer than those who carried with CYP1B1(C/C) genotype(95%CI=1.046~6.080, P=0.039).11.The smokers who carried with CYP1B1(C/C) genotype had a 5.764 fold increased risk of lung cancer than the nonsmokers who carried with CYP1B1(C/C) genotype (95%CI=2.690~12.350,P=0.000); The smokers who carried with CYP1B1(G/C+G/G) genotype had a 12.093 fold increased risk of lung cancer than the nonsmokers who carried with CYP1B1(G/C+G/G) genotype (95 %CI=3.713~39.388,P=0.000).12.The heavy smokers(YP^20) who carried with CYP1B1(G/C+G/G) genotype had a 4.762 fold increased risk of lung cancer than those who carried with CYP1B1(C/C) genotype (95 %CI= 1.300—17.444, /M).O18).13.The frequency of GSTT1(+) and GSTTl(-) genotype was 45.3% and 54.7% in lung cancer group, and 61.8% and 38.2% in control group respectively. A highly significant difference was found between the two groups (x2=8.274, P=0.004).14.The people who carried with GSTTl(-) genotype had a 1.715 fold increased risk of lung cancer than those who carried with GSTT1(+) genotype (95%CI= 1.038-2.853, P=0.038).15.The people who carried with GSTTl(-) genotype had a 2.565 (95% CI= 1.323-4.975, P=0.005) fold increased risk of SCC and 2.149 (95%CI = 0.365—2.863, ^=0.966) fold increased risk of AD than those who
carried with GSTT1(+) genotype.16.The smokers who carried with GSTTl(-) genotype had a 4.088 fold increased risk of lung cancer than those who carried with GSTT1(+) genotype (95%CI= 1.977—8.454, i>=0.000).17.The smokers who carried with GSTTl(-) genotype had a 58.518 fold increased risk of lung cancer than the nonsmokers who carried with GSTTl(-) genotype (95%CI= 12.868-266.119, />=0.000).18.The light smokers(YP<20) who carried with GSTTl(-) genotype had a 3.294 fold increased risk of lung cancer than those who carried with GSTT1(+) genotype(95 % CI = 1.022 -10.619, P =■ 0.046). The heavy smokers(YP$:20) who carried with GSTTl(-) genotype had a 4.296 fold increased risk of lung cancer than those who carried with GSTT1(+) genotype(95%CI= 1.649-11.190, P=0.003).19.The individuals who carried with combination of CYP2A6wt/GSTTl(+) and CYP2A6wt/GSTTl(-) genotypes had a 4.444(95%CI=1.240~ 15.926, P=0.022) and 11.782(95%CI = 2.955-46.985, P=0.000) fold increased risk of lung cancer than those who carried with combination of CYP2A6del /GSTT1(+) genotype respectively.2O.The smokers who carried with combination of CYP2A6wt/GSTTl(+) and CYP2A6wt/GSTTl(-) genotypes had a 13.739 (95%CI=1.396—98.737, P=0.023) fold and 46.255(95%CI =5.314-402.584, P=0.00l) fold increased risk of lung cancer than those carried with combination of CYP2A6del/GSTTl(+) genotype respectively.21.The individuals who carried with combination of CYP1B1 (C/C)/GSTT1(-) and CYP1B1(G/C+G/G)/GSTT1(-) genotypes had a
1.915(95%CI=1.023-3.584, P=0.042) and 2.328(95%CI =1.146-4.728, P=0.019) fold increased risk of lung cancer than those who carried with combination of CYP1B1(C/C)/GSTT1(+) genotype respectively.22.The smokers who carried with combination of CYP1B1(C/C)/ GSTTl(-) and CYP1B1(G/C+G/G)/GSTT1(-) genotypes had a 4.592 (95%CI=2.024 — 10.415, /M).000) and 6.612 (95%CI=2.110-20.724, P=0.001) fold increased risk of lung cancer than those who carried with combination of CYP1B1(C/C)/GSTT1(+) genotype respectively.23 .The individuals who carried with combination of CYP2A6wt/ CYP1B1 (C/C) and CYP2A6wt/CYPlBl(G/C+G/G) genotypes had a 4.568 (95%CI=1.417—14.722, P=0.011) and 6.058 (95%CI=1.714-21.407, />=0.005) fold increased risk of lung cancer than those who carried with combination of CYP1B1(C/C)/GSTT1(+) genotype respectively.Conclusion: (1) CYP2A6wt genotype remarkably increases lung cancer susceptibility of Sichuan Han Nationality population in China, especially increases SCC susceptibility. In addition, a close interaction was existed between CYP2A6wt and smoking in the oncogenesis of lung cancer. (2) CYP1B1(G/C+G/G) genotype remarkably increases lung cancer susceptibility in the smokers of Sichuan Han Nationality population in China. Moreover, a close interaction was existed between CYP1B1(G/C+G/G) genotype and smoking in the oncogenesis of lung cancer. (3) GSTTl(-) genotype remarkably increases SCC and AD susceptibility of Sichuan Han Nationality population in China, especially increases lung cancer susceptibility in smokers. Moreover, there is a close interaction between GSTTl(-) genotype and smoking in the oncogenesis of lung cancer. (4) The
combination of CYP2A6wt/GSTTl(+) , CYP2A6wt/GSTTl(-) > CYP1B1(C/C)/ GSTTl(-) and CYP1B1(G/C+G/G)/GSTT1(-) genotypes remarkably increases lung cancer susceptibility of Sichuan Han Nationality population in China respectively, especially increases lung cancer susceptibility in smokers. Moreover, there are close interactions between these genotypes and smoking in the oncogenesis of lung cancer. (5)The individuals who carried with combination of CYP2A6wt/CYPlBl(C/C) and CYP2A6wt/CYPlBl(G/C+G/G) genotypes remarkably increase lung cancer susceptibility of Sichuan Han Nationality population in China respectively. (6) CYP2A6wt genotype is the strongest genotype in increasing lung cancer risk of Sichuan Han Nationality population in China in our study, the GSTTl(-) genotype take second place, and the role of CYP1B1(G/C+G/G) genotype is unclear.
引文
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31 Wen TAN, Gen-Fu CHEN, Oe-Yin XING, et al. FREQUENCY OF CYP2A6 GENE DELETION AND ITS RELATION TO RISK OF LUNG AND ESOPHAGEAL CANCER IN THE CHINESE POPULATION. Int J Cancer (Pred. Oncol), 2001,95:96-101.
32 Messina ES, Tyndale RF, Sellers EM. A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes. J Pharmaco 1 Exp Ther, 1997,282:1608-1614.
33 Murphy SE, Johnson LM, Pullo DA. Characterization of multiple products of cytochrome P4502A6-catalyzed cotinine metabolism Chem Res Toxicol, 1999,12:639-645.
34 P ianezzaML, Sellers EM, Tyndale RF. Nicotine metabolism defect reduces smoking. Nature, 1998,393:750.
35 Stoilov I, Akarsu AN, Alozie I, et al. Sequence analysis and homology modeling suggest that primary congenital glaucoma on 2p121 results from mutations disrupting either the hinge region or the conserved core structures of cytochrome P4501B1. Am J Hum Genet, 1998, 62: 573-584.
36 Murray GI, Taylor MC, Mcfadyen NC, et al. Tumour specific expression of cytochrome P450 CYP1B1. Cancer Res, 1997,57:3026-3031.
37 Masahiro S, Masanori K, Seiichiro F, et al. CYP1B1 gene in endometrial cancer. Molecular and Cellular Endocrinology, 2003,202:171-176.
38 Bailey LR, Roodi N, Dupont WD, et al. Association of cytochrome P450 1B1(CYP1B1) polymorphism with steroid receptor status in breast cancer. Cancer Res, 1998,58(22):5038-5041.
39 Bamberger AM, Kleinkauf-Houcken A, Bamberger CM, et al.. Molecular and clinical endocrinology of the endometrium. Pathologe, 1999,20:50-55.
40 Bejjani BA, Lewis RA, Tomey KF, et al. Mutations in CYP1B1, the gene for cytochrome P450 1B1, are the predominant cause of primary congenital glaucoma in Saudi Arabia. Am J Hum Genet, 1998,62:325-333.
41 Wu MF, Wu WJ, Chang GCh, et al. Increased expression of cytochrome P4501B1 in peripheral leukocytes from lung cancer patients. Toxicology Letters, 2004,150:211-219.
42 Pinpin L, Han Ch, William L, et al. Association of aryl hydrocarbon receptor and cytochrome P4501B1 expressions in human non-small cell lung cancers. Lung Cancer, 2003, 42:255-261.
43 Lai J, Vesprini D, William Ch, et al. CYP Gene Polymorphisms and Early Menarche. Molecular Genetics and Metabolism, 2001, 74:449-457.
44 Hirvonen A. Genetic factors in individual response to environment exposure. J Occup Environ Med, 1995, 37(1): 37 —43.
45 Mcglynn KA, Buetow KH. Metabolic and H—ras polymorphisms in genetic susceptibility. Cancer Bull, 1994,46(3)220-227.
46 Bharat T, Marcia B, Pamela M, et al. CYP1B1 and CYP19 gene polymorphisms and breast cancer incidence: no association in the ARIC study. Cancer Letters, 2004,207:183-189.
47 Masahiro S, Yuichiro T, Masanori K, et al. Alleles of Polymorphic Sites That Correspond to Hyperactive Variants of CYP1B1 Protein Are Significantly Less Frequent in Japanese as Compared to American and German Populations. Mutation in Brief, 616 (2003) Online.
48 Zheng W, Xie DW, Jin F, et al. Genetic polymorphism of cytochrome P450-1B1 and risk of breast cancer. Cancer Epidemiol Biomarkers Prey, 2000,9:147-150.
49 宋南,林东昕.细胞色素P4501A1基因变异与肺癌易患性.基础医学与临床,1999,19(5):5-9.
50 刘移民,Yan Yan, Beverly D, et al.多环芳烃受体基因与细胞色素P4501A1/1B1基因表达的调控.中国职业医学,2003,30(3):10-13.
51 Lallas TA, McClain SK, Shahin MS, et al. The Glutathione S-transferase Ml genotype in ovarian cancer. Cancer Epi demiol Biomarkers Prey, 2000,9:587
52 Nelson HH, Wiencke JK, Christiani DC, et al. Ethnic differences in the prevalence of the homozygous deteted genotype of glutathione S-transferase theta. Carcinogenesis, 1995, 18(5): 1243-1245.
53 刘茶珍,边建超,江峰,等.谷胱甘肽S转移酶M1、T1和P1基因多态与肝癌易感性研究.中国公共卫生,2002,18(8):935-936.
54 Sai-Mei H, Susann F, Fredrik N. Glutathione s-transferase T1-null genotype interacts synergistically with heavy smoking on lung cancer risk. Environmental and Molecular Mutagenesis, 2001,38:83-86.
55 Lewis SJ, Cherry NM, Niven RM, et al. GSTM1, GSTT1and GSTP1 polymorphisms and lung cancerrisk. Cancer Letters, 2002, 180: 165～171.
56 梁戈玉,浦跃朴,尹立红.南京汉族群体肺癌易感性相关基因的研究.遗传,2004,26(5):584～588.
57 蓝青,何兴舟,Debra Costa,等.谷胱甘肽硫转移酶基因GSTM1及GSTT1缺失与肺癌发病关系的研究.卫生研究,1999,28(1):9～11.
58 张吉凯,胡毅玲,胡巢凤,等.GSTM1和GSTT1基因多态性与女性肺癌易感性的关系.中国公共卫生,2002,18(3):273-275.
59 Saarikoski ST, Voho A, Reinkainen M, et al. Combined effect of polymorphic GST genes on individual susceptibility to lung cancer. Int J Cancer,1998,77:516
60 刘茶珍,边建超,沈福民.毒物代谢酶基因多态性与肝癌遗传易感性研究进展.中华医学遗传学杂志,1998,15(6):3761.
61 Landi S. Mammalian class theta GST and differential susceptibility to carcinogen:a review. Mutation Res, 2000, 463:247-283.
62 Reinemer P, Dirr HW, Ladenstein R, et al. The three dimensional structure of class π glutathione-S-transferase in complex with glutathione sulfonate at 2. 3 Aring; resolution EMBO J, 1991,10:1997-2005
63 Strange RC, Spitereri MA, Ramachandran, et al. Glutathione S-transferase family of enzymes. Mutation Res, 2001,482:2-26.
64 Johansson AS, Stenberg G, Widersten M, et al. Structure activity relationships and thermal stability of human glutathione transferase P1-1 governed by the H-site residue 105. J Mol Biol, 1998, 278:687-698.
65 Cotton SC, Sharp L, Little J, et al. Glutathione Stransferase polymorphisms and colorectal cancer: a HuGE review. Am J Epidemiol, 2000, 151:7-32.
66 Tan KL, Webb GC, Baker RT, et al. Molecular cloning of a cDNA and chromosomal localization of a human theta-class glutathione S-transferase gene (GSTT2) to chromosome 22. Genomics, 1995,25:381-387.
67 Webb G, Vaska V, Coggan M, et al. Chromosomal localization of the gene for the human theta class glutathione transferase (GSTT1). Genomics, 1996,33:121-123.
68 Nelson HH, Wiencke JK, Christiani DC, et al. The prevalence of the homozygous deleted genotype of glutathione S-transferase theta. Carcinogenesis, 1995,16(5):1243-1245.
69 林国芳,谭靖伟,沈建华,等.上海正常人中谷胱甘肽S-转移酶T1基因纯合性缺失[J].癌变.畸变.突变,1998,10(6):345-348
70 杨洁,石宏,董永利,等.云南24个民族群体GSTT1、GSTM1纯合缺失基因型频率的分布.中华医学遗传学杂志,2003,20(1):9-11.
71 Meyer DJ. Theta, a new class of glutathione transferases purified from rat and man. BiochemJ, 1991,274 (Pt2):4091.
72 Dremble S. Human glutathione S-transferase theta (GSTT1):cDNA cloning and the characterization of agenetic polymorphism. Biochem J, 1994,300 (Pt1),2711.
73 Wilce MC, Parker MW.Structure and function of glutathione S-transferase. Biochem Biophys Acta, 1994,120 5(1): 1～181.
74 董传辉,资晓林,愈顺章,等.谷胱甘肽S-转移酶T1基因缺失与肝癌易患性关系的研究.中华公共卫生学报,1997,16(2):1411
75 Bian JC, Shen FM, Shen L, et al. Susceptibility to hepatocellular carcinoma associated with null genotypes of GSTM1 and GSTT1. World J Gastroentero, 2000, 6(2):2281
76 Tiemersma EW, Omer RE, Bunschoten A, et al. Role of genetic polymorphismof glutathione-S-transferase T1 and microsomal epoxide hydyolase in aflatoxin-associated hepatocellular carcinoma. Cancer Epidemiol Biomarkers Prey, 2001, 10(7):7851.
77 钱云,徐耀初,沈洪兵,等.CYP2E1、GSTT1基因多态性与胃癌易感性的关系.中国慢性病预防与控制,2003,11(3):107-109.
78 Jourenkova N, Reinikanen M, Bouchardy C, et al. Effects of glutathione S-transferases GSTM1 and GSTT1 genotypes on lung cancer risk in smokers. Pharmacogenetics, 1997,7:515-518.
79 Saarikoski ST, Yoho A, Reinikainen M, et al. Combined effect of polymorphic GST genes on individual susceptibility to lung cancer. Int J Cancer 1998,77:516-521.
80 Simonato L, Agudo A, Ahrens W, et al. Lung cancer and cigarette smoking in Europe:An update of risk estimates and an assessment of inter-country heterogeneity. Int J Cancer, 2001,91:876-887.
81 Katoh T, Kaneko S, Kohshi K, et al. Genetic polymorphisms of tobacco-and alcohol-related metabolizing enzymes and oral cavity cancer. Int J Cancer, 1999,83:606-609.
82 Kelsey KT, Spitz MR, Zuo ZF, et al. Polymorphisms in the glutathione S-transferase class mu and theta genes interact and increase susceptibility to lung cancer in minority populations (Texas, United States). Cancer Causes Control, 1997, 8:554-559.
83 Zein R, Conforti-Froes N, Au WW. Interactions between genetic predisposition and environmental toxicants for development of lung cancer. Environ Mol Mutagen, 1997, 30:196-204.
84 Conforti-Froes N, Zein R, Abdel-Rahman SZ, et al. Predisposing genes and increased chromosome aberrations in lung cancer cigarette smokers. Mutat Res, 1997,379:53-59.
85 Zein R, Zwischenberger JB, Wood TG, et al. Combined genetic polymorphism and risk for development of lung cancer. Mutat Res, 1997,381:189-200.
86 Joachim S, Ulrike B, Monika P, et al. GSTM1, GSTT1, and GSTP1 polymorphism and lung cancer risk in relation to tobacco smoking. Cancer Letters, 2004,208:65-74.
87 Yu MW, Gladek-Yarborough A, Chiamprasept S, et al. Cytoch-rome P450 2E1 and glutathione S-transferase M1 polymorphisms and susceptibility to hepatocellular carcinoma. Gastroenterology, 1995, 109: 1266-1273.
88 Nimura Y, Yokoyama S, Fujimori M, et al. Genotyping of the CYP1A1 and GSTM1 genes in esophageal carcinoma patients with special reference to smoking. Cancer, 1997, 80:852-857.
89 瞿永华,石于波,钟礼杰,等.非吸烟女性肺癌患者细胞色素P4501A1和GSTM1的基因型.肿瘤,1998,18:80-82.
90 瞿永华,石于波,钟礼杰,等.华人GSTM1,CYP1A1与2E1和APOE等位基因的基因型.肿瘤,1998,18:17-19.
91 陈森清,许林,马建国等应用等位基因特异性PCR和多重差别PCR检测肺癌患者cyp 1A1和GSTM1的遗传多态性.癌变、畸变、突变,1999,11(3):119-121.
92 李代蓉,周清华,袁天柱,等.GSTM1和CYP2E1基因多态性与肺癌遗传易感性关系的研究.中国肺癌杂志,2005,8(1):14-19.
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5 Nakajima T, Elovaara E, Anttila S, et al. Expression and polymorphism of glutathionc s-transferase in human lungs:risk factors in smoking-related lung cancer. Carcinogenesis, 1995, 16(4):707-711.
6 顾艳斐,张树才,赖百塘,等.代谢酶基因多态性与肺癌易感性关系的研究.中国肺癌杂志,2004,7(2):112—117.
7 董彩婷,杨青,江宾,等.四川人群中CYP1A1基因Ile/Val和Msp1位点多态性与肺癌易感性的研究.中国肺癌杂志,2004,7(1):38-42.
8 李代蓉,周清华.肺癌遗传易感性的研究进展.中国肺癌杂志,2003,6(2):158-162.
9 Autrup H. Genetic polymorphisms in human xenobiotica metabolizing enzymes as susceptibility factors in toxic response. Mutat Res, 2000,464(1):65
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11 Bartsch H, Rojas M, Nair U, et al. Genetic cancer susceptibility and DNA adducts: studies in smokers, tobacco chewers, and coke oven workers. Cancer Detect Prey, 1999,23(6):445.
12 M essina ES, Tyndale RF, Sellers EM. A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes. J Pharmacol Exp Ther, 1997,282:1608-1614.
13 Kyoko K, Naoki K, Takahiko K, et al. The Significance of the Homozygous CYP2A6 Deletion on Nicotine Metabolism: A New Genotyping Method of CYP2A6 Using a Single PCR-RFLP. Biochemical and Biophysical Research Communications, 1999, 262:146-151.
14 Miles JS, Bickmore W, Brook JD, et al. Close linkage of the human cytochrome P450ⅡA and P450ⅡB gene subfami-lies:implications for the assignment of substrate specificity. Nucleic Acids Res, 1989,17 (8):2907-2917.
15 Kratz F. Coumarin-7-hydroxylase activity in microsomes from needle biopsies of normal and diseased human liver. Eur J Clin Pbarmacol, 1976,10(2):133-137.
16 Kapitulnik J, Popper PJ, Conney AH. Comparative metabolism of benzo[a]pyrene and drugs in human liver. Clin Pharmacol Ther, 1977,21(2):166-176.
17 Pelkonen O, Sotaniemi EA, Ahokas JT. Coumarin 7-hydroxylase activity in human liver microsomes. Properties of the enzyme and interspecies comparisons. Br J Clin Pharmacol, 1985,19(1):59-66.
18 Cholerton S, Idle ME, Vas A, Gonzalez FJ, et al. Comparison of a novel thin-layer chromatographic-fluorescence detection method with a spectrofluorometric method for the determination of 7-hydroxycoumarin in human urine. J Chromatogr, 1992,575(2):325-330.
19 Rautio A, Kraul H, Kojo A, et al. Inter-individual variability of coumarin 7-hydroxylation in healthy volunteers. Pbarmacogenetics, 1992,2(5):227-233.
20 Chun Xu, Shari Goodz, Edward M, et al. CYP2A6 genetic variation and potential consequences. Advanced Drug Delivery Reviews, 2002,54:1245-1256.
21 Fernandez-Salguero P, Hoffman SM, Cholerton S, et al. A genetic polymorphismin coumarin 7-hydroxylation: sequence of the human CYP2A genes and identification of variant CYP2A6 alleles. Am J Hum Genet, 1995, 57(3):651-660.
22 Miyamoto M, Umetsu Y, Dosaka-Akita H, et al. CYP2A6 gene deletion reduces susceptibility to lung cancer. Biochem Biophys Res Commun, 1999,261(3):658-660.
23 Fernandez—Salguero P, Hoffman SM, Cholerton S, et al. A genetic polymorphismin coumarin 7—hydroxylation: sequence of the human CYP2A genes and identification of variantCYP2A6 alleles. Am J Hum Genet, 1995, 57(3):651-660.
24 Oscarson M, Gullsten H, Rautio A, et al. Genotyping of human cytochrome P450 2A6 (CYP2A6),a nicotine C—oxidase. FEBS Lett, 1998, 438(3):201-205.
25 Kitagawa K, Kunugita N, Katoh T, et al. significance ofthe homozygous CYP2A6 deletion on nicotine metabolism:a new genotyping method of CYP2A6using a single PCR-FLP. Biochem Biophys Res Commun, 1999, 262(1):146-151.
26 Chert GF, Tang YM, Green B, et al. Lowfrequency of CYP2A6 gene polymorphism as revealed by aone-tep polymerase chain reaction method. Pharmacogenetics, 1999, 9(3):327-332.
27 Hu CS, Hong JY, Zhao YJ, et al. One step PCR-RFLP method for analysis of CYP2A6 gene polymorphism. Acta hcad Med Jiangxi, 2002, 42(5):23-25.
28 Mikael O, Roman A, McLellana, H, et al. Characterisation and PCR-based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population. FEBS Letters, 1999,448:105-110.
29 Masami M, Yuri U, Hirotoshi DA, et al. CYP2A6 Gene Deletion Reduces Susceptibility to Lung Cancer. Biochemical and Biophysical Research Communications, 1999, 261:658-660.
30 Marie-Anne Loriota, Sandra Rebuissoua, Mikael Oscarsonb, et al. Genetic polymorphisms of cytochrome P450 2A6 in a case±control study on lung cancer in a French population. Pharmacogenetics, 2001,11:39-44.
31 Wen TAN, Gen-Fu CHEN, Oe-Yin XING, et al. FREQUENCY OF CYP2A6 GENE DELETION AND ITS RELATION TO RISK OF LUNG AND ESOPHAGEAL CANCER IN THE CHINESE POPULATION. Int J Cancer (Pred. Oncol), 2001,95:96-101.
32 Messina ES, Tyndale RF, Sellers EM. A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes. J Pharmaco 1 Exp Ther, 1997,282:1608-1614.
33 Murphy SE, Johnson LM, Pullo DA. Characterization of multiple products of cytochrome P4502A6-catalyzed cotinine metabolism Chem Res Toxicol, 1999,12:639-645.
34 P ianezzaML, Sellers EM, Tyndale RF. Nicotine metabolism defect reduces smoking. Nature, 1998,393:750.
35 Stoilov I, Akarsu AN, Alozie I, et al. Sequence analysis and homology modeling suggest that primary congenital glaucoma on 2p121 results from mutations disrupting either the hinge region or the conserved core structures of cytochrome P4501B1. Am J Hum Genet, 1998, 62: 573-584.
36 Murray GI, Taylor MC, Mcfadyen NC, et al. Tumour specific expression of cytochrome P450 CYP1B1. Cancer Res, 1997,57:3026-3031.
37 Masahiro S, Masanori K, Seiichiro F, et al. CYP1B1 gene in endometrial cancer. Molecular and Cellular Endocrinology, 2003,202:171-176.
38 Bailey LR, Roodi N, Dupont WD, et al. Association of cytochrome P450 1B1(CYP1B1) polymorphism with steroid receptor status in breast cancer. Cancer Res, 1998,58(22):5038-5041.
39 Bamberger AM, Kleinkauf-Houcken A, Bamberger CM, et al.. Molecular and clinical endocrinology of the endometrium. Pathologe, 1999,20:50-55.
40 Bejjani BA, Lewis RA, Tomey KF, et al. Mutations in CYP1B1, the gene for cytochrome P450 1B1, are the predominant cause of primary congenital glaucoma in Saudi Arabia. Am J Hum Genet, 1998,62:325-333.
41 Wu MF, Wu WJ, Chang GCh, et al. Increased expression of cytochrome P4501B1 in peripheral leukocytes from lung cancer patients. Toxicology Letters, 2004,150:211-219.
42 Pinpin L, Han Ch, William L, et al. Association of aryl hydrocarbon receptor and cytochrome P4501B1 expressions in human non-small cell lung cancers. Lung Cancer, 2003, 42:255-261.
43 Lai J, Vesprini D, William Ch, et al. CYP Gene Polymorphisms and Early Menarche. Molecular Genetics and Metabolism, 2001, 74:449-457.
44 Hirvonen A. Genetic factors in individual response to environment exposure. J Occup Environ Med, 1995, 37(1): 37 —43.
45 Mcglynn KA, Buetow KH. Metabolic and H—ras polymorphisms in genetic susceptibility. Cancer Bull, 1994,46(3)220-227.
46 Bharat T, Marcia B, Pamela M, et al. CYP1B1 and CYP19 gene polymorphisms and breast cancer incidence: no association in the ARIC study. Cancer Letters, 2004,207:183-189.
47 Masahiro S, Yuichiro T, Masanori K, et al. Alleles of Polymorphic Sites That Correspond to Hyperactive Variants of CYP1B1 Protein Are Significantly Less Frequent in Japanese as Compared to American and German Populations. Mutation in Brief, 616 (2003) Online.
48 Zheng W, Xie DW, Jin F, et al. Genetic polymorphism of cytochrome P450-1B1 and risk of breast cancer. Cancer Epidemiol Biomarkers Prey, 2000,9:147-150.
49 宋南,林东昕.细胞色素P4501A1基因变异与肺癌易患性.基础医学与临床,1999,19(5):5-9.
50 刘移民,Yan Yan, Beverly D, et al.多环芳烃受体基因与细胞色素P4501A1/1B1基因表达的调控.中国职业医学,2003,30(3):10-13.
51 Lallas TA, McClain SK, Shahin MS, et al. The Glutathione S-transferase Ml genotype in ovarian cancer. Cancer Epi demiol Biomarkers Prey, 2000,9:587
52 Nelson HH, Wiencke JK, Christiani DC, et al. Ethnic differences in the prevalence of the homozygous deteted genotype of glutathione S-transferase theta. Carcinogenesis, 1995, 18(5): 1243-1245.
53 刘茶珍,边建超,江峰,等.谷胱甘肽S转移酶M1、T1和P1基因多态与肝癌易感性研究.中国公共卫生,2002,18(8):935-936.
54 Sai-Mei H, Susann F, Fredrik N. Glutathione s-transferase T1-null genotype interacts synergistically with heavy smoking on lung cancer risk. Environmental and Molecular Mutagenesis, 2001,38:83-86.
55 Lewis SJ, Cherry NM, Niven RM, et al. GSTM1, GSTT1and GSTP1 polymorphisms and lung cancerrisk. Cancer Letters, 2002, 180: 165～171.
56 梁戈玉,浦跃朴,尹立红.南京汉族群体肺癌易感性相关基因的研究.遗传,2004,26(5):584～588.
57 蓝青,何兴舟,Debra Costa,等.谷胱甘肽硫转移酶基因GSTM1及GSTT1缺失与肺癌发病关系的研究.卫生研究,1999,28(1):9～11.
58 张吉凯,胡毅玲,胡巢凤,等.GSTM1和GSTT1基因多态性与女性肺癌易感性的关系.中国公共卫生,2002,18(3):273-275.
59 Saarikoski ST, Voho A, Reinkainen M, et al. Combined effect of polymorphic GST genes on individual susceptibility to lung cancer. Int J Cancer,1998,77:516
60 刘茶珍,边建超,沈福民.毒物代谢酶基因多态性与肝癌遗传易感性研究进展.中华医学遗传学杂志,1998,15(6):3761.
61 Landi S. Mammalian class theta GST and differential susceptibility to carcinogen:a review. Mutation Res, 2000, 463:247-283.
62 Reinemer P, Dirr HW, Ladenstein R, et al. The three dimensional structure of class π glutathione-S-transferase in complex with glutathione sulfonate at 2. 3 Aring; resolution EMBO J, 1991,10:1997-2005
63 Strange RC, Spitereri MA, Ramachandran, et al. Glutathione S-transferase family of enzymes. Mutation Res, 2001,482:2-26.
64 Johansson AS, Stenberg G, Widersten M, et al. Structure activity relationships and thermal stability of human glutathione transferase P1-1 governed by the H-site residue 105. J Mol Biol, 1998, 278:687-698.
65 Cotton SC, Sharp L, Little J, et al. Glutathione Stransferase polymorphisms and colorectal cancer: a HuGE review. Am J Epidemiol, 2000, 151:7-32.
66 Tan KL, Webb GC, Baker RT, et al. Molecular cloning of a cDNA and chromosomal localization of a human theta-class glutathione S-transferase gene (GSTT2) to chromosome 22. Genomics, 1995,25:381-387.
67 Webb G, Vaska V, Coggan M, et al. Chromosomal localization of the gene for the human theta class glutathione transferase (GSTT1). Genomics, 1996,33:121-123.
68 Nelson HH, Wiencke JK, Christiani DC, et al. The prevalence of the homozygous deleted genotype of glutathione S-transferase theta. Carcinogenesis, 1995,16(5):1243-1245.
69 林国芳,谭靖伟,沈建华,等.上海正常人中谷胱甘肽S-转移酶T1基因纯合性缺失[J].癌变.畸变.突变,1998,10(6):345-348
70 杨洁,石宏,董永利,等.云南24个民族群体GSTT1、GSTM1纯合缺失基因型频率的分布.中华医学遗传学杂志,2003,20(1):9-11.
71 Meyer DJ. Theta, a new class of glutathione transferases purified from rat and man. BiochemJ, 1991,274 (Pt2):4091.
72 Dremble S. Human glutathione S-transferase theta (GSTT1):cDNA cloning and the characterization of agenetic polymorphism. Biochem J, 1994,300 (Pt1),2711.
73 Wilce MC, Parker MW.Structure and function of glutathione S-transferase. Biochem Biophys Acta, 1994,120 5(1): 1～181.
74 董传辉,资晓林,愈顺章,等.谷胱甘肽S-转移酶T1基因缺失与肝癌易患性关系的研究.中华公共卫生学报,1997,16(2):1411
75 Bian JC, Shen FM, Shen L, et al. Susceptibility to hepatocellular carcinoma associated with null genotypes of GSTM1 and GSTT1. World J Gastroentero, 2000, 6(2):2281
76 Tiemersma EW, Omer RE, Bunschoten A, et al. Role of genetic polymorphismof glutathione-S-transferase T1 and microsomal epoxide hydyolase in aflatoxin-associated hepatocellular carcinoma. Cancer Epidemiol Biomarkers Prey, 2001, 10(7):7851.
77 钱云,徐耀初,沈洪兵,等.CYP2E1、GSTT1基因多态性与胃癌易感性的关系.中国慢性病预防与控制,2003,11(3):107-109.
78 Jourenkova N, Reinikanen M, Bouchardy C, et al. Effects of glutathione S-transferases GSTM1 and GSTT1 genotypes on lung cancer risk in smokers. Pharmacogenetics, 1997,7:515-518.
79 Saarikoski ST, Yoho A, Reinikainen M, et al. Combined effect of polymorphic GST genes on individual susceptibility to lung cancer. Int J Cancer 1998,77:516-521.
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