CYP1A1和GSTM1基因多态性与内蒙古人群肺癌易感性的关系

背景与目的 肺癌是严重危害人类健康的恶性肿瘤之一，其发病与肺癌人群中某些肺癌相关基因的遗传多态性有关。本研究旨在探讨细胞色素P4501A1（CYP1A1）基因多态性和谷胱甘肽硫转移酶M1（GSTM1）基因多态性与内蒙古人群肺癌易感性的关系。方法 用PCR-RFLP技术分析了原发性肺癌组和住院对照组（各163例）的CYP1A1、GSTM1基因的多态性、基因型分布频率和交互作用。结果 CYP1A1突变型和GSTM1基因缺陷型EGSTM1（-）]频率分布分别为36．8％、65．0％（病例组）和19．0％、48．9％（对照组），二者经χ^2检验差异有显著性（χ^2=12．82，P=0．000；χ^2=9．78，P=0．002）。CYP1A1突变型患肺癌的风险显著增加（OR=2．48，95％CI为1．51～4．08）。GSTM1（-）者患肺癌的风险也显著增加（OR=2．03，95％CI为1．30～3．17）。基因突变的协同分析发现CYP1A1突变型／GSTM1（-）在肺癌组和对照组中的分布频率分别为28．8％和8．0％，二者经χ^2检验有显著性差异（χ^2=23．883，P=0．000）。CYP1A1突变型／GSTM1（-）患肺癌的风险显著增加（OR=4．90，95％CI为2．50～9．83）。无论是在肺癌组还是在对照组，CYP1A1突变型／GSTM1（-）和CYP1A1非突变型／GSTM1（-）在性别间分布频率的差异均无显著性（肺癌组χ^2=0．797，P=0．372；对照组χ^2=0．670，P=0．761）。吸烟与肺癌易感性的统计学分析，结果显示吸烟与肺癌易感性有关（χ^2=14．197，P=0．000），吸烟者患肺癌的风险显著增加（OR=2．33，95％CI为1.50～3．62）。CYP1A1突变型与吸烟关系的协同分析发现，携带CYP1A1突变型基因的吸烟者较携带CYP1A1突变型基因不吸烟者易患肺癌（OR=4．44，95％CI为2．40～8．32，χ^2=23．843，P=0．000）。GSTM1（-）与吸烟关系的协同分析中也发现，携带GSTM1（-）的吸烟者患肺癌的风险显著增加（OR=7．32，95％CI为3．39～15．50，χ^2=36．708，P=0．000）。结论 CYP1A1突变型和GSTM1（-）是内蒙古地区肺癌的易患因素，二者对肺癌的发生有协同作用，吸烟与肺癌的易感性也有关，CYP1A1突变型、GSTM1（-）与吸烟在肺癌的发生上也有相互促进作用。     

广州地区182例汉族人细胞色素P450 1A1和2E1基因多态性与肺癌关系的病例对照研究

背景与目的 肺癌的易感性研究多集中在单个基因的多态性方面，本研究观察了广州地区汉族人群细胞色素P4502E1（CYP2E1）和1A1（CYP1A1）的基因多态性与肺癌的关系，分析其联合作用。方法 采用聚合酶链反应和限制性片段长度多态性技术检测91例初发肺癌患者及91例非肺部疾患同性别患者的CYP2E1和CYP1A1的基因多态性，并分析比较。结果 在两组间平衡吸烟的因素后，CYP2E1和CYP1A1基因多态性分别单独分析时，与肺癌关系较弱，其OR值分别为5．48和1．51，与对照组之间的差异无显著性（P〉0．05）。两者联合分析时，CYP2E1野生型和CYP1A1突变型联合者的OR值为3．00，95％CI为1．03～8．78，其差异有显著性（P〈0．05）。结论 CYP2E1和CYP1A1单一基因的多态性不能增加患肺癌的危险，而两者联合作用时则可增强患肺癌的风险。     

细胞色素CYP2E1和GST M1与肺癌易感性的病例对照研究

目的探讨谷胱甘肽转硫酶(GST)和细胞色素CYP2E1多态性与肺癌易感性的关系.方法选取广州市广东籍新发肺癌病人91例及同期非肺部疾患及相同性别的病人91例作匹配,调查他们的吸烟、饮酒等因素的暴露情况.用聚合酶链式反应(PCR)和限制性片段长度多态性(RFLP)技术检测CYP2E1和GST的基因多态性.结果CYP2E1 C1C1基因型与C1C2基因型比较,其OR为1.82(95%CI=0.95～3.40),GSTM1基因缺失型的OR值为1.26(0.69～2.30),而两者联合分析时,则可增加患肺癌的危险,其OR值为2.13(0.82～5.56),但无统计学意义(P＞0.05).吸烟与肺癌关系密切,其OR值为2.82(1.56～5.12),当吸烟与这两种基因型协同作用时,可明显提高患肺癌的危险性,携带CYP2E1 C1C1基因型的吸烟者的OR值为5.42(2.05～14.32),GSTM1基因缺失型的吸烟者的OR值为4.38(1.81～10.61).多因素logistic回归分析结果表明:文化程度(OR为0.63,0.45～0.86)、吸烟量(OR为1.56,1.14～2.14)、元抽油烟机(OR为3.77,1.48～9.56)、食用动物油(OR为1.67,1.25～2.24)、胡萝卜(OR为0.47,0.22～0.98)、饮酒(OR为6.58,1.53～28.3)、直系亲属肺癌史(OR为3.75,1.64～8.58)等因素与肺癌有关,而上述两种基因均未进入模型.结论CYP2E1和GSTM1在单因素分析中未显示出与肺癌风险的联系.这两种基因分别与吸烟协同作用时明显提高肺癌的危险性.然而在多因素分析中均未进入logistic模型,说明它们均不是肺癌个体易感性的主效基因,而是次效基因.     

GSTM1和CYP2E1基因多态性与肺癌遗传易感性关系的研究

背景与目的肺癌是中国人群恶性肿瘤死因的首位，其发病可能与肺癌人群中某些肺癌相关基因的遗传多态性有关。本研究旨在探讨细胞色素P4502E1(CYP2E1)基因RsaⅠ／PstⅠ多态性和谷胱甘肽转移酶M1(GSTM1)基因多态性与肺癌易感性之间是否存在相关性。方法应用PCR-RFLP和PCR法检测99例人非小细胞肺癌患者和66例同期住院的肺良性疾病患者CYP2E1基因的RsaⅠ／PstⅠ多态性和GSTM1基因多态性，并分析其与肺癌遗传易感性的相关性。结果(1)CYP2E1基因RsaⅠ／PstⅠ多态性的三种基因型在肺癌组和对照组的频率差异没有统计学意义(χ^2=1．374，P=0．241)。(2)肺癌组GSTM1(-)基因型频率显著高于对照组(分别为57．6％和40．9％)(χ^2=4．401，P=0．036)。(3)携带GSTM1(-)基因型的个体患肺癌的危险性显著高于GSTM1( )基因型的个体(OR=1．96，95％CI=1．042～3．689，P=0．037)。(4)与携带c1／c2或c2／c2基因型的不吸烟个体比较，携带c1／c1基因型的吸烟者患肺癌的风险显著增加(OR=3．525，95％CI=1．168～10．638，P=0．025)。(5)联合分析CYP2E1基因RsaⅠ／PstⅠ多态性和GSTM1基因多态性，携带有c1／c1和GSTM1(-)基因型的个体患肺癌的风险显著高于携带GSTM1( )和c1／c2或c2／c2基因型的个体(OR=3．449，95％CO=1．001～11．886，P=0．050)。按照吸烟因素分层，携带有GSTM1(-)和c1／c1基因型的不吸烟个体患肺癌的风险显著高于携带GSTM1( )和c1／c2或c2／c2基因型的不吸烟个体(OR=11．553，95％CI=1．068-124．944，P=0．044)，携带有GSTM1(-)和c1／c2或c2／c2基因型的不吸烟个体患肺癌的风险同样显著高于携带GSTM1( )和c1／c2或c2／c2基因型的不吸烟个体(OR=13．374，95％CI=1．258～142．166，P=0．032)。结论(1)GSTM1(-)基因型增加人群患肺癌的风险；(2)CYP2E1的c1／c1基因型和GSTM1(-)基因型的联合可增加吸烟和不吸烟人群患肺癌的风险。     

细胞色素P450 2E1和1A1多态性与肺癌关系的病例对照研究

目的 :探讨细胞色素P45 0 2E1和P45 0 1A1的多态性与肺癌的关系。方法 :采用聚合酶链式反应和限制性片段长度多态性技术检测新发肺癌患者91例及非肺部疾患同性别的患者 91例的细胞色素CYP 2E1和CYP 1A1的基因多态性 ,并分析比较。结果 :在 2组间平衡吸烟的因素后 ,CYP 2E1和CYP 1A1基因多态性分别单独分析时 ,与肺癌关系较弱 ,其OR值分别为 1 46和 1 5 1,与对照组相比差异无统计学意义 ,P >0 0 5 ;而两者联合分析时 ,CYP2E1C1C1型和CYP 1A1突变型的OR值为 3 0 0 ,95 %CI为 1 0 3～ 8 78,差异有统计学意义 ,χ2 =4 0 2 ,P <0 0 5。结论 :CYP 2E1和CYP 1A1单一基因的多态性不能增加患肺癌的危险 ,而两者联合作用时则可增强患肺癌的风险。     

CYP1A1 GSTM1基因多态性和吸烟与肺癌易感性关系的病例对照研究

目的:探讨天津市居民致癌物代谢酶CYP1A1和GSTM1基因多态性对肺癌易感性的影响。方法:利用限制性片断长度多态性-聚合酶链反应(RFLP-PCR)方法检测原发性肺癌患者和健康对照者细胞色素P450酶基因CYP1A1Msp位点和谷胱甘肽硫转移酶基因GSTM1的多态性情况。结果:肺癌组与对照组之间CYP1A1和GSTM1基因型分布差异均存在统计学显著意义(P<0.05)。携带CYP1A1变异基因型或GSTM1阴性基因型的个体患肺癌的危险性增高,比值比(OR)分别达到2.44(1.04～5.81)和1.84(1.03～3.29)。多因素分析结果显示具有CYP1A1变异基因型、GSTM1阴性基因型的吸烟个体患肺癌的风险较大。结论:CYP1A1Msp位点变异基因型和GSTM1阴性基因型可能是肺癌的易感因素,吸烟与肺癌易感基因之间具有协同作用。     

细胞色素P450 2E1基因多态性与肺癌易感性的研究

目的 :研究与致癌物有关的代谢酶细胞色素P45 0 2E1(CYP 2E1)基因多态性和饮酒与肺癌易感性的关系。方法 :采用聚合酶链反应 (PolymeraseChainReaction ,PCR)和限制性片段长度多态性 (RestrictionFregmentLengthPolymorphisms ,RFLP)方法 ,分析 91例肺癌患者和 138例对照的Rsal认别的CYP 2E1基因型。 结果 :本次研究结果为CYP 2E1基因型频率在肺癌组和对照组的分布差异无显著性意义 (χ2 =1 35 5 ,P >0 0 5 ) ;CYP 2E1C1/C1基因型或饮酒单因素作用的比值比 (OddsRatil,OR)分别为 1 389和 3 33,而两者联合作用的OR为 5 4 1。结论 :CYP 2E1基因多态性与肺癌无明显相关性 ,但与饮酒有联合作用。     

CYP1A1与GSTM1的多态性与原发性肝癌遗传易感性的关系研究

目的：探讨细胞色素P4501A1（cytochorme P4501A1,CYP1A1)与谷胱苷肽S－转移酶M1(glutathione S-transferase M1,GSTM1)的多态性与原发性肝癌遗传易感性的关系。方法：应用等位特异PCR和多重PCR技术对52例原发性肝癌患者和100名健康对照的CYP1A1和GSTM1多态性进行分析。结果：肝癌患者CYP1A1第7外显子462Val的等位变异频率为0．46，显著高于正常对照的变异步率（0．22），病例组GSTM1的纯合型缺失频率（0．65），也显著高于对照组（0．41），携带有CYP1A1Val/Val纯合变异和GSTM1纯合缺失基因型的人患肝癌的风险大大增加，前者的比值比（odds ration,OR)及95％可信区间（confidence interval,95%CI)为4．13（1．28－13．35），后者的OR值及95％CI为2．72（1．35－5．46），二者联合OR值及95％CI为8．50（1．74－41．50）。结论：CYP1A1和GSTM1的多态是原发性肝癌的遗传易感因素，二者的等位变异增加了患肝癌的风险。     

细胞色素P450 2E1基因多态性与肺癌易感性的研究

目的:研究与致癌物有关的代谢酶细胞色素P450 2E1(CYP 2E1)基因多态性和饮酒与肺癌易感性的关系.方法:采用聚合酶链反应(Polymerase Chain Reaction,PCR)和限制性片段长度多态性(Restriction FregmentLength Polymorphisrms,RFLP)方法,分析91例肺癌患者和138例对照的Rsal认别的CYP 2E1基因型.结果:本次研究结果为CYP 2E1基因型频率在肺癌组和对照组的分布差异无显著性意义(X2=1.355,P＞0.05);CYP 2E1C1/C1基因型或饮酒单因素作用的比值比(Odds Ratil,OR)分别为1.389和3.33,而两者联合作用的OR为5.41.结论:CYP 2E1基因多态性与肺癌无明显相关性,但与饮酒有联合作用.     

CYP1A1、CYP2E1基因多态性与癌症易感性的研究进展

人类细胞色素P450（CYP450）在多种内源性及外源性物质的生物代谢中起重要作用。大多数CYP450存在基因多态性,其中CYP1A1、CYP2E1两个基因多态性与癌症的发生密切相关。本文综述了近年来人类细胞色素P4501A1（CYP1A1）和P4502E1（CYP2E1）与癌症易感性之间关系的研究进展。     

CYP1B1, CYP1A1, MPO, and GSTP1 polymorphisms and lung cancer risk in never-smoking Korean women

Polymorphisms in metabolic genes encoding phase I and phase II enzymes are thought to modulate the risk of lung cancer via changes in enzymatic activity. Recently, the effect of these metabolic enzymes and their interaction with environmental factors has been studied in both smokers and also never-smokers, since never-smokers are a good model in which to study genetic susceptibility at low-dose carcinogen exposure. Here, we investigated the association of CYP1A1 Ile462Val, CYP1B1 Leu432Val, GSTP1 Ile105Val, MPO G-463A polymorphisms and lung cancer risk in never-smoking Korean women. In this case-control study of 213 lung cancer patients and 213 age-matched healthy controls, we found that carrying one variant allele of the CYP1A1 Ile462Val polymorphism was associated with a significantly decreased risk of lung adenocarcinoma (adjusted odds ratio (OR)=0.63; 95% confidence interval (CI), 0.41-0.99). Furthermore, the combination of risk genotypes of CYP1B1 Leu432Val with CYP1A1 Ile462Val was associated with the risk of lung adenocarcinoma (adjusted OR=2.16; 95% CI, 1.02-4.57) as well as overall lung cancer (adjusted OR=2.23; 95% CI 1.01-4.89). The polymorphisms of GSTP1 Ile105Val and MPO G-463A showed no significant association with lung cancer. Theses results suggest that the CYP1A1 Ile462Val polymorphism is associated with a reduced risk of lung adenocarcinoma in never-smoking Korean women, whereas specific combinations of variant genotypes for metabolic enzymes increase lung cancer risk considerably.     

Effect of cigarette smoke on CYP1A1, CYP1A2 and CYP2B1/2 of nasal mucosae in F344 rats

Enzymes of the nasal tissue, one of the first tissues to contact inhaled toxicants, are relatively resistant to induction by traditional inducers. Because tobacco smoke has been shown to induce cytochrome P450 1A1 (CYP1A1) in rat and human lung tissue, we hypothesized that it would also alter levels of xenobiotic-metabolizing enzymes in nasal mucosae. In the present study, the effect of mainstream cigarette smoke (MCS) on nasal CYP1A1, CYP1A2 and CYP2B1/2 was explored. Four groups of 30 F344 rats were exposed to MCS (100 mg total particulate matter/m3) or filtered air for 2 or 8 weeks. Western analysis of microsomes from nasal tissue of MCS-exposed rats showed an induction of CYP1A1 in respiratory and olfactory mucosae, as well as liver, kidney and lung. Relative to controls, CYP1A2 levels increased slightly in the liver and olfactory mucosa. CYP2B1/2, which increased in the liver, appeared to decrease in upper and lower respiratory tissues. Little to no immunoreactivity with CYP1A1 antibody was observed in fixed nasal sections of control rats, yet intense immunoreactivity was seen in epithelia throughout the nasal cavity of MCS-exposed rats. Ethoxyresorufin O-deethylase activity (associated with CYP1A1/2) decreased approximately 2-fold in olfactory mucosa, but increased in non-nasal tissues of rats exposed to MCS. Methoxy- and pentoxyresorufin O-dealkylase activities (associated with CYP1A2 and CYP2B1/2, respectively) decreased in olfactory and respiratory mucosae, as well as lung (CYP2B1/2), yet increased in liver. These data suggest that xenobiotic-metabolizing enzymines of the nasal mucosae may be regulated differently than other tissues.      

The influence of genetic polymorphisms in Ahr, CYP1A1, CYP1A2, CYP1B1, GST M1, GST T1 and UGT1A1 on urine 1-hydroxypyrene glucuronide concentrations in healthy subjects from Rio Grande do Sul, Brazil

Polymorphisms in genes encoding polycyclic aromatic hydrocarbon (PAH) metabolizing enzymes may alter metabolism of these carcinogens and contribute to inter-individual difference in urine concentrations. We investigated the influence of genetic polymorphism on PAH metabolism in urine from 199 healthy subjects from Southern Brazil. We measured urine 1-hydroxypyrene glucuronide (1-OHPG) concentrations using immunoaffinity chromatography and synchronous fluorescence spectroscopy and genotyped subjects using standard methods. Genetic variants in CYP1B1 (rs1056827, rs1800440, rs10012) were strongly associated with urine 1-OHPG with P-values < 0.010. Variants in aryl hydrocarbon receptor (Ahr) (rs4986826), CYP1A1 (rs1799814) and CYP1A2 (rs2069514) were also, although less strongly, associated with changes in urine 1-OHPG concentrations. These variants had P-values of 0.074, 0.040 and 0.025, respectively. The median urine 1-OHPG concentrations (pmol/ml) in the homozygous wild-type and homozygous variants for CYP1B1 (rs10012) and the Ahr, CYP1A1 and CYP1A2 variants listed above were 2.16 and 0.10, 2.16 and 0.41, 2.03 and 0.46, 2.19 and 2.79, respectively. We found no effect of deletions in GST M1 or GST T1, or different alleles of UGT1A1*28. Adjusting for age, sex, place of residence, tobacco smoke exposure, maté drinking, cacha?a and barbeque preparation had only a minor impact on the associations. A model containing just exposure variables had an r2 of 0.21; a model with single genotypes for Ahr, CYP1A1, CYP1A2 and CYP1B1 had an r2 of 0.10; and a model combining both exposure and genotype information had a total r2 of 0.33. Our results suggest that CYP1B1 genotypes are strongly associated with urine 1-OHPG concentrations in this population.     

Association of CYP1A1, CYP1A2, GSTM1 and NAT2 gene polymorphisms with colorectal cancer and smoking.

We investigated CYP1A1*2A, CYP1A1*2C, CYP1A2*1C, CYP1A2*1F, GSTM1 and NAT2 gene polymorphisms, involving enzymes which metabolize many carcinogens, with reference to colorectal cancer risk. The distribution of these genotypes was not associated with risk overall. However, the CYP1A1*2A T/C genotype showed a significant association with colorectal cancer risk in never-smokers (odds ratio [OR], 3.06; 95% confidence interval [95% CI], 1.11-8.40; p = 0.030). The risk of the NAT2 rapid genotype in never-smokers was also statistically significantly increased (OR, 5.38; 95%CI, 1.80-16.1; p = 0.003). Furthermore, the joint effects of NAT2 rapid plus other genotypes were associated with colorectal cancer overall (OR, 3.12; 95%CI, 1.15-8.51; p = 0.026, for NAT2 rapid plus combined CYP1A1*2C Ile/Val and Val/Val, OR, 3.25; 95%CI, 1.09-9.74; p = 0.035, for NAT2 rapid plus CYP1A2*1C G/G, and OR, 4.20; 95%CI, 1.09-16.1; p = 0.037, for NAT2 rapid plus GSTM1 null, respectively). In never-smokers, the joint effects of NAT2 rapid plus other genotypes were remarkable (OR, 15.9; 95%CI, 1.87-135.8; p = 0.011, for NAT2 rapid plus combined CYP1A1*2A T/C and C/C, OR, 5.71; 95%CI, 1.49-21.9; p = 0.011, for NAT2 rapid plus combined CYP1A1*2C Ile/Val and Val/Val, and OR, 9.14; 95%CI, 2.05-40.7; p = 0.004, for NAT2 rapid plus CYP1A2*1F A/A, respectively). The joint effect of CYP1A2*1F A/A plus CYP1A2*1C G/G genotypes was also increased in never-smokers (OR, 6.16; 95%CI, 1.26-30.1; p = 0.025). Our findings suggest that the CYP1A1*2A T/C and NAT2 rapid genotypes is associated with colorectal cancer susceptibility without smoking exposure. These results also indicate that the NAT2 in combination with CYP1A1*2C, CYP1A2*1C, or GSTM1 genotypes may strongly confer susceptibility to colorectal cancer. In particular, the combination of NAT2 plus CYP1A1*2A, CYP1A1*2C, or CYP1A2*1F genotypes, and that of CYP1A2*1F plus CYP1A2*1C genotype may define a group of persons who are genetically susceptible to colorectal cancer in never smokers.     

CYP1A1.

CYP1A1 plays an important role in the metabolism of polycyclic hydrocarbons that occur in the environment and several studies suggest that the genetic polymorphism of the gene may play a role in the predisposition to cancer. In order to evaluate the function of CYP1A1 in vivo as a host factor determinant of environmentally-caused cancers in humans, additional investigations are needed involving not only molecular epidemiological approaches in different ethnic populations but also more direct approaches such as the use of gene-targeted mice as a model system.     

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

Associations between genetic polymorphisms of CYP1A1, CYP1A2, CYP2E1, GSTM1 and GSTT1 and prostate cancer (PCa) were analyzed in a case-control study of 315 individuals. The frequency of valine (Val)/valine (Val) genotypes for CYP1A1 was 11.3% in cases compared with 5.5% in controls, this polymorphism thus being associated with a significantly increased risk of PCa (odds ratio=2.4, 95% confidence interval (CI)=1.01-5.57). No links were detected between PCa and polymorphisms in other enzymes. However, the combination of CYP1A1 (Ile/Val and/or Val/Val) polymorphisms with the GSTM1 null type resulted in an OR of 2.2 (CI=1.10-4.57, 1.12-4.20, respectively). This study suggests that the CYP1A1 polymorphism and its combination with GSTM1 may be associated with PCa susceptibility in the Japanese population.