细胞色素氧化酶基因CYP1A2多态性与新疆汉族和维吾尔族人群冠心病的相关性

目的 探讨新疆地区维吾尔（维）族人群、汉族人群细胞色素氧化酶基因CYP1A2（cytochrome c oxidase P1A2）多态性与冠心病的关联性。 方法 我们采用两项独立的病例对照研究∶汉族人群389例冠心病患者(病例组）和411名健康体检者（对照组）;维族人群293冠心病患者（病例组）和408名健康体检者（对照组）。通过实时PCR对CYP1A2基因单核苷酸多态性（SNPs）rs2069522和rs2472304进行基因分型。 结果 仅在汉族人群中,SNP1 (rs2069522)基因型的分布在冠心病组和对照组之间差异均有统计学意义(P < 0.05)。而维族人群中未见显著差异。新疆汉族病例组SNP1 (rs2069522)显性模型(CC vs CT + TT)基因型频率显著高于对照组。调整混杂因素后logistic回归分析表明,新疆汉族人群CC基因型患冠心病的风险显著高于CT + TT基因型者(总体:OR = 1.982,95%CI: 1.174～3.236, P < 0.01;男性: OR = 2.671,95%CI: 1.548～4.314, P < 0.01)。 结论 新疆汉族人群CYP1A2基因中rs2069522的位点与冠心病相关。CC基因型可能是新疆汉族人群而非维吾尔族人群发生冠心病的独立危险因素。     

CYP1A1基因多态性和吸烟对肺癌的易感性

目的采用PCR-RFLP技术测定CYP1A1的mspI和exon 7位点多态性,并观察两者及吸烟对肺癌易感性的影响。方法研究采用等位基因特异性扩增和PCR-RFLP技术,分析CYP1A1基因3'端限制性内切酶mspI和exon 7位点基因的基因多态性。结果 CYP1A1的mspI和exon 7位点各自基因型分布频率均无显著性差异(χ2=1.34,P>0.05);其中mspI突变型TC和CC患肺癌的相对危险性增加(OR=1.18,P<0.05;OR=1.49,P<0.05);exon 7突变型Ile/Val和Val/Val患肺癌的相对危险性亦增加(OR=1.35,P<0.05;OR=2.70,P<0.05);两多态位点联合作用分析,表明携带突变基因的个体肺癌易感性较高(OR=4.42,P<0.05)。对肺癌易感性与吸烟的关系分析,吸烟者患肺癌的危险性是不吸烟者1.77倍(χ2=5.72,P<0.05);携带突变基因且吸烟者肺癌易感性显著增加(OR=2.16,P<0.05;OR=2.63,P<0.05)。结论 CYP1A1突变型基因可能增加肺癌的易感性;CYP1A1突变型基因与吸烟之间存在协同作用,明显提高了患肺癌的风险性。     

细胞色素CYP2A6基因多态性与COPD易感性的关系

目的探讨细胞色素CYP2A6基因多态性与COPD易感性的关系。方法应用聚合酶链反应-限制性片段长度多态性法(PCR-RFLP)检测40例COPD患者及37例健康体检者静脉血细胞色素P450 2A6位点等位基因和基因型。结果 1.COPD患者CYP2A6-163C>A位点基因缺失型(del)和野生型(wt)基因型频率为17.5%、82.5%,健康对照组分别为40.5%、59.5%,两组基因分布频率差异有统计学意义(χ2=5.000,P=0.025),携带CYP2A6wt基因型者较携带CYP2A6del基因型者患COPD风险增加(OR=0.31,95%CI=0.109-0.886,P<0.05)。2.在吸烟者中,携带CYP2A6wt基因型者较携带CYP2A6del基因型者患COPD风险增加(OR=0.24,95%CI=0.064-0.920,P<0.05),在不吸烟者中,携带CYP2A6wt、CYP2A6del基因型者之间患COPD风险无明显差异。结论 1.CYP2A6-163C>A基因多态性可能是COPD发病的危险因素。2.野生型(wt)可能为吸烟者患COPD的一个易感因素。     

代谢酶基因CYP 1A1与广西胃癌遗传易感性的关系

目的探讨代谢酶基因CYP 1A1MSP1多态性与广西地区汉族、壮族人群胃癌遗传易感性之间相关性。方法采用PCR-RFLP技术检测广西地区汉族、壮族人群中121例胃癌患者和138例健康人CYP1A1MSP1多态性的分布频率,分析其与广西地区汉族、壮族人群胃癌遗传易感性的相关性及与吸烟、饮酒在胃癌易感性中的相互作用。结果 (1)CYP 1A1MSP1三种基因型(m1/m1、m1/m2、m2/m2)分布频率在两组间比较差异无统计学意义(χ2=0.901,P=0.342);(2)携带CYP1A1MSP1突变m2基因型的个体较携带m1/m1基因型的个体患胃癌的风险增加(OR=1.509),但差异无统计学意义(P=0.342)。结论单独的CYP 1A1基因MSP1多态性与广西地区汉族、壮族人群胃癌易感性无明显相关性。     

CYP2E1,GSTM1基因多态性与甘肃地区食管癌易感性

目的探讨细胞色素氧化酶P450,GSTM1的基因多态性与甘肃地区食管癌遗传易感性之间的以及基因—基因的交互作用。方法运用病例对照分子流行病学研究方法和聚合酶链反应方法对食管癌病例组和正常对照组基因DNA进行CYP2E1,GSTM1基因分型。结果CYP2E1基因pst1多态性的三种基因型在食管癌组和对照组的频率差异有统计学意义（χ2=12.59,P〈0.05）。携带C1/C1基因型个体发生食管癌的风险是携带其他基因型2.80倍（OR=2.80,95%C I=1.21-6.46）。食管癌组GSTM1（-）基因型频率显著高于对照组（χ2=10.292,P〈0.05）,携带GSTM1（-）的个体患食管癌的危险性显著高于GSTM1（＋）基因型的个体（OR=2.337,95%C I=1.39-3.93）。联合分析CYP2E1基因pst1多态性和GSTM1基因多态性,携带有C1/C1和GSTM1（-）基因型的个体患食管癌的风险高于携带GSTM1（＋）和C1/C2或C2/C2基因型的个体（OR=3.00,95%C I=1.7375-5.182）。结论CYP2E1,GSTM1基因多态性与食管癌易感性有关联,CYP2E1基因C1/C1基因型是食管癌的易感性基因,而GSTM1基因缺失使食管癌危险性增加,CYP2E1,GSTM1存在交互作用。     

哈萨克族食管癌与CYP2E1基因多态性及烟酒嗜好的关系

目的:探讨细胞色素P4502E1(CYP2E1)基因多态性,烟酒嗜好与哈萨克族食管癌易感性的关系.方法:采用1:2配比的病例对照研究方法,调查哈萨克族食管癌患者120例和非食管癌患者240例,采用聚合酶链-限制性片段长度多态(PCR-RFLP)方法检测CYP2E1 RsaⅠ位点的基因型.结果:病例组中CYP2E1 RsaⅠ位点C1/C1、C1/C2、C2/C2基因型频率与对照组比较(78.3%vs53.3%,19.2%vs 37.5%,2.5%vs 9.2%,X~2=21.794,P<0.01)差异有统计学意义:携带C1/C1基因型发生食管癌的危险性是携带C1/C2或C2/C2基因型的3.07倍(95%CI:1.87.5.03);交互作用提示CYP2E1基因多态与吸烟、饮酒均存在交互作用;其危险性远高于各单独作用之和.结论:CYP2E1 RsaⅠ位点基因多态性与大量吸烟、饮酒之间的基因-环境交互作用可增强哈萨克族人群患食管癌的风险.     

细胞色素P450基因多态性与肺癌易感性的相关性分析

目的 探讨代谢活化酶细胞色素P4501A1（CYP1A1）、2D6（CYP2D6）、2E1（CYP2E1）和代谢解毒酶谷胱甘肽硫转移酶（GSTM1）与肺癌易感性的关系。方法采用PCR、PCR—RFLP技术检测原发性肺癌组（279例）及对照组（684例）的CYPlAI、CYP2D6、CYP2E1、GSTM1代谢酶基因型，对不同基因型在两组分布频率的差异进行OR值的统计分析。结果CYPlAl突变等位基因（m）、GSTMl功能缺失型（-）分别可使患肺癌的危险性增加1．64（OR=1．64，95％CI为1．21—2．22，P=0．001）和1．58倍（oR=1．58，95％CI为1，19—2．11，P=0．002）。其中CYPlAl与肺鳞癌、小细胞癌，GSTMl与肺鳞癌及肺腺癌明显相关（均P〈0．05）。同时携带GSTMI（-）和CYPlAl（m）可使患肺癌的危险性明显增加（OR=2．75，95％CI为1．73～4．39，P=O．OOO）。在重度吸烟人群携带GSTMl（-）、CYPlAl（m）、CYP2D6（W）或CYP2ElA基因型均可使患肺癌的危险性显著增加5．71—11．67倍（辟O．000）。结论携带GSTMI（-）及CYPlAl（m）等位基因型者患肺癌的危险性上升，二者有协同作用。在重度吸烟人群，CYP及GSTMl的检测有利于发现肺癌的高危人群。     

AT1R基因及CYP基因多态性与妊娠期高血压疾病的相关性

目的 探讨妊娠期高血压疾病的分子遗传学机制.方法 采用聚合酶链反应-限制性内切酶片段长度多态性技术(PCR-RFLP)分别检测87例妊娠期高血压疾病患者(观察组)和175例正常人(对照组)血管紧张素Ⅱ-1型受体(AT1R)基因A1166-C和醛固酮合成酶(CYP11B2)基因-344 T/C突变位点基因型.基因型及等位基因患妊娠期高血压疾病的风险率以比数比(OR)与95%可信区间(95% CI)表示.结果 观察组中AT1R基因的AC基因型频率为33.3%,C等位基因频率为17.2%,相对于AA基因型、A等位基因,OR值分别为1.803、1.711;CYP11B2基因的TC和CC基因型频率分别为40.2%和17.2%,C等位基因频率为37.4%,相对于TT基因型、T等位基因,OR值分别为1.577、6.081、2.114;AT1R和CYP11B2联合基因型分析显示,相对于AA-TT联合基因型,同时携带AC-TC、AA-CC、AC-CC联合基因型的OR值分别为2.407、6.296、7.870.结论 AT1R基因1166C和CYP11B2基因-344C点突变的等位基因可能增加妊娠期高血压疾病的遗传易感性;二者可能共同参与妊娠期高血压疾病的发生.     

GSTM1, GSTT1, GSTP1 and CYPIA1 genetic polymorphisms and susceptibility to esophageal cancer in a French population： Different pattern of squamous cell carcinoma and adenocarcinoma

AIM: To evaluate the association between CYPIA1 and GSTs genetic polymorphisms and susceptibility to esophageal squamous cell carcinoma (SCC) and esophageal adenocarcinorna (ADC) in a high risk area of northwest of France.METHODS: A case-control study was conducted to investigate the genetic polymorphisms of these enzymes (CYPIAI*2C and GSTP1 exon 7 Val alleles, GSTM1 *2/*2 and GSl-l-l*2/*2 null genotypes). A total of 79 esophagealcancer cases and 130 controls were recruited. RESULTS: GSTM2*2/*2 and CYP1A1*1A/*2C genotype frequencies were higher among squamous cell cardnomas at a level close to statistical significance (OR = 1.83, 95% CI0.88-3.83, P= 0.11; OR = 3.03, 95% CI 0.93-9.90, P= 0.07,respectively). For GSTP1 polymorphism, no difference wasfound between controls and cases, whatever their histological status. Lower frequency of GST/-1 deletion was observed in ADC group compared to controls with a statistically significant difference (OR=13.31, 95% CI 1.66-106.92, P&lt;0.01).CONCLUSION: In SCC, our results are consistent with the strong association of this kind of turnout with tobacco exposure. In ADC, our results suggest 3 distinct hypotheses:(1) activation of exogenous procarcinogens, such as small halogenated compounds by GSTTI‘, (2) contribution of GSTT1 to the inflammatory response of esophageal mucosa, which is known to be a strong risk factor for ADC,possibly through leukotriene synthesis; (3) higher sensitivity to the inflammatory process associated with intracellular depletion of glutathione.     

脂蛋白相关磷脂酶 A2基因 R92 H多态性与中国山东地区汉族人群缺血性卒中及其亚型的相关性

目的：探讨脂蛋白相关磷脂酶A2（lipoprotein-associatedphospholipaseA2,Lp-PLA2）基因多态性位点R92H与中国山东地区汉族人群缺血性卒中及其亚型的相关性。方法纳入中国山东地区386例首次发病的缺血性卒中患者和386名健康对照组,根据TOAST 标准将患者进一步分为大动脉粥样硬化性卒中（ large artery atherosclerotic, LAA）和小动脉闭塞性卒中（ smal artery occlusion, SAO）。采用酶联免疫吸附法测定血清Lp-PLA2水平,聚合酶链反应及基因直接测序法测定R92H基因多态性。结果缺血性卒中组、LAA组和SAO组血清Lp-PLA2水平均高于对照组,差异有统计学意义（P均<0.01）。缺血性卒中组GA（P=0.006）、AA（P=0.020）、AA+GA基因型（P=0.009）以及A等位基因（P=0.001）分布频率均显著高于对照组,LAA组GA+AA基因型（P=0.007）及A等位基因（P<0.001）分布频率与对照组相比亦存在统计学差异,而SAO 组则不然。多变量logistic回归分析显示,GA+AA基因型[优势比（odds ratio, OR）1.43,95％可信区间（confidence interval, CI）1.02~2.00;P=0.029]、GA基因型（OR 1.42,95％CI 1.01~2.00;P=0.037）及A等位基因（OR 1.44,95％CI 1.11~2.18;P=0.028）是缺血性卒中发病的独立危险因素。 GA+AA 基因型（ OR 1.73,95％CI 1.18~2.55;P<0.001）和GA基因型（OR 1.67,95％CI 1.13~2.48;P<0.001）是LAA的独立危险因素,而与S AO 无显著独立相关性。结论缺血性卒中患者血清Lp-PLA2水平升高, LAA组升高最明显;R92H基因多态性可能与中国山东地区汉族人群缺血性卒中的易感性有关。     

CYPIA1, GSTs and mEH polymorphisms and susceptibility to esophageal carcinoma： Study of population from a high- incidence area in north China

AIM: To characterize cytochrome P4501A1 (CYPIA1), glutathione S-transferases (GSTs) and microsomal epoxide hydrolase (mEH) polymorphisms in Chinese esophageal cancer patients. METHODS: Multiplex polymerase chain reaction (PCR) and PCR based restriction fragment length polymorphisms (PCRRFLP) were used to detect polymorphism changes of CYP,GSTs and mEH on esophageal cancerous and precancerous lesions as well as in case control group. All the examination samples were obtained from Linzhou (formerly Linxian), Henan Province, the highest incidence area for esophageal. RESULTS: The frequency of CYP1A1 3‘‘ polymorphism in case control group (26/38, 68 %) was significantly higher than in esophageal squamous cell carcinoma~roup (ESCC) (29/62, 47 %) (P&lt;0.05). A significant difference in the incidence of mEH slow allele variant was observed between case control group (15/38, 39 %) and esophageal dysplasiagroup (22/32, 69 %) or ESCC group (39/62, 63 %) (P&lt;0.05). However, no significant difference was observed among different groups in the polymorphisms of CYPIA1 exon 7, GSTM1, GSTT1, GSTP1 and mEH fast allele. CONCLUSION: The present results suggest that CYPIA1 3‘‘ polymorphism may be one of the promising protectivef actors and its wild gene type may be an indicator for higher susceptibility to esophageal cancer, mEH slow allele variant,associated with the progression of esophageal precancerous lesions, may conthbute to the high susceptibility to esophageal carcinoma.     

CYP1A1, CYP2E1 and EPHX1 polymorphisms in sporadic colorectal neoplasms

AIM To investigate the contribution of polymorphisms in the CYP1A1, CYP2E1 and EPHX1 genes on sporadic colorectal cancer(SCRC) risk. METHODS Six hundred forty-one individuals(227 patients with SCRC and 400 controls) were enrolled in the study. The variables analyzed were age, gender, tobacco and alcohol consumption, and clinical and histopathological tumor parameters. The CYP1A1 *2A, CYP1A1 *2C CYP2E1 *5B and CYP2E1 *6 polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP). The EPHX1 Tyr113 His, EPHX1 His139 Arg and CYP1A1 *2C polymorphisms were detected by real-time PCR. Chisquared test and binary logistic regression were used in the statistical analysis. Haplotype analysis was conducted using the Haploview program, version 2.05.RESULTS Age over 6 2 years was a risk factor for SCRC development(OR = 7.54, 95%CI: 4.94-11.50, P 0.01). Male individuals were less susceptible to SCRC(OR = 0.55, 95%CI: 0.35-0.85, P 0.01). The CYP2E1*5B polymorphism was associated with SCRC in the codominant(heterozygous genotype: OR = 2.66, 95%CI: 1.64-4.32, P 0.01), dominant(OR = 2.82, 95%CI: 1.74-4.55, P 0.01), overdominant(OR = 2.58, 95%CI: 1.59-4.19, P 0.01), and log-additive models(OR = 2.84, 95%CI: 1.78-4.52, P 0.01). The CYP2E1*6 polymorphism was associated with an increased SCRC risk in codominant(heterozygous genotype: OR = 2.81, 95%CI: 1.84-4.28, P 0.01; homozygous polymorphic : OR = 7. 3 2, 9 5 % C I : 1.85-28.96, P 0.01), dominant(OR = 2.97, 95%CI: 1.97-4.50, P 0.01), recessive(OR = 5.26, 95%CI: 1.35-20.50, P = 0.016), overdominant(OR = 2.64, 95%CI: 1.74-4.01, P 0.01), and log-additive models(OR = 2.78, 95%CI: 1.91-4.06, P 0.01). The haplotype formed by the minor alleles of the CYP2E1*5B(C) and CYP2E1*6(A) polymorphisms was associated with SCRC(P = 0.002). However, the CYP1A1 *2A, CYP1A1 *2C, EPHX1 Tyr113 His and EPHX1 His139 Arg polymorphisms were not associated with SCRC.CONCLUSION In conclusion, the results demonstrated that CYP2E1*5B and CYP2E1*6 minor alleles play a role in the development of SCRC.     

Cytochrome P450 (CYP) 1A2, sulfotransferase (SULT) 1A1, and N-acetyltransferase (NAT) 2 polymorphisms and susceptibility to urothelial cancer

Purpose Arylamines are suspected to be the primary causative agent of urothelial cancer in tobacco smoke. In the human liver, arylamines are N-hydroxylated by a cytochrome P450 (CYP)1A2-catalyzed reaction, which produces a substrate for O-esterification that can be catalyzed by N-acetyltransferases (NAT) or sulfotransferases (SULT). Recently, several polymorphisms of CYP1A2, SULT1A1, and NAT2 that affect their activities have been reported.Methods In this study, 306 Japanese patients with urothelial transitional cell carcinoma and 306 healthy controls were compared for frequencies of CYP1A2, SULT1A1, and NAT2 genotypes.Results The frequencies of NAT2 intermediate or slow acetylator genotype were significantly higher in the urothelial cancer patients than in the healthy control subjects [odds ratio (OR)=1.49, 95% confidence interval (95% CI) 1.06–2.09, OR=3.23, 95% CI 1.72–6.08, respectively]. Stratifying by amount of smoking, among subjects who consumed >33.5 pack-years and carried the SULT1A1 *1/*1 or NAT2 slow acetylator genotype, the OR was 1.73 (95% CI 1.01–2.97) whereas it was 7.31 (95% CI 1.90–28.05) in non-smokers who carried the homozygous wild genotype, respectively. The relationships between CYP1A2, SULT1A1, and NAT2 polymorphisms and clinical findings including tumor differentiation, stage, and recurrence rate were analyzed. Only associations between NAT2 genotype and pathological findings were admitted, and the higher OR of NAT2 intermediate and slow acetylator genotype was more likely to present to a low-grade tumor (G1) among heavy-smokers.Conclusions Our results suggest that SULT1A1 *1/*1 and NAT2 slow acetylator genotypes might modulate the effect of carcinogenic arylamines contained in tobacco smoke, and that the modulation of NAT2 intermediate and slow acetylator genotype has a tendency to present a higher risk for highly differentiated tumors among heavy-smokers.     

Relationship between genetic polymorphisms of metabolizing enzymes CYP2E1, GSTM1 and Kazakh＇s esophageal squamous cell cancer in Xinjiang, China

AIM: To analyze the relationship between genetic polymorphisms of metabolizing enzymes CYP2E1, GSTM1 and Kazakh's esophageal squamous cell cancer in China. METHODS: The genotypes of cytochromes P450 (CYP) 2E1 and glutathione S-transferase (GST) M1 were investigated by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) following PCR in 104 Kazakh's patients with esophageal cancer (EC) and 104 non-cancer controls. RESULTS: The frequency of CYP2E1 c1/c1 genotype was significantly higher in patients with cancer (77.9%) than in control subjects (24.0%) (P<0.05; OR, 11.13; 95%CI, 5.84-21.22). The difference of GSTM1 null was significantly more frequent in the cancer (34.6%) vs the control group (3.8%) (P<0.05; OR, 13.24; 95%CI, 4.50-38.89). On the other hand, the combination of GSTM1 presence and CYP2E1 c1/c1 genotypes increased the risk for cancer (P<0.05; OR, 13.42; 95%CI, 6.29-28.3). CONCLUSION: The CYP2E1 c1/c1, GSTM1 deletion genotypes are genetically susceptible biomarkers for ESCC in Kazakh population. Individuals with allele c1 of RsaI polymorphic locus for CYP2E1 may increase the risk of ESCC. Moreover, CYP2E1 wild type (c1/c1) increased the susceptibility to ESCC risk in Kazakh individuals with GSTM1 presence genotype.     

Association between dietary heterocyclic amine levels,genetic polymorphisms of NAT2, CYP1A1, and CYP1A2 and risk of colorectal cancer: A hospital-based case-control study in Japan

Objective. Although associations between dietary HCA intake and colorectal cancer risk have been investigated, results have been suggestive but inconsistent. The aim of this hospital-based case-control study was to examine the impact of heterocyclic amine (HCA) intake on colorectal cancer risk. A further objective was to investigate the possible effect of genetic polymorphisms of NAT2, CYP1A1, and CYP1A2 on colorectal cancer. Material and methods. HCA exposure data were assessed using a self-administered food frequency questionnaire, and estimated HCA intake was verified by measuring the PhIP value in human hair. A total of 117 cases and 238 controls were included in these analyses. Odds ratios (ORs) were calculated using conditional logistic regression analysis to compare intake levels between the first and third tertiles. Results. No statistically significant increase in the risk of colorectal cancer with respect to total HCA intake was shown by analysis (OR = 0.99, 95% CI = 0.21–4.81). Furthermore, no association with risk was seen for individual HCAs, including PhIP, MeIQ, and MeIQx. Although variant alleles of CYP1A2 were associated with colorectal cancer (OR = 0.27; 95% CI = 0.07–0.99), genetic polymorphisms of NAT2, CYP1A1, and CYP1A2 did not influence the association of HCA intake with colorectal cancer. Conclusions. In the present study in subjects with low HCA exposure and with a limited sample size, no association was found between HCA intake and colorectal cancer, or any evidence of influence by genetic polymorphisms of NAT2, CYP1A1, and CYP1A2.     

Role of CYP2D6, CYP1A1, CYP2E1, GSTT1, and GSTM1 genes in the susceptibility to acute leukemias

Acute leukemias (ALs) are heterogeneous diseases. Functional polymorphisms in the genes encoding detoxification enzymes cause inter-individual differences, which contribute to leukemia susceptibility. The CYP2D6, CYP1A1, CYP2E1, GSTT1, and GSTM1 polymorphisms in ALL (n = 156) and AML (n = 94) patients and 140 healthy controls were genotyped by PCR and/or PCR-RFLP using blood or bone marrow samples. No association was observed between the GSTT1 gene deletion and patients (OR = 0.8, 95% CI = 0.4-1.7 for AMLs and OR = 0.9, 95% CI = 0.5-1.6 for ALLs). Patients with ALL and AML had a higher prevalence of the GSTM1 deletions compared to controls but only the difference among adult AML patients (OR = 2.1, 95% CI = 1.0-4.2) was statistically significant. The CYP2D6*3 variant allele frequency was lower in the overall acute leukemia patients (0.6%) compared to controls (P = 0.03). CYP2D6*1/*3 genotype frequency also showed a protective association in AML patients (OR = 0.09, 95% CI = 0.01-1.7; P = 0.04). We also found a risk association for CYP2E1*5 in ALL and AML (OR = 3.6, 95% CI = 1.4-9.4 and OR = 3.9, 95% CI = 1.4-10.5, respectively). No association was found for the studied CYP2D6*4, CYP1A1*2A, and GSTT1"null" variants and the risk of acute leuke-mia (ALL or AML). This case-control study suggests a contribution of CYP2E1, CYP2D6, and GSTM1 "null" variants to the development of acute leukemias.     

Genetic polymorphisms in cytochrome P4502E1, alcohol and aldehyde dehydrogenases and the risk of esophageal squamous cell carcinoma in Gansu Chinese males

AIM：To evaluate the association between genetic polymorphisms in CYP2E1, ALDH2 and ADH1B and the risk of esophageal squamous cell carcinoma （ESCC） in a high risk area of Gansu Province, in Chinese males.
METHODS： A case-control study was conducted to investigate the genetic polymorphisms of these enzymes （CYP2E1 ＊c1/＊c2, ALDH2 ＊1/＊2 and ADH1B ＊1/＊1 genotypes）. A total of 80 esophageal cancer cases and 480 controls were recruited.
RESULTS： Compared with controls, cases had a greater prevalence of heavier alcohol consumption （53.8% vs 16.2%） and a higher proportion of alcohol drinkers with 〉 30 drink-years （28.8% vs 13.5%）. Heavier alcohol consumption and alcohol drinking with 〉 30 drink- years increased the risk of ESCC, with ORs （95% CI） of 3.20 （1.32-9.65） and 1.68 （0.96-3.21）. CYP2E1 （＊c1/＊c1）, ALDH2 （＊1/＊2） and ADH1B （＊1/＊1） genotype frequencies were higher among patients with squamous cell carcinomas, at a level close to statistical significance （P = 0.014; P = 0.094; P = 0.0001 respectively）. There were synergistic interactions among alcohol drinking and ALDH2, ADH1B and CYP2E1 genotypes. The risk of the ESCC in moderate-to-heavy drinkers with an inactive ALDH2 encoded by ALDH2 ＊1/＊2 as well as ADH1B encoded by ADH1B ＊1/＊1 and CYP2E1 encoded by CYP2E1 ＊c1/＊c1 was higher than that in the never/rare-to-light drinkers with an active ALDH2 （＊1/＊1 genotype） as well as ADH1B （＊1/＊2 ＋ ＊2/＊2） and CYP2E1 （＊c1/＊c2 ＋ ＊c2/＊c2） genotypes, with a statistically significant difference; ORs （95% CI） of 8.58 （3.28-22.68）, 27.12 （8.52-70.19） and 7.64 （2.82-11.31） respectively. The risk of the ESCC in moderate-to-heavy drinkers with ALDH2 （＊1/＊2） combined the ADH1B （＊1/＊1） genotype or ALDH2 （＊1/＊2） combined the CYP2E1 （＊c1/＊c1） genotype leads to synergistic interactions, higher than drinkers with ALDH2 （＊1/＊1） ＋ ADH1B （＊1/＊2 ＋ ＊2/＊     

Mean corpuscular volume and ADH1C genotype in white patients with alcohol-associated diseases

BACKGROUND: Alcohol abuse is associated with several gastrointestinal diseases, such as esophageal carcinoma, chronic alcoholic pancreatitis, and liver cirrhosis. Increased mean corpuscular volume (MCV) has been recognized as a biomarker for alcohol abuse and heavy drinkers. Recent studies from Japan revealed that macrocytosis is related to ALDH-2/2 genotype, leading to increased acetaldehyde accumulation. It has also demonstrated that increased MCV values could also be an independent biomarker for esophageal cancer in Asians. Therefore, the aim of the current study was to investigate possible associations of MCV value with polymorphisms of ADH1C in white patients with alcohol-associated esophageal carcinoma, chronic alcoholic pancreatitis, and alcoholic cirrhosis as well as in heavy drinkers without organ damage. METHODS: In this study, a total of 510 alcoholic patients were enrolled with esophageal cancer (n = 98), chronic pancreatitis (n = 98), alcoholic liver cirrhosis (n = 151), and alcohol abuse without gastrointestinal disease (n = 163). ADH1C genotyping was performed by PCR-based restriction fragment length polymorphism (PCR-RFLP) analysis from whole blood. The relation between MCV and ADH1C gene polymorphisms (ADH1C*1 and 1C*2) controlled for the amount of drinking, smoking, and age were investigated using both univariate and multivariate analysis. RESULTS: In univariate analysis, higher alcohol consumption was associated with increased MCV. Other variables were not associated with macrocytosis. In multiple linear regression analysis, after adjustment for age and smoking, higher alcohol consumption and female sex were independently associated with higher MCV values. No other variables, including which alcohol-associated disease the patient had, had an independent effect. Adding ADH genotype rendered no independent significant effect on MCV value. CONCLUSIONS: In a white population, MCV values were not associated with genotype polymorphisms of ADH1C. In contrast to findings in Asians, macrocytosis does not seem to be an independent biomarker for esophageal cancer. The role of ADH1C polymorphism in increasing MCV and the potential use of MCV as a marker for esophageal carcinoma are still pending.     

Inhibition of procarcinogen-bioactivating human CYP1A1, CYP1A2 and CYP1B1 enzymes by melatonin

Abstract:  Administration of melatonin to rodents decreases the incidence of tumorigenesis initiated by benzo[ a ]pyrene or 7,12-dimethylbenz[ a ]anthracene, which requires bioactivation by cytochrome P450 enzymes, such as CYP1A1, CYP1A2 and CYP1B1, to produce carcinogenic metabolites. The present study tested the hypothesis that melatonin is a modulator of human CYP1 catalytic activity and gene expression. As a comparison, we also investigated the effect of melatonin on the catalytic activity of CYP2A6, which is also a procarcinogen-bioactivating enzyme. Melatonin (3–300 μ m ) decreased 7-ethoxyresorufin O -dealkylation catalyzed by human hepatic microsomes and recombinant CYP1A1, CYP1A2 and CYP1B1, whereas it did not affect coumarin 7-hydroxylation catalyzed by hepatic microsomes or recombinant CYP2A6. Melatonin inhibited CYP1 enzymes by mixed inhibition, with apparent K _i values (mean ± S.E.M.) of 59 ± 1 (CYP1A1), 12 ± 1 (CYP1A2), 14 ± 2 (CYP1B1) and 46 ± 8 μ m (hepatic microsomes). Additional experiments indicated that melatonin decreased benzo[ a ]pyrene hydroxylation catalyzed by hepatic microsomes and CYP1A2 but not by CYP1A1 or CYP1B1. Treatment of MCF-10A human mammary epithelial cells with melatonin (up to 300 μ m ) did not affect basal or benzo[ a ]pyrene-inducible CYP1A1 or CYP1B1 gene expression. Consistent with this finding, melatonin did not influence reporter activity in aryl hydrocarbon receptor-dependent pGudluc6.1-transfected MCF-10A cells treated with or without benzo[ a ]pyrene, as assessed in an in vitro cell-based luciferase reporter gene assay. Overall, melatonin is an in vitro inhibitor of human CYP1 catalytic activity, and it may be useful to develop potent analogues of melatonin as potential cancer chemopreventive agents that block CYP1-mediated chemical carcinogenesis.