代谢酶基因遗传变异与焦炉工DNA损伤的关联性研究
|
摘要
多环芳烃(polycyclic aromatic hydrocarbons, PAHs)是焦炉逸散物(coke oven emission,COE)中最主要且最重要的致癌成分,可导致机体DNA损伤,而DNA损伤是焦炉工肺癌发病的主要原因。PAHs与多环芳烃受体(aryl hydrocarbon receptor, AhR)结合,导致AhR空间结构发生变化,入核后诱导多种外源性化学物代谢酶的合成,如I相代谢酶细胞色素P4501A1(cytochrome P4501A1, CYP1A1)、细胞色素P4501B1(cytochrome P4501B1, CYP1B1)、细胞色素P4502B6(cytochrome P4502B6, CYP2B6)、细胞色素P4502E1(cytochrome P4502E1, CYP2E1)。PAHs必须经过代谢酶的代谢活化之后才具有致癌性,其毒性除与本身的理化性质有关外,还与个体间遗传变异有关。在职业流行病学癌症危险度的研究中发现,作为体内致癌物PAHs代谢的关键酶CYPs,其亚家族成员CYP1A1、CYP1B1、CYP2B6和CYP2E1催化PAHs中重要致癌物苯并芘(benzo[a]pyrene, B[a]P)经CYPs催化代谢为终产物苯并(a)芘二氢二醇环氧化物(benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide, BPDE),此终产物可与DNA和血浆中的白蛋白形成共价加合物,导致DNA的损伤。据我们所知,目前国内外研究均采用1-OHP作为PAHs职业暴露标志物,由于1-OHP生物半衰期比较短,只能反映短期内的PAHs的暴露水平,且绝大部分经尿液排出,参与DNA损伤的量极少,因此存在局限性。血浆BPDE-白蛋白加合物在血中含量较高,生物半衰期较长,可反映PAHs长期暴露水平,尽管血浆BPDE-白蛋白加合物在焦炉工人中的应用已有报道,但还未见有关研究其作为PAHs暴露标志物的报道,因此,本研究试图通过代谢酶与焦炉工血浆BPDE-白蛋白加合物及DNA损伤的关联研究,探讨焦炉工血浆BPDE-白蛋白加合物作为PAHs暴露标志物的可行性,以及在遗传学的基础上找到与焦炉工PAHs暴露与癌症风险的潜在敏感因素,为焦炉作业工人的职业暴露危害防治提供科学依据。本研究共分以下三个部分:
第一部分研究对象基本情况
采用职业流行病学调查方法,选取202例男性焦炉工人作为暴露组,96例来自同一工厂的男性机关管理人员以及医务人员作为对照组。通过问卷调查获得研究人群的一般资料,如年龄、工龄、吸烟及饮酒等。采用反相高效液相色潽法(reverse phase-high performance liquid chromatography, RP-HPLC)测定血浆中BPDE-白蛋白加合物水平以及碱性单细胞凝胶电泳实验检测彗星尾距(Olive Tail Moment, OTM)。结果显示,两组研究人群在年龄、工龄、吸烟及饮酒方面没有显著性差异(P>0.05)。焦炉作业工人血浆BPDE-白蛋白加合物水平(经自然对数转换后),在暴露组为(3.55( 2.37-4.11 ))显著高于对照组(3.06(1.47-2.85)),差异有显著性意义(P<0.01);外周血淋巴细胞OTM值(经自然对数转换后),在暴露组为(1.25±1.09)显著高于对照组(0.55±0.93),差异有显著性意义(P<0.01)。本部分结果提示焦炉工人中PAHs暴露标志物血浆BPDE-白蛋白加合物水平以及外周血淋巴细胞OTM值与对照组比较具有显著性差异。
第二部分代谢酶基因多态性与血浆BPDE-白蛋白加合物的关联性研究
焦炉工血浆BPDE-白蛋白加合物具有化学特性,因此其形成可能受诸多因素如PAHs外环境暴露水平、体内代谢酶的作用、以及吸烟、饮酒、饮食和生活方式等的影响。本部分通过对影响焦炉工血浆BPDE-白蛋白加合物形成的因素、代谢酶基因多态性与血浆中BPDE-白蛋白加合物水平的关联研究,探讨焦炉工血浆BPDE-白蛋白加合物作为PAHs的暴露标志物的可行性。根据国际人类基因组单体型图计划(International HapMap project, HapMap)数据库挑选了I相代谢酶中4个关键酶基因共12个标记性单核苷酸多态性(tagging single nucleotide polymorphism, tagSNPs),采用基质辅助激光解析电离飞行时间质谱技术,对298名焦炉工人进行基因分型,结果发现经校正了年龄、工龄、吸烟和饮酒因素后,在暴露组中,CYP2B6基因rs3760657位点GA+AA基因型携带者血浆BPDE-白蛋白加合物水平(3.31(2.01-4.07))显著低于GG基因型携带者(3.59(2.67-4.27)),差异有显著性意义(P<0.05)。单体型对分析结果显示,在对照组中,CYP2E1基因GC/GT单体型对携带者血浆BPDE-白蛋白加合物水平最低为(3.00(0.96-3.73)),与人群中分布最广泛的CG/CG单体型对相比(3.63(2.97-4.25)),差别有显著性意义(P<0.05)。本部分结果提示代谢酶基因的遗传变异是影响焦炉工血浆中BPDE-白蛋白加合物水平的主要因素,可将焦炉工血浆BPDE-白蛋白加合物作为PAHs的暴露标志物。
第三部分代谢酶基因多态性与焦炉工DNA损伤的关联性研究
体内的致癌物PAHs(以致癌性最强的B[a]P为代表),一般先由I相代谢酶CYPs氧化、还原、水解等作用,改变毒物的功能基团,使其降解或转变为亲电子极团而具致癌作用,其代谢产物BPDE与体内DNA和/或蛋白质形成共价加合物,造成DNA损伤。然而,目前流行病学研究资料中,有关代谢酶基因遗传变异与DNA损伤关联性研究甚少,且各结论间存在争议。因此,我们假设代谢酶基因遗传变异在焦炉工DNA损伤过程中起着重要的作用,探讨代谢酶基因遗传变异与DNA损伤的关联。利用第二部分的代谢酶基因12个tagSNPs的分型资料,按经对数转换后的血浆BPDE-白蛋白加合物水平的三分位数分为低暴露组、中暴露组和高暴露组3组。结果发现在高暴露组中,CYP2B6基因rs1042389位点TC基因型携带者外周血淋巴细胞OTM值(1.04±1.06)显著低于TT基因型携带者(1.51±1.05),差异有显著性意义(P<0.05)。CYP1A1基因、CYP1B1基因和CYP2E1基因的遗传变异与焦炉工DNA损伤程度无显著关联。综上所述,本研究结果提示,焦炉工人暴露于PAHs后其暴露标志物血浆BPDE-白蛋白加合物水平均明显增高,且代谢酶基因多态性是影响其形成的主要因素,因此,我们认为可以将焦炉工血浆BPDE-白蛋白加合物作为PAHs的暴露标志物;与PAHs相关的代谢酶对焦炉工人DNA损伤效应有重要关联,个体易感性差异对遗传效应有重要影响。
本研究的创新之处在于:(1)首次发现代谢酶基因尤其是CYP2B6基因多态性可降低血浆中BPDE-白蛋白加合物的水平;(2)探讨了代谢酶基因的遗传变异与DNA损伤程度的关联性,发现CYP2B6基因遗传变异显著降低了焦炉工DNA的损伤程度。
本课题局限性以及有待深入研究的方面有:(1) PAHs的代谢过程复杂,涉及到多种代谢酶基因,而这些基因可能都存在有大量SNPs,本次研究仅是初步探讨了I相代谢酶CYP1A1、CYP1B1、CYP2B6和CYP2E1四个基因的12个SNPs位点与PAHs致DNA损伤之间的关联,但其他代谢酶基因多态性对PAHs致机体的影响,如何评价焦炉工人的整体代谢过程,基因与基因的联合作用、基因与环境之间的复杂联合作用等,都需要进一步研究。因此我们目前所探讨的代谢酶基因的多态性对PAHs致机体效应的风险影响是不足的;(2)随着全基因组关联研究(genome-wide association studies, GWAS)的实施,本次少数基因少数位点的研究在解释科学假设时是不够的,因此有必要在更大的样本中验证本研究获得的阳性结果;(3)此外,对SNPs位点的细胞功能学研究不足,如可采用报告基因转染,凝胶迁移滞后实验等技术深入验证启动子区域SNPs的功能改变。
Polycyclic aromatic hydrocarbons (PAHs) may cause DNA damage, which is the main cause for lung cancer of coke oven workers. Epidemiological studies have showed that coke oven workers had different DNA damage levels with a similar environmental PAHs exposure levels, suggesting that genetic variations may play an important role in the individual’s genetic toxicity. PAHs are regulated by aryl hydrocarbon receptor (AhR). Upon ligand activation, the AhR translocates into nucleus, induce xenobiotics metabolic enzymes synthesis, including cytochrome P4501A1 (CYP1A1), cytochrome P4501B1 (CYP1B1), cytochrome P4502B6 (CYP2B6) and cytochrome P4502E1 (CYP2E1).
Although urinary 1-hyrdroxyprene (1-OHP) was used as PAHs exposure markers in numerous studies, there are limitations because urinary 1-OHP is used to assess recent exposure to PAHs only. Plasma BPDE-Alb adducts may be considered as PAHs exposure markers in coke oven workers because of its longer half-life. Therefore, we attempted to discuss the feasibility about using plasma BPDE-Alb adducts as PAHs exposure markers and hypothesized that the single nucleotide polymorphisms (SNPs) which exist in the CYP1A1 gene, CYP1B1 gene, CYP2B6 gene and CYP2E1 gene may affect the DNA damage in coke oven workers. This study aimed to identify the associations between genetic variants of CYP1A1, CYP1B1, CYP2B6 and CYP2E1 genes and plasma BPDE-Alb adducts, and DNA damage levels of coke oven workers, which would identify exposure markers and find the cancer risk potential sensitive factors for occupational exposure risk prevention.
PartⅠEpidemiology study of research subjects
A total of 298 male subjects were recruited from a steel plant in Taiyuan, northern China, of whom 202 coke oven workers were defined as exposure groups, the other 96 non coke oven workers from the same plant were used as control groups. We detected the plasma BPDE-Alb adducts levels using reverse phase-high performance liquid chromatography (RP-HPLC), and measured Olive Tail Moment (OTM) by alkaline single cell gel electrophoresis experiment. The results showed that there were no significant difference of age, length of work, smoking and drinking between the exposure and control groups (P>0.05). The in-transformed plasma BPDE-Alb adducts concentration (median, 25-75 percentile) in coke oven workers (3.55(2.37-4.11)) was significantly higher than control groups (3.06(1.47-2.85)) (P<0.01). The in-transformed Olive Tail Moment value in coke oven workers (1.25±1.09) was higher than control groups (0.55±0.93) (P<0.01). These results demonstrated that there were significant differences of plasma BPDE-Alb adduct levels and OTM values between coke oven workers and control groups.
PartⅡAssociations of genetic variations in metabolism enzymes genes and plasma BPDE-Alb adducts in coke oven workers
There are many factors including PAHs environmental exposure levels, metabolic enzyme function, smoking and drinking may influence plasma BPDE-Alb adducts levels. In this part, we discussed the feasibility of using plasma BPDE-Alb adducts as PAHs exposure markers in coke oven workers. According to the Han Chinese Beijing data in the HapMap project, we selected 12 tagSNPs in metabolic enzymes gene. We genotyped the selected tagSNPs in 298 study subjects by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) techniques. Our results indicated in exposed groups CYP2B6 gene rs3760657 loci GA+AA genotype carriers had significantly lower plasma BPDE-Alb adducts (3.31(2.01-4.07)) compared with GG genotype carriers (3.59(2.67-4.27)) (P<0.05). The diplotype analysis revealed that the CYP2E1 GC/GT diplotype carriers had the lowest plasma BPDE-Alb adducts levels (3.00(0.96-3.73)) compared with that of the most widely distributed CG/CG diplotype carriers (3.63(2.97-4.25)) (P<0.05) in control groups. The results of this part suggested that the main factor affect plasma BPDE-Alb adducts levels was the genetic variations of CYP2B6 gene. The results of this part warrant validation by larger populations.
PartⅢAssociations of genetic variations in metabolism enzymes genes and DNA damage in coke oven workers
Carcinogens PAHs are oxidated, reducted, hydrolyzed and changed toxic function first commonly by I phase metabolic enzymes CYPs. DNA damage is induced by the end products BPDE of PAHs through direct DNA and/or protein binding. Therefore, we hypothesized that the genetic variations in CYPs genes play an important role in DNA damage in coke oven workers, and explored the associations of genetic variations in CYPs genes and DNA damage. We divided the sujects into three groups according to plasma BPDE-Alb adducts. The results showed that CYP2B6 gene rs1042389 loci TC genotype carriers DNA damage levels (1.04±1.06) was lower than TT genotype carriers (1.51±1.05) in high exposure groups (P<0.05). However, there were no associations between the other genes (CYP1A1 gene, CYP1B1 gene and CYP2E1 gene) and DNA damage levels in the three groups. The results of this part suggested that genetic variations in CYP2B6 gene may prevent coke oven workers from DNA damage.
In summary, we selected 12 tagSNPs in the CYP1A1, CYP1B1, CYP2B6 and CYP2E1 genes and detected their associations with plasma BPDE-Alb adducts levels and DNA damage. There are some advantages in this study, to our knowledge, it was the first study using plasma BPDE-Alb adducts as PAHs exposure markers; Our study provided the first evidence that genetic variations in CYP2B6 gene were associated with plasma BPDE-Alb adducts and DNA damage.
There were several limitations in our study that need to be addressed. First, it was insufficient only discussed the association among CYP1A1, CYP1B1, CYP2B6 and CYP2E1 genes and DNA damage, for the complex process of PAHs metabolism. Second, the association between SNPs in the CYP2B6 gene and plasma BPDE-Alb adducts and DNA damage should be validated by larger population studies. Finally, there were no functional investigations of positive SNPs sites in this study.
第一部分研究对象基本情况
采用职业流行病学调查方法,选取202例男性焦炉工人作为暴露组,96例来自同一工厂的男性机关管理人员以及医务人员作为对照组。通过问卷调查获得研究人群的一般资料,如年龄、工龄、吸烟及饮酒等。采用反相高效液相色潽法(reverse phase-high performance liquid chromatography, RP-HPLC)测定血浆中BPDE-白蛋白加合物水平以及碱性单细胞凝胶电泳实验检测彗星尾距(Olive Tail Moment, OTM)。结果显示,两组研究人群在年龄、工龄、吸烟及饮酒方面没有显著性差异(P>0.05)。焦炉作业工人血浆BPDE-白蛋白加合物水平(经自然对数转换后),在暴露组为(3.55( 2.37-4.11 ))显著高于对照组(3.06(1.47-2.85)),差异有显著性意义(P<0.01);外周血淋巴细胞OTM值(经自然对数转换后),在暴露组为(1.25±1.09)显著高于对照组(0.55±0.93),差异有显著性意义(P<0.01)。本部分结果提示焦炉工人中PAHs暴露标志物血浆BPDE-白蛋白加合物水平以及外周血淋巴细胞OTM值与对照组比较具有显著性差异。
第二部分代谢酶基因多态性与血浆BPDE-白蛋白加合物的关联性研究
焦炉工血浆BPDE-白蛋白加合物具有化学特性,因此其形成可能受诸多因素如PAHs外环境暴露水平、体内代谢酶的作用、以及吸烟、饮酒、饮食和生活方式等的影响。本部分通过对影响焦炉工血浆BPDE-白蛋白加合物形成的因素、代谢酶基因多态性与血浆中BPDE-白蛋白加合物水平的关联研究,探讨焦炉工血浆BPDE-白蛋白加合物作为PAHs的暴露标志物的可行性。根据国际人类基因组单体型图计划(International HapMap project, HapMap)数据库挑选了I相代谢酶中4个关键酶基因共12个标记性单核苷酸多态性(tagging single nucleotide polymorphism, tagSNPs),采用基质辅助激光解析电离飞行时间质谱技术,对298名焦炉工人进行基因分型,结果发现经校正了年龄、工龄、吸烟和饮酒因素后,在暴露组中,CYP2B6基因rs3760657位点GA+AA基因型携带者血浆BPDE-白蛋白加合物水平(3.31(2.01-4.07))显著低于GG基因型携带者(3.59(2.67-4.27)),差异有显著性意义(P<0.05)。单体型对分析结果显示,在对照组中,CYP2E1基因GC/GT单体型对携带者血浆BPDE-白蛋白加合物水平最低为(3.00(0.96-3.73)),与人群中分布最广泛的CG/CG单体型对相比(3.63(2.97-4.25)),差别有显著性意义(P<0.05)。本部分结果提示代谢酶基因的遗传变异是影响焦炉工血浆中BPDE-白蛋白加合物水平的主要因素,可将焦炉工血浆BPDE-白蛋白加合物作为PAHs的暴露标志物。
第三部分代谢酶基因多态性与焦炉工DNA损伤的关联性研究
体内的致癌物PAHs(以致癌性最强的B[a]P为代表),一般先由I相代谢酶CYPs氧化、还原、水解等作用,改变毒物的功能基团,使其降解或转变为亲电子极团而具致癌作用,其代谢产物BPDE与体内DNA和/或蛋白质形成共价加合物,造成DNA损伤。然而,目前流行病学研究资料中,有关代谢酶基因遗传变异与DNA损伤关联性研究甚少,且各结论间存在争议。因此,我们假设代谢酶基因遗传变异在焦炉工DNA损伤过程中起着重要的作用,探讨代谢酶基因遗传变异与DNA损伤的关联。利用第二部分的代谢酶基因12个tagSNPs的分型资料,按经对数转换后的血浆BPDE-白蛋白加合物水平的三分位数分为低暴露组、中暴露组和高暴露组3组。结果发现在高暴露组中,CYP2B6基因rs1042389位点TC基因型携带者外周血淋巴细胞OTM值(1.04±1.06)显著低于TT基因型携带者(1.51±1.05),差异有显著性意义(P<0.05)。CYP1A1基因、CYP1B1基因和CYP2E1基因的遗传变异与焦炉工DNA损伤程度无显著关联。综上所述,本研究结果提示,焦炉工人暴露于PAHs后其暴露标志物血浆BPDE-白蛋白加合物水平均明显增高,且代谢酶基因多态性是影响其形成的主要因素,因此,我们认为可以将焦炉工血浆BPDE-白蛋白加合物作为PAHs的暴露标志物;与PAHs相关的代谢酶对焦炉工人DNA损伤效应有重要关联,个体易感性差异对遗传效应有重要影响。
本研究的创新之处在于:(1)首次发现代谢酶基因尤其是CYP2B6基因多态性可降低血浆中BPDE-白蛋白加合物的水平;(2)探讨了代谢酶基因的遗传变异与DNA损伤程度的关联性,发现CYP2B6基因遗传变异显著降低了焦炉工DNA的损伤程度。
本课题局限性以及有待深入研究的方面有:(1) PAHs的代谢过程复杂,涉及到多种代谢酶基因,而这些基因可能都存在有大量SNPs,本次研究仅是初步探讨了I相代谢酶CYP1A1、CYP1B1、CYP2B6和CYP2E1四个基因的12个SNPs位点与PAHs致DNA损伤之间的关联,但其他代谢酶基因多态性对PAHs致机体的影响,如何评价焦炉工人的整体代谢过程,基因与基因的联合作用、基因与环境之间的复杂联合作用等,都需要进一步研究。因此我们目前所探讨的代谢酶基因的多态性对PAHs致机体效应的风险影响是不足的;(2)随着全基因组关联研究(genome-wide association studies, GWAS)的实施,本次少数基因少数位点的研究在解释科学假设时是不够的,因此有必要在更大的样本中验证本研究获得的阳性结果;(3)此外,对SNPs位点的细胞功能学研究不足,如可采用报告基因转染,凝胶迁移滞后实验等技术深入验证启动子区域SNPs的功能改变。
Polycyclic aromatic hydrocarbons (PAHs) may cause DNA damage, which is the main cause for lung cancer of coke oven workers. Epidemiological studies have showed that coke oven workers had different DNA damage levels with a similar environmental PAHs exposure levels, suggesting that genetic variations may play an important role in the individual’s genetic toxicity. PAHs are regulated by aryl hydrocarbon receptor (AhR). Upon ligand activation, the AhR translocates into nucleus, induce xenobiotics metabolic enzymes synthesis, including cytochrome P4501A1 (CYP1A1), cytochrome P4501B1 (CYP1B1), cytochrome P4502B6 (CYP2B6) and cytochrome P4502E1 (CYP2E1).
Although urinary 1-hyrdroxyprene (1-OHP) was used as PAHs exposure markers in numerous studies, there are limitations because urinary 1-OHP is used to assess recent exposure to PAHs only. Plasma BPDE-Alb adducts may be considered as PAHs exposure markers in coke oven workers because of its longer half-life. Therefore, we attempted to discuss the feasibility about using plasma BPDE-Alb adducts as PAHs exposure markers and hypothesized that the single nucleotide polymorphisms (SNPs) which exist in the CYP1A1 gene, CYP1B1 gene, CYP2B6 gene and CYP2E1 gene may affect the DNA damage in coke oven workers. This study aimed to identify the associations between genetic variants of CYP1A1, CYP1B1, CYP2B6 and CYP2E1 genes and plasma BPDE-Alb adducts, and DNA damage levels of coke oven workers, which would identify exposure markers and find the cancer risk potential sensitive factors for occupational exposure risk prevention.
PartⅠEpidemiology study of research subjects
A total of 298 male subjects were recruited from a steel plant in Taiyuan, northern China, of whom 202 coke oven workers were defined as exposure groups, the other 96 non coke oven workers from the same plant were used as control groups. We detected the plasma BPDE-Alb adducts levels using reverse phase-high performance liquid chromatography (RP-HPLC), and measured Olive Tail Moment (OTM) by alkaline single cell gel electrophoresis experiment. The results showed that there were no significant difference of age, length of work, smoking and drinking between the exposure and control groups (P>0.05). The in-transformed plasma BPDE-Alb adducts concentration (median, 25-75 percentile) in coke oven workers (3.55(2.37-4.11)) was significantly higher than control groups (3.06(1.47-2.85)) (P<0.01). The in-transformed Olive Tail Moment value in coke oven workers (1.25±1.09) was higher than control groups (0.55±0.93) (P<0.01). These results demonstrated that there were significant differences of plasma BPDE-Alb adduct levels and OTM values between coke oven workers and control groups.
PartⅡAssociations of genetic variations in metabolism enzymes genes and plasma BPDE-Alb adducts in coke oven workers
There are many factors including PAHs environmental exposure levels, metabolic enzyme function, smoking and drinking may influence plasma BPDE-Alb adducts levels. In this part, we discussed the feasibility of using plasma BPDE-Alb adducts as PAHs exposure markers in coke oven workers. According to the Han Chinese Beijing data in the HapMap project, we selected 12 tagSNPs in metabolic enzymes gene. We genotyped the selected tagSNPs in 298 study subjects by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) techniques. Our results indicated in exposed groups CYP2B6 gene rs3760657 loci GA+AA genotype carriers had significantly lower plasma BPDE-Alb adducts (3.31(2.01-4.07)) compared with GG genotype carriers (3.59(2.67-4.27)) (P<0.05). The diplotype analysis revealed that the CYP2E1 GC/GT diplotype carriers had the lowest plasma BPDE-Alb adducts levels (3.00(0.96-3.73)) compared with that of the most widely distributed CG/CG diplotype carriers (3.63(2.97-4.25)) (P<0.05) in control groups. The results of this part suggested that the main factor affect plasma BPDE-Alb adducts levels was the genetic variations of CYP2B6 gene. The results of this part warrant validation by larger populations.
PartⅢAssociations of genetic variations in metabolism enzymes genes and DNA damage in coke oven workers
Carcinogens PAHs are oxidated, reducted, hydrolyzed and changed toxic function first commonly by I phase metabolic enzymes CYPs. DNA damage is induced by the end products BPDE of PAHs through direct DNA and/or protein binding. Therefore, we hypothesized that the genetic variations in CYPs genes play an important role in DNA damage in coke oven workers, and explored the associations of genetic variations in CYPs genes and DNA damage. We divided the sujects into three groups according to plasma BPDE-Alb adducts. The results showed that CYP2B6 gene rs1042389 loci TC genotype carriers DNA damage levels (1.04±1.06) was lower than TT genotype carriers (1.51±1.05) in high exposure groups (P<0.05). However, there were no associations between the other genes (CYP1A1 gene, CYP1B1 gene and CYP2E1 gene) and DNA damage levels in the three groups. The results of this part suggested that genetic variations in CYP2B6 gene may prevent coke oven workers from DNA damage.
In summary, we selected 12 tagSNPs in the CYP1A1, CYP1B1, CYP2B6 and CYP2E1 genes and detected their associations with plasma BPDE-Alb adducts levels and DNA damage. There are some advantages in this study, to our knowledge, it was the first study using plasma BPDE-Alb adducts as PAHs exposure markers; Our study provided the first evidence that genetic variations in CYP2B6 gene were associated with plasma BPDE-Alb adducts and DNA damage.
There were several limitations in our study that need to be addressed. First, it was insufficient only discussed the association among CYP1A1, CYP1B1, CYP2B6 and CYP2E1 genes and DNA damage, for the complex process of PAHs metabolism. Second, the association between SNPs in the CYP2B6 gene and plasma BPDE-Alb adducts and DNA damage should be validated by larger population studies. Finally, there were no functional investigations of positive SNPs sites in this study.
引文
1. IARC, IARC Monographs on the evaluation of carcinogenic risks to human.No.32, part 1, polynuclear aromatic compounds. IARC, 1983.
2. Lodovici M, Luceri C, Guglielmi F, et al. Benzo(a)pyrene diolepoxide (BPDE)-DNA adduct levels in leukocytes of smokers in relation to polymorphism of CYP1A1, GSTM1, GSTP1, GSTT1, and mEH. Cancer Epidemiol Biomarkers Prev, 2004, 13(8): 1342-1348.
3. Wang S, Chanock S, Tang D, et al. Assessment of interactions between PAH exposure and genetic polymorphisms on PAH-DNA adducts in African American, Dominican, and Caucasian mothers and newborns. Cancer Epidemiol Biomarkers Prev, 2008, 17(2): 405-413.
4. Hu Y, Li G, Xue X, et al. PAH-DNA adducts in a Chinese population: relationship to PAH exposure, smoking and polymorphisms of metabolic and DNA repair genes. Biomarkers, 2008, 13(1): 27-40.
5. Shimada T, Watanabe J and Kawajiri K. Catalytic properties of polymorphic human cytochrome P450 1B1 variants. Carcinogenesis, 1999, 20: 1607-1613.
6. Mammen JS, Pittman GS and Li Y. Single amino acid mutations, but not common polymorphisms, decrease the activity of CYP1B1 against (-)benzo[a] pyrene-7R-trans-7, 8-dihydrodiol. Carcinogenesis, 2003, 24: 1247-1255.
7. Aklillu E, Ovrebo S and Botnen IV. Characterization of common CYP1B1 variants with different capacity for benzo[a]pyrene-7, 8-dihydrodiol epoxide formation from benzo[a]pyrene. Cancer Res, 2005, 65: 5105-5111.
8. Bandiera S, Weidlich S and Harth V. Proteasomal degradation of human CYP1B1:effect of the Asn453Ser polymorphism on the post-translational regulation of CYP1B1 expression. Mol Pharmacol, 2005, 67: 435-443.
9. Christian CA, Renato BF, Paul TS, et al. 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. Carcinogenesis, 2007, 28: 112-117.
10. Yang M, Jang JY and Kim S. Genetic effects on urinary 1-hydroxypyrene levels in a Korean population. Carcinogenesis, 2003, 24: 1085-1089.
11. Rihs HP, Pesch B and Kappler M. Occupational exposure to polycyclic aromatic hydrocarbons in German industries: association between exogenous exposure and urinary metabolites and its modulation by enzyme polymorphisms. Toxicol Lett, 2005, 157: 241-255.
12. Rendic S. Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev, 2002, 34(1-2): 83-448.
13. Zanger UM, Klein K, Saussele T, et al. Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics, 2007, 8(7): 743-759.
14. Zhang J, Tian Q, Zhu YZ, et al. Reversal of resistance to oxazaphosphorines. Curr Cancer Drug Targets, 2006, 6(5): 385-407.
15.戴宇飞,冷曙光,潘祖飞,等.萘代谢产物-白蛋白加合物作为焦炉工接触生物标志物的初步探讨.中华预防医学杂志, 2004, 38(6): 392-395.
16. Nan HM, Kim H, Lim HS, et al. Effects of occupation, lifestyle and genetic polymorphisms of CYP1A1, CYP2E1, GSTM1 and GSTT1 on urinary 1-hydrox- ypyrene and 2-naphthol concentrations. Carcinogenesis, 2001, 22(5): 787-793.
17. Wells PG, McCallum GP, Lam KC, et al. Oxidative DNA Damage and Repair in Teratogenesis and Neurodevelopmental. Birth Defects Res C Embryo Today, 2010, 90(2):103-109. Review
18. Seidel A, Spickenheuer A, Straif K, et al. New biomarkers of occupational exposure to polycyclic aromatic hydrocarbons. J Toxicol Environ Health A, 2008, 71(11-12): 734-745.
19. Autrup H, Vestergaard AB and Okkels H. Transplacental transfer of environmental genotoxins: polycyclic aromatic hydrocarbon-albumin in non-smoking women, and the effect of maternal GSTM1 genotype. Carcinogenesis, 1995, 16(6): 1305-1309.
20. Melikian AA, Sun P, Pierpont C, et al. Gas chromatography–mass spectrometric determination of benzo[a]pyrene and chrysene diol epoxide globin adducts in humans. Cancer Epidemiol Biomarkers Prev, 1997, 6: 833-839.
21. Scherer G, Frank S, Riedel K, et al. Biomonitoring of exposure to polycyclic aromatic hydrocarbons of nonoccupationally exposed persons. Cancer Epidemiol Biomarkers Prev, 2000, 9: 373-380.
22. Pastorelli R, Guanci M, Cerri A, et al. Impact of inherited polymorphisms in glutathione S-transferase M1, microsomal epoxide hydrolase, cytochrome 450 enzymes on DNA, and blood protein adducts of benzo[a]pyrene-diol epoxide. Cancer Epidemiol Biomarkers Prev, 1998, 7: 703-709.
23. Day BW, Skipper PL and Zaia J. Enantiospecificity of covalent adduct formation by benzo[a]pyrene anti-diol epoxide with human serum albumin. Chem Res Toxicol, 1994, 7(6): 829-835.
24. Hemminki K. DNA adducts in biomonitoring. J Occup Environ Med, 1999, 37(1): 44-49.
25. Meyer MJ and Bechtold WE. Protein adducts biomarkers: state of the art. Environ Health Perspect, 1996, 104(5): 879-882.
26. Nielsen PS, de Pater N, Okkels H, et al. Environmental air pollution and DNA adducts in Copenhagen bus drivers--effect of GSTM1 and NAT2 genotypes on adduct levels. Carcinogenesis, 1996, 17(5): 1021-1027.
27. Pastorelli R, Cerri A, Minoia C, et al. Benzo[a]pyrene diolepoxide adducts to albumin in workers exposed to polycyclic aromatic hydrocarbons: association with specific CYP1A1, GSTM1, GSTP1 and EHPX genotypes. Biomarkers, 2001, 357-374.
28. Van Delft JH, Steenwinkel MS, van Asten JG, et al. Biological monitoring the exposure to polycyclic aromatic hydrocarbons of coke oven workers in relation to smoking and genetic polymorphisms for GSTM1 and GSTT1. Ann Occup Hyg, 2001, 45(5): 395-408.
29. Chen YW, BaiY, Yuan J, et al. Association of polymorphisms in AhR, CYP1A1, GSTM1 and GSTT1 genes with levels of DNA damage in peripheral blood lymphocytes among coke-oven workers. Cancer Epidemiol Biomarkers Prev, 2006, 15(9): 1703-1707.
30. Wang H, Chen WH, Zheng HY, et al. Association between plasma BPDE-Alb adducts concentrations and DNA damage of peripheral blood lymphocytes among coke oven workers. Occup Environ Med, 2007, 64:753-758.
31. IARC, Monographs on the evaluation of the carcinogenic risk of chemicals to humans. Polycyclic aromatic hydrocarbons. Industrial exposure in aluminum production, coal gasification, coke production, and iron and steel founding. IARC, 1984, 34.
32. IARC, Monographs on the evaluation of the carcinogenic risk of chemicals to humans. IARC, 1987, Suppl. 7.
33. Akin FJ, Chamberlain WJ and Chortyk OT. Mouse skin tumorigenesis and induction of aryl hydrocarbon hydroxylase by tobacco smoke fractions. J Natl Cancer Inst, 1975, 54(4):907-912.
34.王红.博士毕业论文.华中科技大学图书馆, 2005.
35. Frank S, Renner T, Ruppert T, et al. Determination of albumin adducts of (+)-anti-benzo[a]pyrene-diol-epoxide using a high-performance liquid chromatographic column switching technique for sample preparation and gas chromatography-mass spectrometry for the final detection. J Chromatogr B Biomed Sci Appl, 1998, 713(2):331-337.
36. Islam GA, Greibrokk T, Harvey RG, et al. HPLC analysis of benzo[a]pyrene-albumin adducts in benzo[a]pyrene exposed rats. Detection of cis-tetrols arising from hydrolysis of adducts of anti- and syn-BPDE-III with proteins. Chem Biol Interact, 1999, 123(2):133-148.
37.郭嘉,罗晔,陈延林,等.燃煤烟气中多环芳烃(PAHs)光化学降解的研究.能源环境保护, 2006, 20(2):25-28.
38.王芳.博士毕业论文.华中科技大学图书馆, 2009.
39. Vaghef H, Wisén AC and Hellman B. Demonstration of benzo[a]pyrene-induced DNA damage in mice by alkaline single cell gel electrophoresis: evidence for strand breaks in liver but not in lymphocytes and bone marrow. Pharmacol Toxicol, 1996, 78(1):37-43.
40.朱志良,庄志雄,黄钰,等.单细胞凝胶电泳图像分析系统的研制与应用.中华劳动卫生职业病杂志, 2001, 19:298-300.
41. Tas S, Buche JP and Lauwery SR. Determinants of benzo[a]pyrene-diol-epoxide adducts to albumin in workers exposed to polycyclic aromatic hydrocarbons. Int Arch Occup Environ Health, 1994, 66: 343-348.
42. Salagovic J, Kalina I and Dubayova K. Induction of singles strand DNA breaks in workers professionally exposed to polycyclic aromatic hydrocarbons. Neoplasma, 1995, 42:115-118.
43. Popp W, Vahrenholz C and Schell C. DNA single strand breakage, DNA adducts, and sister chromatid exchange in lymphocytes and phenanthrene and pyrene metabolites in urine of coke oven workers. Occup Environ Med, 1997, 54: 176-183.
44.冷曙光,郑玉新,牛勇,等.焦炉作业工人多环芳烃暴露与外周血淋巴细胞DNA损伤的关系.中华劳动卫生职业病杂志, 2004, 22(4): 250-253.
45. Van Rooij JC, Bodelier-Bade MM and JongeneeIen FJ. Estimation of individual dermal and respiratory uptake of polycyclic aromatic hydrocarbons in 12 coke oven workers. Br J Ind Med, 1993, 50: 623-632.
46. Kang DH, Rothman N, Poirier MC, et al. Interindividual differences in the concentration of 1-hydroxypyrene-glucuronide in urine and polycyclic aromatic hydrocarbon-DNA adducts in peripheral white blood cells after charbroiled beef consumption. Carcinogenesis, 1995, 6(5):1079-1085.
47. Strickland P, Kang D and Sithisarankul P. Polycyclic aromatic hydrocarbon metabolites in urine as biomarkers of exposure and effect. Environ Health Perspect, 1996, 104(5):927-932. Review.
48. Wu MT, Mao IF, Ho CK, et al. Urinary 1-hydroxypyrene concentrations in coke oven workers. Occup Environ Med, 1998, 55(7):461-467.
41. Tas S, Buche JP and Lauwery SR. Determinants of benzo[a]pyrene-diol-epoxide adducts to albumin in workers exposed to polycyclic aromatic hydrocarbons. Int Arch Occup Environ Health, 1994, 66: 343-348.
42. Salagovic J, Kalina I and Dubayova K. Induction of singles strand DNA breaks in workers professionally exposed to polycyclic aromatic hydrocarbons. Neoplasma, 1995, 42:115-118.
43. Popp W, Vahrenholz C and Schell C. DNA single strand breakage, DNA adducts, and sister chromatid exchange in lymphocytes and phenanthrene and pyrene metabolites in urine of coke oven workers. Occup Environ Med, 1997, 54: 176-183.
44.冷曙光,郑玉新,牛勇,等.焦炉作业工人多环芳烃暴露与外周血淋巴细胞DNA损伤的关系.中华劳动卫生职业病杂志, 2004, 22(4): 250-253.
45. Van Rooij JC, Bodelier-Bade MM and JongeneeIen FJ. Estimation of individual dermal and respiratory uptake of polycyclic aromatic hydrocarbons in 12 coke oven workers. Br J Ind Med, 1993, 50: 623-632.
46. Kang DH, Rothman N, Poirier MC, et al. Interindividual differences in the concentration of 1-hydroxypyrene-glucuronide in urine and polycyclic aromatic hydrocarbon-DNA adducts in peripheral white blood cells after charbroiled beef consumption. Carcinogenesis, 1995, 6(5):1079-1085.
47. Strickland P, Kang D and Sithisarankul P. Polycyclic aromatic hydrocarbon metabolites in urine as biomarkers of exposure and effect. Environ Health Perspect, 1996, 104(5):927-932. Review.
48. Wu MT, Mao IF, Ho CK, et al. Urinary 1-hydroxypyrene concentrations in coke oven workers. Occup Environ Med, 1998, 55(7):461-467.
59. Weng MW, Hsiao YM, Chiou HL, et al. Alleviation of benzo[a]pyrene -diolepoxide-DNA damage in human lung carcinoma by glutathione S-transferase M2. DNA Repair (Amst), 2005, 4(4): 493-502.
60. Leng S, Bernauer A, Stidley CA, et al. Association between common genetic variation in Cockayne syndrome A and B genes and nucleotide excision repair capacity among smokers. Cancer Epidemiol Biomarkers Prev, 2008, 17(8): 2062-2069.
61. Zhu Y, Yang H, Chen Q, et al. Modulation of DNA damage/DNA repair capacity by XPC polymorphisms. DNA Repair (Amst), 2008, 7(2): 141-148.
62. Zhao H, Wang LE, Li D, et al. Genotypes and haplotypes of ERCC1 and ERCC2/XPD genes predict levels of benzo[a]pyrene diol epoxide-induced DNA adducts in cultured primary lymphocytes from healthy individuals: a genotype -phenotype correlation analysis. Carcinogenesis, 2008, 29(8): 1560-1566.
63. Wilms LC, Hollman PC, Boots AW, et al. Protection by quercetin and quercetin-rich fruit juice against induction of oxidative DNA damage and formation of BPDE-DNA adducts in human lymphocytes. Mutat Res, 2005, 582(1-2): 155-162.
64. Singletary KW, Barnes SL and van Breemen RB. Ethanol inhibits benzo[a] pyrene-DNA adduct removal and increases 8-oxo-deoxyguanosine formation in human mammary epithelial cells. Cancer Lett, 2004, 203(2): 139-144.
65. Schwerdtle T, Walter I and Hartwig A. Arsenite and its biomethylated metabolites interfere with the formation and repair of stable BPDE-induced DNA adducts in human cells and impair XPAzf and Fpg. DNA Repair (Amst), 2003, 2(12): 1449-1463.
66. Garg R and Maru G. Dietary curcumin enhances benzo[a]pyrene-induced apoptosis resulting in a decrease in BPDE-DNA adducts in mice. J Environ Pathol Toxicol Oncol, 2009, 28(2): 121-131.
67. Yang M, Jang JY, Kim S, et al. Genetic effects on urinary 1-hydroxypyrene levels in a Korean population. Carcinogenesis, 2003, 24(6):1085-1089.
68. Rihs HP, Pesch B, Kappler M, et al. Occupational exposure to polycyclic aromatic hydrocarbons in German industries: association between exogenous exposure and urinary metabolites and its modulation by enzyme polymorphisms. Toxicol Lett, 2005, 157(3):241-55.
69. Chen B, Hu Y, Jin T, Lu D, et al. The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentrations in Chinese coke oven workers. Sci Total Environ, 2007, 381(1-3): 38-46.
70. Santella RM, Perera FP, Young TL, et al. Polycyclic aromatic hydrocarbon-DNA and protein adducts in coal tar treated patients and controls and their relationship to glutathione S-transferase genotype. Mutat Res, 1995, 334(2): 117-124.
71. Omland O, Sherson D, Hansen AM, et al. Exposure of iron foundry workers to polycyclic aromatic hydrocarbons: benzo[a]pyrene-albumin adducts and 1-hydroxypyrene as biomarkers for exposure. Occup Environ Med, 1994, 51(8): 513-518.
72. Jongeneelen FJ. Benchmark guideline for urinary 1-hydroxypyrene as biomarker of occupational exposure to polycyclic aromatic hydrocarbons. Ann Occup Hyg, 2001, 45(1): 3-13.
73. Jongeneelen FJ. Biological monitoring of environmental exposure to polycyclic aromatic hydrocarbons; 1-hydroxypyrene in urine of people. Toxicol Lett, 1994,72(1-3): 205-211.
74. LeBlanc A, Shen S, Lew K, et al. Detection of benzo[a]pyrene diol epoxide-DNA adducts in mononuclear white blood cells by CE immunoassay and its application to studying the effect of glutathione depletion. Electrophoresis, 2009, 30(9): 1558-1563.
75. Al-Saleh I, Arif J, El-Doush I, et al. Carcinogen DNA adducts and the risk of colon cancer: case-control study. Biomarkers, 2008, 13(2): 201-216.
76. Topinka J, Milcova A, Libalova H, et al. Biomarkers of exposure to tobacco smoke and environmental pollutants in mothers and their transplacental transfer to the foetus. Part I: bulky DNA adducts. Mutat Res, 2009, 669(1-2): 13-19.
77. Li D, Wang LE, Chang P, et al. In vitro benzo[a]pyrene diol epoxide-induced DNA adducts and risk of squamous cell carcinoma of head and neck. Cancer Res, 2007, 67(12): 5628-5634.
78. Lee BM, Kwack SJ and Kim HS. Age-related changes in oxidative DNA damage and benzo[a]pyrene diolepoxide-I (BPDE-I)-DNA adduct levels in human stomach. J Toxicol Environ Health A, 2005, 68(19): 1599-1610.
79. Lodovici M, Luceri C, Guglielmi F, et al. Benzo[a]pyrene diolepoxide (BPDE)-DNA adduct levels in leukocytes of smokers in relation to polymorphism of CYP1A1, GSTM1, GSTP1, GSTT1, and mEH. Cancer Epidemiol Biomarkers Prev, 2004, 13(8): 1342-1348.
80. Hemminki K, Koskinen M and Zhao C. DNA adducts as a marker for cancer risk? Int J Cancer, 2001, 92(6): 923-926.
81. Padrós J and Pelletier E. In vivo formation of (+)-anti-benzo[a]pyrene diol-epoxide-plasma albumin adducts in fish. Mar Environ Res, 2000, 50(1-5): 347-351.
82. Ozbal CC, Skipper PL, Yu MC, et al. Quantification of (7S,8R)-dihydroxy -(9R,10S)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene adducts in human serum albumin by laser-induced fluorescence: implications for the in vivo metabolism of benzo[a]pyrene. Cancer Epidemiol Biomarkers Prev, 2000, 9(7): 733-739.
83. Kwack SJ and Lee BM. Correlation between DNA and protein adduct and benzo[a]pyrene diol epoxide I-triglyceride adduct detected in vitro and in vivo. Carcinogenesis, 2000, 21(4): 629-932.
84. K?fferlein HU, Marczynski B, Mensing T, et al. Albumin and hemoglobin adducts of benzo[a]pyrene in humans--analytical methods, exposure assessment, and recommendations for future directions. Crit Rev Toxicol, 2010, 40(2): 126-50. Review.
85. Olsson AC, Fevotte J, Fletcher T, et al. Occupational exposure to polycyclic aromatic hydrocarbons and lung cancer risk: a multicenter study in Europe. Occup Environ Med, 2010, 67(2): 98-103.
86. Armstrong BG and Gibbs G. Exposure-response relationship between lung cancer and polycyclic aromatic hydrocarbons (PAHs). Occup Environ Med, 2009, 66(11): 740-746.
87. Wu MT, Huang SL and Ho CK. Cytochrome P450 1A1 MspI polymorphism and urinary 1-hydroxypyrene concentrations in coke-oven workers. Cancer Epidemiol Biomarkers Prev, 1998, 7: 823-829.
88. Han EH, Kim HG, Im JH, et al. Up-regulation of CYP1A1 by rutaecarpine is dependent on aryl hydrocarbon receptor and calcium. Toxicology, 2009, 266(1-3): 38-47.
89. Lee CY, Chew EH and Go ML. Functionalized aurones as inducers of NAD(P)H: quinone oxidoreductase 1 that activates AhR/XRE and Nrf2/ARE signaling pathways: synthesis, evaluation and SAR. Eur J Med Chem, 2010, 45(7): 2957-2971.
90. Anwar-Mohamed A and El-Kadi AO. Sulforaphane induces CYP1A1 mRNA, protein, and catalytic activity levels via an AhR-dependent pathway in murine hepatoma Hepa 1c1c7 and human HepG2 cells. Cancer Lett, 2009, 275(1): 93-101.
91. Iba MM, Shin M and Caccavale RJ. Cytochromes P4501 (CYP1): catalytic activities and inducibility by diesel exhaust particle extract and benzo[a]pyrene in intact human lung ex vivo. Toxicology, 2010, 273(1-3): 35-44.
92. Conney AH. Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons. Cancer Res, 1982, 42: 4875 -4917.
93. Li R, Shugart YY, Zhou W, et al. Common genetic variations of the cytochrome P450 1A1 gene and risk of hepatocellular carcinoma in a Chinese population. Eur J Cancer, 2009, 45(7): 1239-1247.
94.孙品,张忠彬,吴芬,等.细胞色素CYP1A1基因多态与慢性苯中毒遗传易感性.工业卫生与职业病, 2007, 33(4): 197-201.
95. Jia WH, Pan QH, Qin HD, et al. A case-control and a family-based association study revealing an association between CYP2E1 polymorphisms and nasopharyngeal carcinoma risk in Cantonese. Carcinogenesis, 2009, 30(12): 2031-2036.
1. Conny AH. Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons. Cancer Res, 1982, 42: 4875- 4917.
2. Hecht SS. Tobacco smoke carcinogens and breast cancer. Environm Molec Mutagen, 2002, 39: 119-126.
3. Pelkonen O and Nebert DW. Metabolism of polycyclic aromatic hydrocarbons: etiologic role in carcinogenesis. Pharmacol Rev, 1982, 34: 189-222.
4. Nebert DW, Dalton TP, Okey AB, et al. Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J Biol Chem, 2004, 279(23): 23847-23850.
5. Fujii-Kuriyama Y and Mimura J. Molecular mechanisms of AhR functions in the regulation of cytochrome P450 genes. Biochem Biophys Res Commun, 2005, 338(1): 311-317.
6. Gelboin H. Benzo[a]pyrene metabolism, activation and carcinogenesis: role of regulation of mixed-function oxidases and related enzymes. Physiol Rev, 1980, 60: 107-1165.
7. Park J, Shigenaga MK and Ames BN. Induction of cytochrome P4501A1 by 2, 3, 7,
8-tetrachlorodibenzo-p-dioxin or indol (3, 2-b) carbazole is associated with oxidative DNA damage. Proc Natl Acad Sci USA, 1996, 93: 2322-2327.
8. Cohen GM, Mehta R and Brown M. Large interindividual variations in metabolism of benzo[a]pyrene by peripheral lung tissue from lung cancer patients. Int J Cancer, 1979, 24: 129-133.
9. Prough RA, Sipal Z and Jakobsson SW. Metabolism of benzo[a]pyrene by human lung microsomal fractions. Life Sci, 1977, 21: 629-1636.
10. Rojas M, Camus AM, Alexandrov K, et al. Stereoselective metabolism of (–)-benzo[a]pyrene-7, 8-diol by human lung microsomes and peripheral blood lymphocytes: effect of smoking. Carcinogenesis, 1992, 13: 929-933.
11. Harris C, Autrup H, Connor R, et al. Interindividual variation in binding of benzo[a] pyrene to DNA in cultured human bronchi. Science, 1976, 194: 1067-1069.
12. Bartsch H, Castegnaro M, Rojas M, et al. Expression of pulmonary cytochrome P4501A1 and carcinogen-DNA adduct formation in high risk subjects for tobacco-related lung cancer. Toxicol Lett, 1992. 64: 477-483.
13. Kawajiri K, Nakachi K, Imai K, et al. Identification of genetically high risk individuals to lung cancer by DNA polymorphism of the cytochrome P4501A1 gene. FEBS Lett, 1990, 263: 131-133.
14. Cosma G, Crofts F, Currie D, et al. Racial differences in restriction fragment length polymorphisms and messenger RNA inducibility of human CYP1A1 gene. Cancer Epidemiol Biomarkers Prev, 1993, 2: 53-57.
15. Crofts F, Taioli E, Tranchman J, et al. Functional significance of different human CYP1A1 genotypes. Carcinogenesis, 1994, 15: 2961-2963.
16. Wedlund PJ, Kimura S, Gonzales FJ, et al. 1462V mutation in the human CYP1A1 gene: lack of correlation with either the MspI kb (M2) allele or CYP1A1 inducibility in a three-generation family of East-Mediterranean descent. Pharmacogenetics, 1994, 4: 24-26.
17. Iba MM, Shin M and Caccavale RJ. Cytochromes P4501 (CYP1): catalytic activities and inducibility by diesel exhaust particle extract and benzo[a]pyrene in intacthuman lung ex vivo. Toxicology, 2010, 273(1-3): 35-44.
18. Shimada T and Guengerich FP. Inhibition of human cytochrome P450 1A1-, 1B1-mediated activation of procarcinogens to metabolites by polycyclic aromatic hydrocarbons. Chem Res Toxicol, 2006, 19: 288-294.
19. Buters JT, Sakai S, Richter T, et al. Cytochrome P450 CYP1B1 determines susceptibility to 7, 12-dimethylbenz[a]anthracene-induced lymphomas. Proc Natl Acad Sci USA, 1999, 96(5): 1977-1982.
20. Uno S, Dalton TP, and Dragin N, et al. Oral benzo[a]pyrene in Cyp1 knockout mouse lines: CYP1A1 important in detoxication, CYP1B1 metabolism required for immune damage independent of total-body burden and clearance rate. Mol Pharmacol, 2006, 69(4): 1103-1114.
21. Hakkola J, Pasanen M, Pelkonen O, et al. Expression of CYP1B1 in human adult and fetal tissues and differential inducibility of CYP1B1 and CYP1A1 by Ah receptor ligands in human placenta and cultured cells. Carcinogenesis, 1997, 18(2): 391-397.
22. Butkiewicz D, Grzybowska E, Hemminki K, et al. Modulation of DNA adduct levels in human mononuclear white blood cells and granulocytes by CYP1A1 CYP2D6 and GSTM1 genetic polymorphisms. Mutat Res, 1998, 415(1-2): 97-108.
23. Sutter TR, Tang YM and Hayers CL. Complete cDNA sequence of a human dioxin-inducible mRNA identifies a new gene subfamily of cytochmme P450 that maps to chromosome 2. J Biol Chem, 1994, 269(18): l3092-l3099.
24. Mammen JS, Pittman GS and Li Y. Single amino acid mutations, but not common polymorphisms, decrease the activity of CYP1B1 against (-)benzo[a]pyrene- 7R-trans-7,8-dihydrodiol. Carcinogenesis, 2003, 24: 1247-1255.
25. Aklillu E, Ovrebo S and Botnen IV. Characterization of common CYP1B1 variantswith different capacity for benzo[a]pyrene-7,8-dihydrodiol epoxide formation from benzo[a]pyrene. Cancer Res, 2005, 65: 5105-5111.
26. Bandiera S, Weidlich S and Harth V. Proteasomal degradation of human CYP1B1: effect of the Asn453Ser polymorphism on the post-translational regulation of CYP1B1 expression. Mol Pharmacol, 2005, 67: 435-443.
27. Christian CA, Fagundes RB, Strickland PT, et al. The influences of genetic polymorphisms in Ahr, CYP1A1, CYP1A2, CYP1B1, GST M1, GSTT1 and UGT1A1 on urine 1-hydroxypyrene glucuronide concentrations in healthy subjects from Rio Grande do Sul, Brazil. Carcinogenesis, 2007, 28: 112-117.
28. Yang M, Jang JY and Kim S. Genetic effects on urinary 1-hydroxypyrene levels in a Korean population. Carcinogenesis, 2003, 24: 1085-1089.
29. Rihs HP, Pesch B and Kappler M. Occupational exposure to polycyclic aromatic hydrocarbons in German industries: association between exogenous exposure and urinary metabolites and its modulation by enzyme polymorphisms. Toxicol Lett, 2005, 157: 241-255.
30. Kato S, Bowman ED, Harrington AM, et al. Human lung carcinogen-DNA adduct levels mediated by genetic polymorphisms in vivo. J Natl Cancer Inst, 1995, 87(12): 902-907.
31.戴宇飞,冷曙光,潘祖飞,等.萘代谢产物-白蛋白加合物作为焦炉工接触生物标志物的初步探讨.中华预防医学杂志, 2004, 38(6): 392-395.
32. Nan HM, Kim H, Lim HS, et al. Effects of occupation, lifestyle and genetic polymorphisms of CYP1A1, CYP2E1, GSTM1 and GSTT1 on urinary 1-hydrox- ypyrene and 2-naphthol concentrations. Carcinogenesis, 2001, 22(5): 787-793.
33. Rendic S. Summary of information on human CYP enzymes: human P450metabolism data. Drug Metab Rev, 2002, 34(1-2): 438-448.
34. Zanger UM, Klein K, Saussele T, et al. Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics, 2007, 8(7): 743-759.
35. Zhang J, Tian Q, Zhu YZ, et al. Reversal of resistance to oxazaphosphorines. Curr Cancer Drug Targets, 2006, 6(5): 385-407.
36. Morisseau C and Hammock BD. Epoxide hydrolases: mechanisms, inhibitor designs, and biological roles. Annu Rev Pharmacol Toxicol, 2005, 45: 311-333.
37. Gsur A, Zidek T, Schnattinger K, et al. Association of microsomal epoxide hydrolase polymorphisms and lung cancer risk. Br J Cancer, 2003, 89(4): 702-706.
38. Huang WY, Chatterjee N, Chanock S, et al. Microsomal epoxide hydrolase polymorphisms and risk for advanced colorectal adenoma. Cancer Epidemiol Biomarkers Prev, 2005, 14(1): 152-157.
39. Tang SC, Sheu GT, Wong RH, et al. Expression of glutathione S-transferase M2 in stage I/II non-small cell lung cancer and alleviation of DNA damage exposure to benzo[a]pyrene. Toxicol Lett, 2010, 192(3): 316-323.
40. 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 Prev, 1999, 23(6): 445-453.
41. Ntais C, Polycarpou A and Ioannidis JP. Association of GSTM1, GSTT1, and GSTP1 gene polymorphisms with the risk of prostate cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev, 2005, 14(1): 176-181.
42. Guillemette C, Millikan RC, Newman B, et al. Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and association with breast cancer amongAfrican Americans. Cancer Res, 2000, 60(4): 950-956.
43. 43 Vogel A, Ockenga J, Ehmer U, et al. Polymorphisms of the carcinogen detoxifying UDP-glucuronosyltransferase UGT1A7 in proximal digestive tract cancer. Z Gastroenterol, 2002, 40(7): 497-502.
44. Watabe T, Ishizuka T, Isobe M, et al. A 7-hydroxymethyl sulfate ester as an active metabolite of 7, 12-dimethylbenz[alpha]anthracene. Science, 1982, 215(4531): 403-405.
45. Surh YJ and Tannenbaum SR. Sulfotransferase-mediated activation of 7,8,9,10-tetrahydro-7-ol,7,8-dihydrodiol,and7,8,9,10-tetraol derivatives of benzo[a] pyrene. Chem Res Toxicol, 1995, 8(5): 693-698.
46. Lampen A, Ebert B, Stumkat L, et al. Induction of gene expression of xenobiotic metabolism enzymes and ABC-transport proteins by PAH and a reconstituted PAH mixture in human Caco-2 cells. Biochim Biophys Acta, 2004, 1681(1): 38-46.
47. Raftogianis RB, Wood TC, Otterness DM, et al. Phenol sulfotransferase pharmacogenetics in humans: association of common SULT1A1 alleles with TS PST phenotype. Biochem Biophys Res Commun, 1997, 239(1): 298-304.
48. Wang Y, Spitz MR, Tsou AM, et al. Sulfotransferase (SULT) 1A1 polymorphism as a predisposition factor for lung cancer: a case-control analysis. Lung Cancer, 2002, 35(2): 137-142.
49. Zheng L, Wang Y, Schabath MB, et al. Sulfotransferase 1A1 (SULT1A1) polymorphism and bladder cancer risk: a case-control study. Cancer Lett, 2003, 202(1): 61-69.
50. Lilla C, Risch A, Kropp S, et al. SULT1A1 genotype, active and passive smoking, and breast cancer risk by age 50 years in a German case-control study. Breast CancerRes, 2005, 7(2): 229-237.
51. Hung RJ, Boffetta P, Brennan P, et al. Genetic polymorphisms of MPO, COMT, MnSOD, NQO1, interactions with environmental exposures and bladder cancer risk. Carcinogenesis, 2004, 25(6): 973-978.
52. Sharp SY, Kelland LR, Valenti MR, et al. Establishment of an isogenic human colon tumor model for NQO1 gene expression: application to investigate the role of DT-diaphorase in bioreductive drug activation in vitro and in vivo. Mol Pharmacol, 2000, 58(5): 1146-1155.
53. Saldivar SJ, Wang Y, Zhao H, et al. An association between a NQO1 genetic polymorphism and risk of lung cancer. Mutat Res, 2005, 582(1-2): 71-78.
54. Lewis SJ, Cherry NM, Niven RM, et al. Polymorphisms in the NAD(P)H: quinone oxidoreductase gene and small cell lung cancer risk in a UK population. Lung Cancer, 2001, 34(2): 177-183.
55. Sunaga N, Kohno T, Yanagitani N, et al. Contribution of the NQO1 and GSTT1 polymorphisms to lung adenocarcinoma susceptibility. Cancer Epidemiol Biomarkers Prev, 2002, 11(8): 730-738.
56. Niwa Y, Hirose K, Nakanishi T, et al. Association of the NAD (P) H: quinone oxidoreductase C609T polymorphism and the risk of cervical cancer in Japanese subjects. Gynecol Oncol, 2005, 96(2): 423-429.
57. Palackal NT, Burczynski ME, Harvey RG, et al. The ubiquitous aldehyde reductase (AKR1A1) oxidizes proximate carcinogen trans-dihydrodiols to o-quinones: potential role in polycyclic aromatic hydrocarbon activation. Biochemistry, 2001, 40(36): 10901-10910.
58. Jiang H, Shen YM, Quinn AM, et al. Competing roles of cytochrome P450 1A1/1B1and aldo-keto reductase 1A1 in the metabolic activation of (+/-)-7, 8-dihydroxy-7, 8-dihydro-benzo[a]pyrene in human bronchoalveolar cell extracts. Chem Res Toxicol, 2005, 18(2): 365-374.
59. Hyndman D, Bauman DR, Heredia VV, et al. The aldo-keto reductase superfamily homepage. Chem Biol Interact, 2003, (621-631):143-144.
60. Shimada T, Watanabe J and Kawajiri K. Catalytic properties of polymorphic human cytochrome P450 1B1 variants. Carcinogenesis, 1999, 20: 1607-1613.
61. Joseph P and Jaiswal AK. NAD(P)H: quinone oxidoreductase1 (DT diaphorase) specifically prevents the formation of benzo[a]pyrene quinone-DNA adducts generated by cytochrome P4501A1 and P450 reductase. Proc Natl Acad Sci USA, 1994, 91(18): 8413-8417.
2. Lodovici M, Luceri C, Guglielmi F, et al. Benzo(a)pyrene diolepoxide (BPDE)-DNA adduct levels in leukocytes of smokers in relation to polymorphism of CYP1A1, GSTM1, GSTP1, GSTT1, and mEH. Cancer Epidemiol Biomarkers Prev, 2004, 13(8): 1342-1348.
3. Wang S, Chanock S, Tang D, et al. Assessment of interactions between PAH exposure and genetic polymorphisms on PAH-DNA adducts in African American, Dominican, and Caucasian mothers and newborns. Cancer Epidemiol Biomarkers Prev, 2008, 17(2): 405-413.
4. Hu Y, Li G, Xue X, et al. PAH-DNA adducts in a Chinese population: relationship to PAH exposure, smoking and polymorphisms of metabolic and DNA repair genes. Biomarkers, 2008, 13(1): 27-40.
5. Shimada T, Watanabe J and Kawajiri K. Catalytic properties of polymorphic human cytochrome P450 1B1 variants. Carcinogenesis, 1999, 20: 1607-1613.
6. Mammen JS, Pittman GS and Li Y. Single amino acid mutations, but not common polymorphisms, decrease the activity of CYP1B1 against (-)benzo[a] pyrene-7R-trans-7, 8-dihydrodiol. Carcinogenesis, 2003, 24: 1247-1255.
7. Aklillu E, Ovrebo S and Botnen IV. Characterization of common CYP1B1 variants with different capacity for benzo[a]pyrene-7, 8-dihydrodiol epoxide formation from benzo[a]pyrene. Cancer Res, 2005, 65: 5105-5111.
8. Bandiera S, Weidlich S and Harth V. Proteasomal degradation of human CYP1B1:effect of the Asn453Ser polymorphism on the post-translational regulation of CYP1B1 expression. Mol Pharmacol, 2005, 67: 435-443.
9. Christian CA, Renato BF, Paul TS, et al. 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. Carcinogenesis, 2007, 28: 112-117.
10. Yang M, Jang JY and Kim S. Genetic effects on urinary 1-hydroxypyrene levels in a Korean population. Carcinogenesis, 2003, 24: 1085-1089.
11. Rihs HP, Pesch B and Kappler M. Occupational exposure to polycyclic aromatic hydrocarbons in German industries: association between exogenous exposure and urinary metabolites and its modulation by enzyme polymorphisms. Toxicol Lett, 2005, 157: 241-255.
12. Rendic S. Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev, 2002, 34(1-2): 83-448.
13. Zanger UM, Klein K, Saussele T, et al. Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics, 2007, 8(7): 743-759.
14. Zhang J, Tian Q, Zhu YZ, et al. Reversal of resistance to oxazaphosphorines. Curr Cancer Drug Targets, 2006, 6(5): 385-407.
15.戴宇飞,冷曙光,潘祖飞,等.萘代谢产物-白蛋白加合物作为焦炉工接触生物标志物的初步探讨.中华预防医学杂志, 2004, 38(6): 392-395.
16. Nan HM, Kim H, Lim HS, et al. Effects of occupation, lifestyle and genetic polymorphisms of CYP1A1, CYP2E1, GSTM1 and GSTT1 on urinary 1-hydrox- ypyrene and 2-naphthol concentrations. Carcinogenesis, 2001, 22(5): 787-793.
17. Wells PG, McCallum GP, Lam KC, et al. Oxidative DNA Damage and Repair in Teratogenesis and Neurodevelopmental. Birth Defects Res C Embryo Today, 2010, 90(2):103-109. Review
18. Seidel A, Spickenheuer A, Straif K, et al. New biomarkers of occupational exposure to polycyclic aromatic hydrocarbons. J Toxicol Environ Health A, 2008, 71(11-12): 734-745.
19. Autrup H, Vestergaard AB and Okkels H. Transplacental transfer of environmental genotoxins: polycyclic aromatic hydrocarbon-albumin in non-smoking women, and the effect of maternal GSTM1 genotype. Carcinogenesis, 1995, 16(6): 1305-1309.
20. Melikian AA, Sun P, Pierpont C, et al. Gas chromatography–mass spectrometric determination of benzo[a]pyrene and chrysene diol epoxide globin adducts in humans. Cancer Epidemiol Biomarkers Prev, 1997, 6: 833-839.
21. Scherer G, Frank S, Riedel K, et al. Biomonitoring of exposure to polycyclic aromatic hydrocarbons of nonoccupationally exposed persons. Cancer Epidemiol Biomarkers Prev, 2000, 9: 373-380.
22. Pastorelli R, Guanci M, Cerri A, et al. Impact of inherited polymorphisms in glutathione S-transferase M1, microsomal epoxide hydrolase, cytochrome 450 enzymes on DNA, and blood protein adducts of benzo[a]pyrene-diol epoxide. Cancer Epidemiol Biomarkers Prev, 1998, 7: 703-709.
23. Day BW, Skipper PL and Zaia J. Enantiospecificity of covalent adduct formation by benzo[a]pyrene anti-diol epoxide with human serum albumin. Chem Res Toxicol, 1994, 7(6): 829-835.
24. Hemminki K. DNA adducts in biomonitoring. J Occup Environ Med, 1999, 37(1): 44-49.
25. Meyer MJ and Bechtold WE. Protein adducts biomarkers: state of the art. Environ Health Perspect, 1996, 104(5): 879-882.
26. Nielsen PS, de Pater N, Okkels H, et al. Environmental air pollution and DNA adducts in Copenhagen bus drivers--effect of GSTM1 and NAT2 genotypes on adduct levels. Carcinogenesis, 1996, 17(5): 1021-1027.
27. Pastorelli R, Cerri A, Minoia C, et al. Benzo[a]pyrene diolepoxide adducts to albumin in workers exposed to polycyclic aromatic hydrocarbons: association with specific CYP1A1, GSTM1, GSTP1 and EHPX genotypes. Biomarkers, 2001, 357-374.
28. Van Delft JH, Steenwinkel MS, van Asten JG, et al. Biological monitoring the exposure to polycyclic aromatic hydrocarbons of coke oven workers in relation to smoking and genetic polymorphisms for GSTM1 and GSTT1. Ann Occup Hyg, 2001, 45(5): 395-408.
29. Chen YW, BaiY, Yuan J, et al. Association of polymorphisms in AhR, CYP1A1, GSTM1 and GSTT1 genes with levels of DNA damage in peripheral blood lymphocytes among coke-oven workers. Cancer Epidemiol Biomarkers Prev, 2006, 15(9): 1703-1707.
30. Wang H, Chen WH, Zheng HY, et al. Association between plasma BPDE-Alb adducts concentrations and DNA damage of peripheral blood lymphocytes among coke oven workers. Occup Environ Med, 2007, 64:753-758.
31. IARC, Monographs on the evaluation of the carcinogenic risk of chemicals to humans. Polycyclic aromatic hydrocarbons. Industrial exposure in aluminum production, coal gasification, coke production, and iron and steel founding. IARC, 1984, 34.
32. IARC, Monographs on the evaluation of the carcinogenic risk of chemicals to humans. IARC, 1987, Suppl. 7.
33. Akin FJ, Chamberlain WJ and Chortyk OT. Mouse skin tumorigenesis and induction of aryl hydrocarbon hydroxylase by tobacco smoke fractions. J Natl Cancer Inst, 1975, 54(4):907-912.
34.王红.博士毕业论文.华中科技大学图书馆, 2005.
35. Frank S, Renner T, Ruppert T, et al. Determination of albumin adducts of (+)-anti-benzo[a]pyrene-diol-epoxide using a high-performance liquid chromatographic column switching technique for sample preparation and gas chromatography-mass spectrometry for the final detection. J Chromatogr B Biomed Sci Appl, 1998, 713(2):331-337.
36. Islam GA, Greibrokk T, Harvey RG, et al. HPLC analysis of benzo[a]pyrene-albumin adducts in benzo[a]pyrene exposed rats. Detection of cis-tetrols arising from hydrolysis of adducts of anti- and syn-BPDE-III with proteins. Chem Biol Interact, 1999, 123(2):133-148.
37.郭嘉,罗晔,陈延林,等.燃煤烟气中多环芳烃(PAHs)光化学降解的研究.能源环境保护, 2006, 20(2):25-28.
38.王芳.博士毕业论文.华中科技大学图书馆, 2009.
39. Vaghef H, Wisén AC and Hellman B. Demonstration of benzo[a]pyrene-induced DNA damage in mice by alkaline single cell gel electrophoresis: evidence for strand breaks in liver but not in lymphocytes and bone marrow. Pharmacol Toxicol, 1996, 78(1):37-43.
40.朱志良,庄志雄,黄钰,等.单细胞凝胶电泳图像分析系统的研制与应用.中华劳动卫生职业病杂志, 2001, 19:298-300.
41. Tas S, Buche JP and Lauwery SR. Determinants of benzo[a]pyrene-diol-epoxide adducts to albumin in workers exposed to polycyclic aromatic hydrocarbons. Int Arch Occup Environ Health, 1994, 66: 343-348.
42. Salagovic J, Kalina I and Dubayova K. Induction of singles strand DNA breaks in workers professionally exposed to polycyclic aromatic hydrocarbons. Neoplasma, 1995, 42:115-118.
43. Popp W, Vahrenholz C and Schell C. DNA single strand breakage, DNA adducts, and sister chromatid exchange in lymphocytes and phenanthrene and pyrene metabolites in urine of coke oven workers. Occup Environ Med, 1997, 54: 176-183.
44.冷曙光,郑玉新,牛勇,等.焦炉作业工人多环芳烃暴露与外周血淋巴细胞DNA损伤的关系.中华劳动卫生职业病杂志, 2004, 22(4): 250-253.
45. Van Rooij JC, Bodelier-Bade MM and JongeneeIen FJ. Estimation of individual dermal and respiratory uptake of polycyclic aromatic hydrocarbons in 12 coke oven workers. Br J Ind Med, 1993, 50: 623-632.
46. Kang DH, Rothman N, Poirier MC, et al. Interindividual differences in the concentration of 1-hydroxypyrene-glucuronide in urine and polycyclic aromatic hydrocarbon-DNA adducts in peripheral white blood cells after charbroiled beef consumption. Carcinogenesis, 1995, 6(5):1079-1085.
47. Strickland P, Kang D and Sithisarankul P. Polycyclic aromatic hydrocarbon metabolites in urine as biomarkers of exposure and effect. Environ Health Perspect, 1996, 104(5):927-932. Review.
48. Wu MT, Mao IF, Ho CK, et al. Urinary 1-hydroxypyrene concentrations in coke oven workers. Occup Environ Med, 1998, 55(7):461-467.
41. Tas S, Buche JP and Lauwery SR. Determinants of benzo[a]pyrene-diol-epoxide adducts to albumin in workers exposed to polycyclic aromatic hydrocarbons. Int Arch Occup Environ Health, 1994, 66: 343-348.
42. Salagovic J, Kalina I and Dubayova K. Induction of singles strand DNA breaks in workers professionally exposed to polycyclic aromatic hydrocarbons. Neoplasma, 1995, 42:115-118.
43. Popp W, Vahrenholz C and Schell C. DNA single strand breakage, DNA adducts, and sister chromatid exchange in lymphocytes and phenanthrene and pyrene metabolites in urine of coke oven workers. Occup Environ Med, 1997, 54: 176-183.
44.冷曙光,郑玉新,牛勇,等.焦炉作业工人多环芳烃暴露与外周血淋巴细胞DNA损伤的关系.中华劳动卫生职业病杂志, 2004, 22(4): 250-253.
45. Van Rooij JC, Bodelier-Bade MM and JongeneeIen FJ. Estimation of individual dermal and respiratory uptake of polycyclic aromatic hydrocarbons in 12 coke oven workers. Br J Ind Med, 1993, 50: 623-632.
46. Kang DH, Rothman N, Poirier MC, et al. Interindividual differences in the concentration of 1-hydroxypyrene-glucuronide in urine and polycyclic aromatic hydrocarbon-DNA adducts in peripheral white blood cells after charbroiled beef consumption. Carcinogenesis, 1995, 6(5):1079-1085.
47. Strickland P, Kang D and Sithisarankul P. Polycyclic aromatic hydrocarbon metabolites in urine as biomarkers of exposure and effect. Environ Health Perspect, 1996, 104(5):927-932. Review.
48. Wu MT, Mao IF, Ho CK, et al. Urinary 1-hydroxypyrene concentrations in coke oven workers. Occup Environ Med, 1998, 55(7):461-467.
59. Weng MW, Hsiao YM, Chiou HL, et al. Alleviation of benzo[a]pyrene -diolepoxide-DNA damage in human lung carcinoma by glutathione S-transferase M2. DNA Repair (Amst), 2005, 4(4): 493-502.
60. Leng S, Bernauer A, Stidley CA, et al. Association between common genetic variation in Cockayne syndrome A and B genes and nucleotide excision repair capacity among smokers. Cancer Epidemiol Biomarkers Prev, 2008, 17(8): 2062-2069.
61. Zhu Y, Yang H, Chen Q, et al. Modulation of DNA damage/DNA repair capacity by XPC polymorphisms. DNA Repair (Amst), 2008, 7(2): 141-148.
62. Zhao H, Wang LE, Li D, et al. Genotypes and haplotypes of ERCC1 and ERCC2/XPD genes predict levels of benzo[a]pyrene diol epoxide-induced DNA adducts in cultured primary lymphocytes from healthy individuals: a genotype -phenotype correlation analysis. Carcinogenesis, 2008, 29(8): 1560-1566.
63. Wilms LC, Hollman PC, Boots AW, et al. Protection by quercetin and quercetin-rich fruit juice against induction of oxidative DNA damage and formation of BPDE-DNA adducts in human lymphocytes. Mutat Res, 2005, 582(1-2): 155-162.
64. Singletary KW, Barnes SL and van Breemen RB. Ethanol inhibits benzo[a] pyrene-DNA adduct removal and increases 8-oxo-deoxyguanosine formation in human mammary epithelial cells. Cancer Lett, 2004, 203(2): 139-144.
65. Schwerdtle T, Walter I and Hartwig A. Arsenite and its biomethylated metabolites interfere with the formation and repair of stable BPDE-induced DNA adducts in human cells and impair XPAzf and Fpg. DNA Repair (Amst), 2003, 2(12): 1449-1463.
66. Garg R and Maru G. Dietary curcumin enhances benzo[a]pyrene-induced apoptosis resulting in a decrease in BPDE-DNA adducts in mice. J Environ Pathol Toxicol Oncol, 2009, 28(2): 121-131.
67. Yang M, Jang JY, Kim S, et al. Genetic effects on urinary 1-hydroxypyrene levels in a Korean population. Carcinogenesis, 2003, 24(6):1085-1089.
68. Rihs HP, Pesch B, Kappler M, et al. Occupational exposure to polycyclic aromatic hydrocarbons in German industries: association between exogenous exposure and urinary metabolites and its modulation by enzyme polymorphisms. Toxicol Lett, 2005, 157(3):241-55.
69. Chen B, Hu Y, Jin T, Lu D, et al. The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentrations in Chinese coke oven workers. Sci Total Environ, 2007, 381(1-3): 38-46.
70. Santella RM, Perera FP, Young TL, et al. Polycyclic aromatic hydrocarbon-DNA and protein adducts in coal tar treated patients and controls and their relationship to glutathione S-transferase genotype. Mutat Res, 1995, 334(2): 117-124.
71. Omland O, Sherson D, Hansen AM, et al. Exposure of iron foundry workers to polycyclic aromatic hydrocarbons: benzo[a]pyrene-albumin adducts and 1-hydroxypyrene as biomarkers for exposure. Occup Environ Med, 1994, 51(8): 513-518.
72. Jongeneelen FJ. Benchmark guideline for urinary 1-hydroxypyrene as biomarker of occupational exposure to polycyclic aromatic hydrocarbons. Ann Occup Hyg, 2001, 45(1): 3-13.
73. Jongeneelen FJ. Biological monitoring of environmental exposure to polycyclic aromatic hydrocarbons; 1-hydroxypyrene in urine of people. Toxicol Lett, 1994,72(1-3): 205-211.
74. LeBlanc A, Shen S, Lew K, et al. Detection of benzo[a]pyrene diol epoxide-DNA adducts in mononuclear white blood cells by CE immunoassay and its application to studying the effect of glutathione depletion. Electrophoresis, 2009, 30(9): 1558-1563.
75. Al-Saleh I, Arif J, El-Doush I, et al. Carcinogen DNA adducts and the risk of colon cancer: case-control study. Biomarkers, 2008, 13(2): 201-216.
76. Topinka J, Milcova A, Libalova H, et al. Biomarkers of exposure to tobacco smoke and environmental pollutants in mothers and their transplacental transfer to the foetus. Part I: bulky DNA adducts. Mutat Res, 2009, 669(1-2): 13-19.
77. Li D, Wang LE, Chang P, et al. In vitro benzo[a]pyrene diol epoxide-induced DNA adducts and risk of squamous cell carcinoma of head and neck. Cancer Res, 2007, 67(12): 5628-5634.
78. Lee BM, Kwack SJ and Kim HS. Age-related changes in oxidative DNA damage and benzo[a]pyrene diolepoxide-I (BPDE-I)-DNA adduct levels in human stomach. J Toxicol Environ Health A, 2005, 68(19): 1599-1610.
79. Lodovici M, Luceri C, Guglielmi F, et al. Benzo[a]pyrene diolepoxide (BPDE)-DNA adduct levels in leukocytes of smokers in relation to polymorphism of CYP1A1, GSTM1, GSTP1, GSTT1, and mEH. Cancer Epidemiol Biomarkers Prev, 2004, 13(8): 1342-1348.
80. Hemminki K, Koskinen M and Zhao C. DNA adducts as a marker for cancer risk? Int J Cancer, 2001, 92(6): 923-926.
81. Padrós J and Pelletier E. In vivo formation of (+)-anti-benzo[a]pyrene diol-epoxide-plasma albumin adducts in fish. Mar Environ Res, 2000, 50(1-5): 347-351.
82. Ozbal CC, Skipper PL, Yu MC, et al. Quantification of (7S,8R)-dihydroxy -(9R,10S)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene adducts in human serum albumin by laser-induced fluorescence: implications for the in vivo metabolism of benzo[a]pyrene. Cancer Epidemiol Biomarkers Prev, 2000, 9(7): 733-739.
83. Kwack SJ and Lee BM. Correlation between DNA and protein adduct and benzo[a]pyrene diol epoxide I-triglyceride adduct detected in vitro and in vivo. Carcinogenesis, 2000, 21(4): 629-932.
84. K?fferlein HU, Marczynski B, Mensing T, et al. Albumin and hemoglobin adducts of benzo[a]pyrene in humans--analytical methods, exposure assessment, and recommendations for future directions. Crit Rev Toxicol, 2010, 40(2): 126-50. Review.
85. Olsson AC, Fevotte J, Fletcher T, et al. Occupational exposure to polycyclic aromatic hydrocarbons and lung cancer risk: a multicenter study in Europe. Occup Environ Med, 2010, 67(2): 98-103.
86. Armstrong BG and Gibbs G. Exposure-response relationship between lung cancer and polycyclic aromatic hydrocarbons (PAHs). Occup Environ Med, 2009, 66(11): 740-746.
87. Wu MT, Huang SL and Ho CK. Cytochrome P450 1A1 MspI polymorphism and urinary 1-hydroxypyrene concentrations in coke-oven workers. Cancer Epidemiol Biomarkers Prev, 1998, 7: 823-829.
88. Han EH, Kim HG, Im JH, et al. Up-regulation of CYP1A1 by rutaecarpine is dependent on aryl hydrocarbon receptor and calcium. Toxicology, 2009, 266(1-3): 38-47.
89. Lee CY, Chew EH and Go ML. Functionalized aurones as inducers of NAD(P)H: quinone oxidoreductase 1 that activates AhR/XRE and Nrf2/ARE signaling pathways: synthesis, evaluation and SAR. Eur J Med Chem, 2010, 45(7): 2957-2971.
90. Anwar-Mohamed A and El-Kadi AO. Sulforaphane induces CYP1A1 mRNA, protein, and catalytic activity levels via an AhR-dependent pathway in murine hepatoma Hepa 1c1c7 and human HepG2 cells. Cancer Lett, 2009, 275(1): 93-101.
91. Iba MM, Shin M and Caccavale RJ. Cytochromes P4501 (CYP1): catalytic activities and inducibility by diesel exhaust particle extract and benzo[a]pyrene in intact human lung ex vivo. Toxicology, 2010, 273(1-3): 35-44.
92. Conney AH. Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons. Cancer Res, 1982, 42: 4875 -4917.
93. Li R, Shugart YY, Zhou W, et al. Common genetic variations of the cytochrome P450 1A1 gene and risk of hepatocellular carcinoma in a Chinese population. Eur J Cancer, 2009, 45(7): 1239-1247.
94.孙品,张忠彬,吴芬,等.细胞色素CYP1A1基因多态与慢性苯中毒遗传易感性.工业卫生与职业病, 2007, 33(4): 197-201.
95. Jia WH, Pan QH, Qin HD, et al. A case-control and a family-based association study revealing an association between CYP2E1 polymorphisms and nasopharyngeal carcinoma risk in Cantonese. Carcinogenesis, 2009, 30(12): 2031-2036.
1. Conny AH. Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons. Cancer Res, 1982, 42: 4875- 4917.
2. Hecht SS. Tobacco smoke carcinogens and breast cancer. Environm Molec Mutagen, 2002, 39: 119-126.
3. Pelkonen O and Nebert DW. Metabolism of polycyclic aromatic hydrocarbons: etiologic role in carcinogenesis. Pharmacol Rev, 1982, 34: 189-222.
4. Nebert DW, Dalton TP, Okey AB, et al. Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J Biol Chem, 2004, 279(23): 23847-23850.
5. Fujii-Kuriyama Y and Mimura J. Molecular mechanisms of AhR functions in the regulation of cytochrome P450 genes. Biochem Biophys Res Commun, 2005, 338(1): 311-317.
6. Gelboin H. Benzo[a]pyrene metabolism, activation and carcinogenesis: role of regulation of mixed-function oxidases and related enzymes. Physiol Rev, 1980, 60: 107-1165.
7. Park J, Shigenaga MK and Ames BN. Induction of cytochrome P4501A1 by 2, 3, 7,
8-tetrachlorodibenzo-p-dioxin or indol (3, 2-b) carbazole is associated with oxidative DNA damage. Proc Natl Acad Sci USA, 1996, 93: 2322-2327.
8. Cohen GM, Mehta R and Brown M. Large interindividual variations in metabolism of benzo[a]pyrene by peripheral lung tissue from lung cancer patients. Int J Cancer, 1979, 24: 129-133.
9. Prough RA, Sipal Z and Jakobsson SW. Metabolism of benzo[a]pyrene by human lung microsomal fractions. Life Sci, 1977, 21: 629-1636.
10. Rojas M, Camus AM, Alexandrov K, et al. Stereoselective metabolism of (–)-benzo[a]pyrene-7, 8-diol by human lung microsomes and peripheral blood lymphocytes: effect of smoking. Carcinogenesis, 1992, 13: 929-933.
11. Harris C, Autrup H, Connor R, et al. Interindividual variation in binding of benzo[a] pyrene to DNA in cultured human bronchi. Science, 1976, 194: 1067-1069.
12. Bartsch H, Castegnaro M, Rojas M, et al. Expression of pulmonary cytochrome P4501A1 and carcinogen-DNA adduct formation in high risk subjects for tobacco-related lung cancer. Toxicol Lett, 1992. 64: 477-483.
13. Kawajiri K, Nakachi K, Imai K, et al. Identification of genetically high risk individuals to lung cancer by DNA polymorphism of the cytochrome P4501A1 gene. FEBS Lett, 1990, 263: 131-133.
14. Cosma G, Crofts F, Currie D, et al. Racial differences in restriction fragment length polymorphisms and messenger RNA inducibility of human CYP1A1 gene. Cancer Epidemiol Biomarkers Prev, 1993, 2: 53-57.
15. Crofts F, Taioli E, Tranchman J, et al. Functional significance of different human CYP1A1 genotypes. Carcinogenesis, 1994, 15: 2961-2963.
16. Wedlund PJ, Kimura S, Gonzales FJ, et al. 1462V mutation in the human CYP1A1 gene: lack of correlation with either the MspI kb (M2) allele or CYP1A1 inducibility in a three-generation family of East-Mediterranean descent. Pharmacogenetics, 1994, 4: 24-26.
17. Iba MM, Shin M and Caccavale RJ. Cytochromes P4501 (CYP1): catalytic activities and inducibility by diesel exhaust particle extract and benzo[a]pyrene in intacthuman lung ex vivo. Toxicology, 2010, 273(1-3): 35-44.
18. Shimada T and Guengerich FP. Inhibition of human cytochrome P450 1A1-, 1B1-mediated activation of procarcinogens to metabolites by polycyclic aromatic hydrocarbons. Chem Res Toxicol, 2006, 19: 288-294.
19. Buters JT, Sakai S, Richter T, et al. Cytochrome P450 CYP1B1 determines susceptibility to 7, 12-dimethylbenz[a]anthracene-induced lymphomas. Proc Natl Acad Sci USA, 1999, 96(5): 1977-1982.
20. Uno S, Dalton TP, and Dragin N, et al. Oral benzo[a]pyrene in Cyp1 knockout mouse lines: CYP1A1 important in detoxication, CYP1B1 metabolism required for immune damage independent of total-body burden and clearance rate. Mol Pharmacol, 2006, 69(4): 1103-1114.
21. Hakkola J, Pasanen M, Pelkonen O, et al. Expression of CYP1B1 in human adult and fetal tissues and differential inducibility of CYP1B1 and CYP1A1 by Ah receptor ligands in human placenta and cultured cells. Carcinogenesis, 1997, 18(2): 391-397.
22. Butkiewicz D, Grzybowska E, Hemminki K, et al. Modulation of DNA adduct levels in human mononuclear white blood cells and granulocytes by CYP1A1 CYP2D6 and GSTM1 genetic polymorphisms. Mutat Res, 1998, 415(1-2): 97-108.
23. Sutter TR, Tang YM and Hayers CL. Complete cDNA sequence of a human dioxin-inducible mRNA identifies a new gene subfamily of cytochmme P450 that maps to chromosome 2. J Biol Chem, 1994, 269(18): l3092-l3099.
24. Mammen JS, Pittman GS and Li Y. Single amino acid mutations, but not common polymorphisms, decrease the activity of CYP1B1 against (-)benzo[a]pyrene- 7R-trans-7,8-dihydrodiol. Carcinogenesis, 2003, 24: 1247-1255.
25. Aklillu E, Ovrebo S and Botnen IV. Characterization of common CYP1B1 variantswith different capacity for benzo[a]pyrene-7,8-dihydrodiol epoxide formation from benzo[a]pyrene. Cancer Res, 2005, 65: 5105-5111.
26. Bandiera S, Weidlich S and Harth V. Proteasomal degradation of human CYP1B1: effect of the Asn453Ser polymorphism on the post-translational regulation of CYP1B1 expression. Mol Pharmacol, 2005, 67: 435-443.
27. Christian CA, Fagundes RB, Strickland PT, et al. The influences of genetic polymorphisms in Ahr, CYP1A1, CYP1A2, CYP1B1, GST M1, GSTT1 and UGT1A1 on urine 1-hydroxypyrene glucuronide concentrations in healthy subjects from Rio Grande do Sul, Brazil. Carcinogenesis, 2007, 28: 112-117.
28. Yang M, Jang JY and Kim S. Genetic effects on urinary 1-hydroxypyrene levels in a Korean population. Carcinogenesis, 2003, 24: 1085-1089.
29. Rihs HP, Pesch B and Kappler M. Occupational exposure to polycyclic aromatic hydrocarbons in German industries: association between exogenous exposure and urinary metabolites and its modulation by enzyme polymorphisms. Toxicol Lett, 2005, 157: 241-255.
30. Kato S, Bowman ED, Harrington AM, et al. Human lung carcinogen-DNA adduct levels mediated by genetic polymorphisms in vivo. J Natl Cancer Inst, 1995, 87(12): 902-907.
31.戴宇飞,冷曙光,潘祖飞,等.萘代谢产物-白蛋白加合物作为焦炉工接触生物标志物的初步探讨.中华预防医学杂志, 2004, 38(6): 392-395.
32. Nan HM, Kim H, Lim HS, et al. Effects of occupation, lifestyle and genetic polymorphisms of CYP1A1, CYP2E1, GSTM1 and GSTT1 on urinary 1-hydrox- ypyrene and 2-naphthol concentrations. Carcinogenesis, 2001, 22(5): 787-793.
33. Rendic S. Summary of information on human CYP enzymes: human P450metabolism data. Drug Metab Rev, 2002, 34(1-2): 438-448.
34. Zanger UM, Klein K, Saussele T, et al. Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics, 2007, 8(7): 743-759.
35. Zhang J, Tian Q, Zhu YZ, et al. Reversal of resistance to oxazaphosphorines. Curr Cancer Drug Targets, 2006, 6(5): 385-407.
36. Morisseau C and Hammock BD. Epoxide hydrolases: mechanisms, inhibitor designs, and biological roles. Annu Rev Pharmacol Toxicol, 2005, 45: 311-333.
37. Gsur A, Zidek T, Schnattinger K, et al. Association of microsomal epoxide hydrolase polymorphisms and lung cancer risk. Br J Cancer, 2003, 89(4): 702-706.
38. Huang WY, Chatterjee N, Chanock S, et al. Microsomal epoxide hydrolase polymorphisms and risk for advanced colorectal adenoma. Cancer Epidemiol Biomarkers Prev, 2005, 14(1): 152-157.
39. Tang SC, Sheu GT, Wong RH, et al. Expression of glutathione S-transferase M2 in stage I/II non-small cell lung cancer and alleviation of DNA damage exposure to benzo[a]pyrene. Toxicol Lett, 2010, 192(3): 316-323.
40. 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 Prev, 1999, 23(6): 445-453.
41. Ntais C, Polycarpou A and Ioannidis JP. Association of GSTM1, GSTT1, and GSTP1 gene polymorphisms with the risk of prostate cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev, 2005, 14(1): 176-181.
42. Guillemette C, Millikan RC, Newman B, et al. Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and association with breast cancer amongAfrican Americans. Cancer Res, 2000, 60(4): 950-956.
43. 43 Vogel A, Ockenga J, Ehmer U, et al. Polymorphisms of the carcinogen detoxifying UDP-glucuronosyltransferase UGT1A7 in proximal digestive tract cancer. Z Gastroenterol, 2002, 40(7): 497-502.
44. Watabe T, Ishizuka T, Isobe M, et al. A 7-hydroxymethyl sulfate ester as an active metabolite of 7, 12-dimethylbenz[alpha]anthracene. Science, 1982, 215(4531): 403-405.
45. Surh YJ and Tannenbaum SR. Sulfotransferase-mediated activation of 7,8,9,10-tetrahydro-7-ol,7,8-dihydrodiol,and7,8,9,10-tetraol derivatives of benzo[a] pyrene. Chem Res Toxicol, 1995, 8(5): 693-698.
46. Lampen A, Ebert B, Stumkat L, et al. Induction of gene expression of xenobiotic metabolism enzymes and ABC-transport proteins by PAH and a reconstituted PAH mixture in human Caco-2 cells. Biochim Biophys Acta, 2004, 1681(1): 38-46.
47. Raftogianis RB, Wood TC, Otterness DM, et al. Phenol sulfotransferase pharmacogenetics in humans: association of common SULT1A1 alleles with TS PST phenotype. Biochem Biophys Res Commun, 1997, 239(1): 298-304.
48. Wang Y, Spitz MR, Tsou AM, et al. Sulfotransferase (SULT) 1A1 polymorphism as a predisposition factor for lung cancer: a case-control analysis. Lung Cancer, 2002, 35(2): 137-142.
49. Zheng L, Wang Y, Schabath MB, et al. Sulfotransferase 1A1 (SULT1A1) polymorphism and bladder cancer risk: a case-control study. Cancer Lett, 2003, 202(1): 61-69.
50. Lilla C, Risch A, Kropp S, et al. SULT1A1 genotype, active and passive smoking, and breast cancer risk by age 50 years in a German case-control study. Breast CancerRes, 2005, 7(2): 229-237.
51. Hung RJ, Boffetta P, Brennan P, et al. Genetic polymorphisms of MPO, COMT, MnSOD, NQO1, interactions with environmental exposures and bladder cancer risk. Carcinogenesis, 2004, 25(6): 973-978.
52. Sharp SY, Kelland LR, Valenti MR, et al. Establishment of an isogenic human colon tumor model for NQO1 gene expression: application to investigate the role of DT-diaphorase in bioreductive drug activation in vitro and in vivo. Mol Pharmacol, 2000, 58(5): 1146-1155.
53. Saldivar SJ, Wang Y, Zhao H, et al. An association between a NQO1 genetic polymorphism and risk of lung cancer. Mutat Res, 2005, 582(1-2): 71-78.
54. Lewis SJ, Cherry NM, Niven RM, et al. Polymorphisms in the NAD(P)H: quinone oxidoreductase gene and small cell lung cancer risk in a UK population. Lung Cancer, 2001, 34(2): 177-183.
55. Sunaga N, Kohno T, Yanagitani N, et al. Contribution of the NQO1 and GSTT1 polymorphisms to lung adenocarcinoma susceptibility. Cancer Epidemiol Biomarkers Prev, 2002, 11(8): 730-738.
56. Niwa Y, Hirose K, Nakanishi T, et al. Association of the NAD (P) H: quinone oxidoreductase C609T polymorphism and the risk of cervical cancer in Japanese subjects. Gynecol Oncol, 2005, 96(2): 423-429.
57. Palackal NT, Burczynski ME, Harvey RG, et al. The ubiquitous aldehyde reductase (AKR1A1) oxidizes proximate carcinogen trans-dihydrodiols to o-quinones: potential role in polycyclic aromatic hydrocarbon activation. Biochemistry, 2001, 40(36): 10901-10910.
58. Jiang H, Shen YM, Quinn AM, et al. Competing roles of cytochrome P450 1A1/1B1and aldo-keto reductase 1A1 in the metabolic activation of (+/-)-7, 8-dihydroxy-7, 8-dihydro-benzo[a]pyrene in human bronchoalveolar cell extracts. Chem Res Toxicol, 2005, 18(2): 365-374.
59. Hyndman D, Bauman DR, Heredia VV, et al. The aldo-keto reductase superfamily homepage. Chem Biol Interact, 2003, (621-631):143-144.
60. Shimada T, Watanabe J and Kawajiri K. Catalytic properties of polymorphic human cytochrome P450 1B1 variants. Carcinogenesis, 1999, 20: 1607-1613.
61. Joseph P and Jaiswal AK. NAD(P)H: quinone oxidoreductase1 (DT diaphorase) specifically prevents the formation of benzo[a]pyrene quinone-DNA adducts generated by cytochrome P4501A1 and P450 reductase. Proc Natl Acad Sci USA, 1994, 91(18): 8413-8417.