Rojas M, Alexandrov K, Cascorbi I, Brockmöller J, Likhachev A, Pozharisski K, Bouvier G, Auburtin G, Mayer L, Kopp-Schneider A, Roots I, Bartsch H
Division of Toxicology and Cancer Risk Factors, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Pharmacogenetics. 1998 Apr;8(2):109-18.
Levels of anti-benzo[a]pyrene diol-epoxide DNA adducts were analysed by high-pressure liquid chromatography/fluorimetric detection in non-tumorous lung tissues from 20 lung cancer patients and in white blood cells from 20 polycyclic aromatic hydrocarbon exposed coke oven workers. All were current tobacco smokers. CYP1A1 mutations (MspI at 6235 nt, Ile-Val462) and GSTM1 deletion polymorphisms in each individual were analysed in genomic DNA by PCR/restriction fragment length polymorphism. Independently of the CYP1A1 genotype (1) all 23 samples in the two groups with non-detectable adducts (< 0.2 per 10(8) nt) were of GSTM1 active genotype; (2) the 17 samples with detectable adducts (> or = 0.2 per 10(8) nt) in the two groups were GSTM1*0/0. The difference in adduct levels between GSTM10/0 and GSTM1 active genotype was highly significant (p < 0.00005). Among GSTM1-deficient individuals (n = 17), a subgroup of 14 individuals with CYP1A11/*1 (wild-type, n = 7) or heterozygous genotype (*1/*2A or *1/2B, n = 7) showed low levels of BPDE DNA-adducts (range: 0.2-1.3 per 10(8) nt). (3) Three individuals with the rare combination CYP1A12A/*2A or *2A/B and GSTM10/0 showed significantly higher adduct levels (median: 17.4 adducts/10(8) nt, range 1.9-44; p = 0.017). Therefore, combination of homozygous mutated CYP1A1 and GSTM10/*0 genotypes lead, at a similar or even lower smoking dose, to a stronger increase of anti-benzo[a]pyrene diol-epoxide DNA adduct levels than found in individuals with CYP1A1 and GSTM1 wild-type. These data provide a mechanistic understanding of epidemiological studies that correlated these 'at risk' genotypes with increased smoking-related lung cancers.
采用高压液相色谱/荧光检测法，对20例肺癌患者的非肿瘤肺组织以及20名暴露于多环芳烃的焦炉工人的白细胞中的抗苯并[a]芘二醇环氧化物DNA加合物水平进行了分析。所有受试者均为当前吸烟者。通过聚合酶链反应/限制性片段长度多态性分析基因组DNA中每个个体的CYP1A1突变（6235 nt处的MspI，Ile-Val462）和GSTM1缺失多态性。与CYP1A1基因型无关：（1）两组中加合物检测不到（<0.2/10⁸ nt）的所有23个样本均为GSTM1活性基因型；（2）两组中加合物可检测到（≥0.2/10⁸ nt）的17个样本为GSTM1*0/0。GSTM10/0与GSTM1活性基因型之间的加合物水平差异具有高度显著性（p<0.00005）。在GSTM1缺陷个体（n = 17）中，14例CYP1A11/*1（野生型，n = 7）或杂合基因型（*1/2A或1/2B，n = 7）的亚组显示BPDE DNA加合物水平较低（范围：0.2 - 1.3/10⁸ nt）。（3）3例具有罕见组合CYP1A12A/2A或2A/B且GSTM10/0的个体显示出显著更高的加合物水平（中位数：17.4个加合物/10⁸ nt，范围1.9 - 44；p = 0.017）。因此，纯合突变的CYP1A1和GSTM10/*0基因型组合，在吸烟剂量相似甚至更低的情况下，比CYP1A1和GSTM1野生型个体导致抗苯并[a]芘二醇环氧化物DNA加合物水平更强的升高。这些数据为将这些“高危 ”基因型与吸烟相关肺癌增加相关联的流行病学研究提供了机制上的理解。
