Butkiewicz D, Grzybowska E, Hemminki K, Ovrebø S, Haugen A, Motykiewicz G, Chorazy M
Department of Tumor Biology, Institute of Oncology, Gliwice, Poland.
Mutat Res. 1998 Jul 8;415(1-2):97-108. doi: 10.1016/s1383-5718(98)00064-3.
The CYP1A1, CYP2D6 and GSTM1 genes encode biotransforming enzymes involved in activation and detoxification of xenobiotics. Metabolically activated chemical compounds may interact with DNA and form adducts. In this study, the effect of the GSTM1, CYP1A1 exon 7 and CYP2D6 polymorphisms on DNA adduct levels was studied in 170 healthy volunteers. DNA adducts levels were measured by 32P-postlabelling in mononuclear white blood cells (WBC, lymphocytes and monocytes) and granulocytes collected in summer and winter. The influence of the genotype on the level of DNA adducts in both types of WBCs was observed only in summer samples. Individuals with GSTM1 deficient (null) genotype had significantly elevated level of adducts in mononuclear WBCs (p = 0.045) and granulocytes (p = 0.031) compared to GSTM1 positives. Higher adduct levels in carriers of combined GSTM1(null)/CYP1A1-Ile/Val genotype were found in both types of WBCs when compared to GSTM1(+)/CYP1A1-Ile/Ile genotype carriers (p = 0.046 in granulocytes, p = 0.092 in mononuclear WBCs). CYP2D6 wild-type homozygotes (EMs) and heterozygotes (HEMs) were shown to have significantly higher mononuclear WBC DNA adduct levels than mutant homozygotes (PMs) (p = 0.037 and p = 0.014). When confounding factors associated with PAH exposure were taken into account a statistically significant effect of CYP1A1 exon 7 polymorphism on DNA adduct levels was found (p = 0.012 in mononuclear WBCs, p = 0.043 in granulocytes). In a subgroup of current smokers (n = 95) high DNA adduct levels in granulocytes were associated with GSTM1(null) genotype, and increased adduct levels in mononuclear WBCs correlated with CYP2D6 EM and HEM genotypes. In winter samples the association between the genotype and DNA adduct levels was not observed.
细胞色素P450 1A1（CYP1A1）、细胞色素P450 2D6（CYP2D6）和谷胱甘肽S-转移酶M1（GSTM1）基因编码参与外源性物质激活和解毒的生物转化酶。经代谢激活的化合物可能与DNA相互作用并形成加合物。在本研究中，对170名健康志愿者进行了GSTM1、CYP1A1第7外显子和CYP2D6基因多态性对DNA加合物水平影响的研究。通过32P后标记法测量夏季和冬季采集的单核白细胞（白细胞、淋巴细胞和单核细胞）和粒细胞中的DNA加合物水平。仅在夏季样本中观察到基因型对两种类型白细胞中DNA加合物水平的影响。与GSTM1阳性个体相比，GSTM1基因缺陷（无效）基因型个体的单核白细胞（p = 0.045）和粒细胞（p = 0.031）中的加合物水平显著升高。与GSTM1（+）/CYP1A1-Ile/Ile基因型携带者相比，GSTM1（无效）/CYP1A1-Ile/Val联合基因型携带者的两种类型白细胞中的加合物水平均较高（粒细胞中p = 0.046，单核白细胞中p = 0.092）。细胞色素P450 2D6野生型纯合子（EMs）和杂合子（HEMs）的单核白细胞DNA加合物水平显著高于突变型纯合子（PMs）（p = 0.037和p = 0.014）。当考虑与多环芳烃暴露相关的混杂因素时，发现CYP1A1第7外显子多态性对DNA加合物水平有统计学显著影响（单核白细胞中p = 0.012，粒细胞中p = 0.043）。在当前吸烟者亚组（n = 95）中，粒细胞中高DNA加合物水平与GSTM1（无效）基因型相关，单核白细胞中加合物水平升高与CYP2D6 EM和HEM基因型相关。在冬季样本中未观察到基因型与DNA加合物水平之间的关联。
