Rothman N, Shields P G, Poirier M C, Harrington A M, Ford D P, Strickland P T
Environmental Epidemiology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Mol Carcinog. 1995 Sep;14(1):63-8. doi: 10.1002/mc.2940140111.
Carcinogenic polycyclic aromatic hydrocarbons (PAHs) form DNA adducts via a complex metabolic activation pathway that includes cytochrome P450 (CYP) 1A1, whereas intermediate metabolites can be detoxified by conjugation through pathways including glutathione s-transferase M1 (GSTM1). PAH-DNA adducts can be measured in peripheral white blood cells (WBCs) and should reflect the net effect of competing activation and detoxification pathways and DNA repair as well as exposure. We have previously shown that WBC PAH-DNA adducts measured by an enzyme-linked immunosorbent assay (ELISA) were associated with recent, frequent consumption of charbroiled food among 47 nonsmoking wildland fire-fighters who provided two blood samples 8 wk apart. In the investigation reported here, which was performed in the same population, we measured the association between the GSTM1 null genotype, which results in loss of enzyme activity, and PAH-DNA adduct levels, hypothesizing that subjects with this genotype would have higher levels of DNA adducts because of their decreased ability to detoxify PAH metabolites. However, PAH-DNA adduct levels were nonsignificantly lower in subjects with the GSTM1 null genotype (n = 28) compared with other subjects (n = 19) (median 0.04 fmol/microgram DNA vs 0.07 fmol/microgram DNA, respectively, P = 0.45, Wilcoxon rank-sum test). Adduct levels were also lower in the nine subjects heterozygous or homozygous for the CYP1A1 exon 7 polymorphism (which codes for a valine rather than isoleucine and is thought to be associated with greater CYP1A1 activity) compared with the 38 wild-type subjects (P = 0.12). In the entire group, there was a positive association between consuming charbroiled food and PAH-DNA adduct formation (r = 0.24, P = 0.02, Spearman rank-order correlation). This association was weaker in the subgroup of subjects with the GSTM1 null genotype (r = 0.03, P = 0.84) and stronger among the remaining subjects (r = 0.57, P = 0.0002). These results suggest that the GSTM1 null genotype and CYP1A1 exon 7 polymorphism are not associated with increased susceptibility for PAH-DNA adduct formation in peripheral WBCs measured by ELISA in nonsmoking populations.
致癌性多环芳烃（PAHs）通过包括细胞色素P450（CYP）1A1在内的复杂代谢激活途径形成DNA加合物，而中间代谢产物可通过包括谷胱甘肽S-转移酶M1（GSTM1）在内的途径进行结合解毒。PAH-DNA加合物可在外周血白细胞（WBCs）中检测到，应能反映竞争性激活和解毒途径、DNA修复以及暴露的净效应。我们之前已表明，通过酶联免疫吸附测定（ELISA）检测的WBC PAH-DNA加合物与47名非吸烟野外消防员近期频繁食用炭烤食物有关，这些消防员相隔8周提供了两份血液样本。在本报告的同一人群中进行的调查中，我们测量了导致酶活性丧失的GSTM1无效基因型与PAH-DNA加合物水平之间的关联，假设具有该基因型的受试者由于其解毒PAH代谢产物的能力降低，DNA加合物水平会更高。然而，与其他受试者（n = 19）相比，GSTM1无效基因型受试者（n = 28）的PAH-DNA加合物水平无显著降低（中位数分别为0.04 fmol/μg DNA和0.07 fmol/μg DNA，P = 0.45，Wilcoxon秩和检验）。与38名野生型受试者相比，CYP1A1外显子7多态性（编码缬氨酸而非异亮氨酸，被认为与更高的CYP1A1活性相关）杂合或纯合的9名受试者的加合物水平也较低（P = 0.12）。在整个组中，食用炭烤食物与PAH-DNA加合物形成之间存在正相关（r = 0.24，P = 0.02，Spearman等级相关）。在GSTM1无效基因型受试者亚组中这种相关性较弱（r = 0.03，P = 0.84），而在其余受试者中较强（r = 0.57，P = 0.0002）。这些结果表明，在非吸烟人群中，通过ELISA测量外周血白细胞中PAH-DNA加合物形成的易感性增加与GSTM1无效基因型和CYP1A1外显子7多态性无关。
