Environmental and Occupational Medicine and Epidemiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA.
Cancer Epidemiol Biomarkers Prev. 2010 Jun;19(6):1492-7. doi: 10.1158/1055-9965.EPI-09-1195. Epub 2010 May 25.
Polymorphisms in carcinogen detoxification enzymes, NAT2 and GSTM1, have been suggested as susceptibility factors for DNA damage and lung cancer. However, little information is available on DNA adduct burden in the lung tissue and polymorphisms in NAT2 and GST genes. We investigated the independent and combined effects of the metabolic gene polymorphisms of NAT2 and GSTs on DNA adduct formation in different tissues (lung and blood) in lung cancer patients.
DNA adducts were measured in lung and blood by the (32)P-postlabeling assay. Multiple regression models were used to assess adjusted percent change in DNA adduct levels associated with GST and NAT2 genotypes.
After adjusting for potential confounders, as well as for other GST gene variants, lung adduct levels significantly increased by 150.3% [95% confidence interval (95% CI), 35.4-362.6%] for the GSTM1 null and by 73.9% (95% CI, -3.2% to 212.4%) for the NAT2 slow acetylator genotype, respectively. No association was seen with polymorphisms of other GST genes such as GSTT1 and GSTP1. The high-risk group, the combined GSTM1 null plus NAT2 slow, had significantly enhanced levels of lung adducts by 295% (95% CI, 72.7-803.5%) over those associated with single genes, suggesting a synergistic effect on DNA damage in the target lung tissue.
The increase in DNA adduct levels in lung is associated with the GSTM1 null and NAT2 slow genotypes alone or in combination.
These results suggest that GSTM1 and NAT2 genotypes play an independent and interactive role in the formation of carcinogen DNA adduct in the lung.
致癌物质解毒酶 NAT2 和 GSTM1 的多态性被认为是 DNA 损伤和肺癌的易感因素。然而，关于肺癌患者肺组织中的 DNA 加合物负担和 NAT2 和 GST 基因多态性的信息很少。我们研究了 NAT2 和 GST 基因代谢基因多态性对肺癌患者不同组织（肺和血液）中 DNA 加合物形成的独立和联合作用。
通过（32）P-后标记法测定肺和血液中的 DNA 加合物。多变量回归模型用于评估与 GST 和 NAT2 基因型相关的 DNA 加合物水平的调整百分比变化。
在调整了潜在混杂因素以及其他 GST 基因变异后，GSTM1 缺失型的肺组织 DNA 加合物水平分别显著增加了 150.3%（95%可信区间[95%CI]，35.4-362.6%），NAT2 慢乙酰化基因型则增加了 73.9%（95%CI，-3.2%-212.4%）。其他 GST 基因如 GSTT1 和 GSTP1 的多态性与肺组织 DNA 加合物水平无关。高危组，即 GSTM1 缺失加 NAT2 慢型，其肺组织 DNA 加合物水平显著升高 295%（95%CI，72.7-803.5%），提示两种基因的协同作用导致了靶肺组织的 DNA 损伤。
肺组织中 DNA 加合物水平的增加与 GSTM1 缺失和 NAT2 慢型基因型单独或联合存在有关。
这些结果表明，GSTM1 和 NAT2 基因型在肺组织中致癌物质 DNA 加合物的形成中发挥独立和交互作用。
