Wang Y, Ichiba M, Iyadomi M, Zhang J, Tomokuni K
Department of Community Health Science, Saga Medical School, Nabeshima, Japan.
Ind Health. 1998 Oct;36(4):337-46. doi: 10.2486/indhealth.36.337.
Although cigarette smoking is one major determinant of lung carcinogenesis, not all smokers develop cancer. This phenomenon is due to individual variation in genetic susceptibility to carcinogens, nutrition, and lifestyle. Previous studies have shown that genetic polymorphism of metabolic enzymes and plasma micronutrients are associated with lung cancer risk. DNA adducts may serve as a molecular dosimeter for exposure to carcinogens. In this cross-sectional study, we analyzed the blood samples of 158 subjects to evaluate the effects of polymorphisms of cytochrome P450 1A1 (CYP1A1), glutathione S-transferase M1 (GSTM1), T (GSTT), N-acetytransferase 2 (NAT2), and aldehyde dehydrogenase 2 (ALDH2) as well as the effects of plasma beta-carotene and alpha-tocopherol on lymphocyte DNA adducts measured by 32P-postlabeling analysis. The DNA adduct level of smokers (mean +/- SD, 1.26 +/- 0.79/10(8) nucleotides) was significantly higher than that of nonsmokers (0.87 +/- 0.33, P = 0.007). Smokers with CYP1A1 minor homozygotes and GSTM1 null genotypes had a significantly higher level of DNA adducts than those without (P = 0.027 for homozygotes, P = 0.049 for heterozygotes). Smokers with NAT2 minor homozygotes also tended to have a higher DNA adduct level than those with heterozygotes and wild alleles, but the difference was not statistically significant. The DNA adduct level of smokers with ALDH2 heterozygotes was significantly higher than that of smokers with minor homozygotes (P = 0.045). When smokers were divided into "high" and "low" groups according to mean level of plasma beta-carotene or alpha-tocopherol, in the low beta-carotene group, the subjects with CYP1A1 minor homozygotes had higher DNA adduct levels than those with other CYP1A1 genotypes. Smokers with GSTT null genotype and high beta-carotene tended to have a higher DNA adduct level than those with GSTT present and high beta-carotene (P = 0.07), and those with GSTT null genotype and low beta-carotene (P = 0.07). There was weak correlation between DNA adduct level and number of cigarettes smoked per day in the low plasma beta-carotene group (r = 0.28, n = 36, p < 0.1). These results suggested that polymorphisms of CYP1A1, GSTM1, T, NAT2, and ALDH2, and plasma beta-carotene may modulate the level of DNA adducts.
尽管吸烟是肺癌发生的一个主要决定因素，但并非所有吸烟者都会患癌。这种现象是由于个体在对致癌物的遗传易感性、营养状况和生活方式方面存在差异。先前的研究表明，代谢酶的基因多态性和血浆微量营养素与肺癌风险相关。DNA加合物可作为接触致癌物的分子剂量计。在这项横断面研究中，我们分析了158名受试者的血液样本，以评估细胞色素P450 1A1（CYP1A1）、谷胱甘肽S-转移酶M1（GSTM1）、T（GSTT）、N-乙酰转移酶2（NAT2）和醛脱氢酶2（ALDH2）的多态性以及血浆β-胡萝卜素和α-生育酚对通过32P后标记分析法测量的淋巴细胞DNA加合物的影响。吸烟者的DNA加合物水平（平均值±标准差，1.26±0.79/10(8)核苷酸）显著高于非吸烟者（0.87±0.33，P = 0.007）。具有CYP1A1次要纯合子和GSTM1缺失基因型的吸烟者的DNA加合物水平显著高于没有这些基因型的吸烟者（纯合子P = 0.027，杂合子P = 0.049）。具有NAT2次要纯合子的吸烟者的DNA加合物水平也往往高于具有杂合子和野生等位基因的吸烟者，但差异无统计学意义。具有ALDH2杂合子的吸烟者的DNA加合物水平显著高于具有次要纯合子基因型的吸烟者（P = 0.045）。当根据血浆β-胡萝卜素或α-生育酚的平均水平将吸烟者分为“高”和“低”组时，在低β-胡萝卜素组中，具有CYP1A1次要纯合子的受试者的DNA加合物水平高于具有其他CYP1A1基因型的受试者。具有GSTT缺失基因型且β-胡萝卜素水平高的吸烟者的DNA加合物水平往往高于具有GSTT且β-胡萝卜素水平高的吸烟者（P = 0.07），以及具有GSTT缺失基因型且β-胡萝卜素水平低的吸烟者（P = 0.07）。在低血浆β-胡萝卜素组中，DNA加合物水平与每日吸烟支数之间存在弱相关性（r = 0.28，n = 36，p < 0.1）。这些结果表明，CYP1A1、GSTM1、T、NAT2和ALDH2的多态性以及血浆β-胡萝卜素可能调节DNA加合物的水平。
