Li D, Firozi P F, Wang L E, Bosken C H, Spitz M R, Hong W K, Wei Q
Departments of Gastrointestinal Oncology and Digestive Diseases, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Cancer Res. 2001 Feb 15;61(4):1445-50.
Levels of DNA adducts vary greatly in vivo, attributable to individual differences in enzymatic bioactivation of benzo(a)pyrene. We developed an assay to measure the levels of DNA adducts induced in vitro by benzo(a)pyrene diol epoxide (BPDE), a bioactivated form of benzo(a)pyrene. In this large molecular epidemiological study of lung cancer, we tested the hypothesis that the level of in vitro BPDE-induced adducts is associated with risk of lung cancer. This hospital-based case-control study included 221 newly diagnosed lung cancer cases and 229 healthy controls frequency matched on age, sex, ethnicity, and smoking status. Short-term cultured peripheral blood lymphocytes from each subject were exposed in vitro to BPDE (4 microm) for 5 h, and the 32P-postlabeling method was then used to measure BPDE-induced DNA adducts in the host cells. Overall, the patients had significantly higher levels of BPDE-DNA adducts than did the controls (mean +/- SD per 107 nucleotides, 93.2+/-89.3 for cases versus 63.7+/-61.1 for controls; P = 0.001). Univariate and multivariate logistic regression analyses were performed to calculate the crude and adjusted odds ratios and their 95% confidence intervals. When the median adduct level of controls (46/10(7) nucleotides) was used as the cutoff point, 64% of cases had higher levels (odds ratio, 2.15; 95% confidence interval, 1.39-3.33, adjusted for age, sex, ethnicity, body mass index, recent weight loss, pack-years smoked, smoking in the last 24 h, and family history of cancer). Stratified analyses showed consistently higher levels of BPDE-induced adducts in cases than in controls, regardless of subgroup of age, sex, ethnicity, body mass index, recent weight loss, pack-years smoked, smoking in the last 24 h, and family history of cancer. A significant dose-response relationship between the quartile levels of BPDE-induced DNA adducts and the risk of lung cancer was observed (trend test, P < 0.001). The significant association between the level of in vitro BPDE-induced DNA adducts and risk for lung cancer suggests that subjects very sensitive to BPDE-induced DNA damage may have a suboptimal ability to remove the BPDE-DNA adducts and so are susceptible to tobacco carcinogen exposure and, therefore, may be at increased risk of lung cancer.
体内DNA加合物水平差异很大，这归因于苯并(a)芘酶促生物活化过程中的个体差异。我们开发了一种检测方法，用于测量苯并(a)芘二醇环氧化物（BPDE，苯并(a)芘的一种生物活化形式）在体外诱导产生的DNA加合物水平。在这项针对肺癌的大型分子流行病学研究中，我们检验了以下假设：体外BPDE诱导的加合物水平与肺癌风险相关。这项基于医院的病例对照研究纳入了221例新诊断的肺癌病例和229名健康对照，后者在年龄、性别、种族和吸烟状况方面进行了频率匹配。将每个受试者短期培养的外周血淋巴细胞在体外暴露于BPDE（4微摩尔）5小时，然后使用32P后标记法测量宿主细胞中BPDE诱导的DNA加合物。总体而言，患者的BPDE-DNA加合物水平显著高于对照组（每107个核苷酸的平均值±标准差，病例组为93.2±89.3，对照组为63.7±61.1；P = 0.001）。进行单因素和多因素逻辑回归分析以计算粗比值比和调整后的比值比及其95%置信区间。当以对照组的加合物水平中位数（46/10(7)个核苷酸）作为截断点时，64%的病例加合物水平更高（比值比为2.15；95%置信区间为1.39 - 3.33，对年龄、性别、种族、体重指数、近期体重减轻、吸烟包年数、过去24小时内吸烟情况和癌症家族史进行了调整）。分层分析显示，无论年龄、性别、种族、体重指数、近期体重减轻、吸烟包年数、过去24小时内吸烟情况和癌症家族史的亚组如何，病例组中BPDE诱导的加合物水平始终高于对照组。观察到BPDE诱导的DNA加合物四分位数水平与肺癌风险之间存在显著的剂量反应关系（趋势检验，P < 0.001）。体外BPDE诱导的DNA加合物水平与肺癌风险之间的显著关联表明，对BPDE诱导的DNA损伤非常敏感的受试者清除BPDE-DNA加合物的能力可能欠佳，因此易受烟草致癌物暴露影响，进而可能患肺癌的风险增加。
