Zhu Jijiang, Chang Ping, Bondy Melissa L, Sahin Aysegul A, Singletary Sonja E, Takahashi Satoru, Shirai Tomoyuki, Li Donghui
Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Epidemiol Biomarkers Prev. 2003 Sep;12(9):830-7.
2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP), the most abundant heterocyclic amine (HCA) in cooked food, is a mammary carcinogen in female rats. In humans, consumption of well-done meat and PhIP intake have been associated with an increased risk of breast cancer, but PhIP-DNA adducts have not been analyzed in breast tissues from women having unknown exposure to HCAs. Using an immunohistochemistry (IHC) method, we measured PhIP-DNA adducts in normal breast tissues of 106 women having newly diagnosed breast cancer in comparison with those of 49 women undergoing reduction mammoplasty. The IHC method was first validated in MCF-7 cells treated with different doses of N-hydroxy-PhIP. We detected significant dose-response relationship and correlation (r=0.94) between the levels of PhIP-DNA adducts detected by IHC and 32P-postlabeling. Using IHC, PhIP-DNA adducts were detected in 82 and 71% of the normal breast tissue sections from the cancer and control patients respectively. The median (range) absorbance was 0.18 (0-0.57) and 0.08 (0-0.38) in the cancer and control patients, respectively (P<0.001). Using the median in the controls as a cutoff point, 71% of the cancer patients and 47% of the controls were distributed in the higher range (chi2=8.17; P=0.004). Logistic regression analysis demonstrated an OR of 4.03 (95% CI, 1.41-11.53) after adjusting for age and ethnicity (P=0.009). Stratified analyses did not find any significant effect of age, ethnicity, smoking, well-done meat consumption, dietary intake of PhIP, or polymorphisms of CYP1A1, CYP1B1, NAT2, and GSTM1 genes on the level of PhIP-DNA adducts. However, a potential interactive effect of well-done meat consumption and NAT2 genotype on the level of PhIP-DNA adducts was observed (P=0.047). This is the first study of detection of PhIP-DNA adducts in breast tissue samples obtained from women having unknown exposure to HCAs. These data strongly support the hypothesis that HCA exposure contributes to human breast cancer among genetically susceptible individuals.
2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）是烹饪食物中最常见的杂环胺（HCA），是雌性大鼠的乳腺致癌物。在人类中，食用熟透的肉类和摄入PhIP与患乳腺癌风险增加有关，但尚未对接触HCA情况不明的女性乳腺组织中的PhIP-DNA加合物进行分析。我们采用免疫组织化学（IHC）方法，测量了106例新诊断为乳腺癌的女性正常乳腺组织中的PhIP-DNA加合物，并与49例行乳房缩小成形术的女性进行了比较。该IHC方法首先在经不同剂量N-羟基-PhIP处理的MCF-7细胞中得到验证。我们检测到通过IHC检测的PhIP-DNA加合物水平与32P后标记法之间存在显著的剂量反应关系和相关性（r = 0.94）。使用IHC方法，分别在癌症患者和对照患者的82%和71%的正常乳腺组织切片中检测到PhIP-DNA加合物。癌症患者和对照患者的中位（范围）吸光度分别为0.18（0 - 0.57）和0.08（0 - 0.38）（P < 0.001）。以对照组的中位值为截断点，71%的癌症患者和47%的对照者分布在较高范围（χ2 = 8.17；P = 0.004）。逻辑回归分析显示，在调整年龄和种族后，比值比为4.03（95%可信区间，1.41 - 11.53）（P = 0.009）。分层分析未发现年龄、种族、吸烟、食用熟透的肉类、PhIP的饮食摄入量或CYP1A1、CYP1B1、NAT2和GSTM1基因多态性对PhIP-DNA加合物水平有任何显著影响。然而，观察到食用熟透的肉类和NAT2基因型对PhIP-DNA加合物水平有潜在的交互作用（P = 0.047）。这是首次对接触HCA情况不明的女性乳腺组织样本中PhIP-DNA加合物进行检测的研究。这些数据有力地支持了以下假设：在遗传易感个体中，接触HCA会导致人类患乳腺癌。
