title: Detection of 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine-DNA adducts in normal breast tissues and risk of breast cancer.
abstract: 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.
mesh_terms: D000328:Adult; D001940:Breast / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002273:Carcinogens / Q000378:metabolism / Q000494:pharmacology; D018736:DNA Adducts / Q000032:analysis* / Q000097:blood / Q000235:genetics; D004032:Diet / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000737:chemistry; D008460:Meat / Q000009:adverse effects; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D012307:Risk Factors; D014407:Tumor Cells, Cultured
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D007093:Imidazoles; D011725:Pyridines; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine