Characterization of a major aromatic DNA adduct detected in human breast tissues.
A bulky DNA adduct (Spot 1) was previously detected in normal adjacent breast tissues of 41% (36/87) of women with breast cancer and in none (0/29) of the noncancer controls by (32)P-postlabeling. To characterize this adduct, it was chromatographically compared with DNA adduct profiles generated in several in vitro and in vivo experimental systems. First, MCF-7 cells were exposed to a number of chemical carcinogens, that is, benzo[a]pyrene (B[a]P), 4-OH-B[a]P, 9-OH-B[a]P, 11-OH-B[a]P, B[a]P-trans-4,5-dihydrodiol, 1-nitropyrene, 6-nitrochrysene, dibenzo[a,l]pyrene, benzo[c]phenanthrene, dibenzo[a,h]anthracene, 3-methylcholanthrene, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Spot 1 was detected as a minor adduct in cells treated with B[a]P but not other compounds. Second, to determine whether Spot 1 is derived from lipid peroxidation products or estrogen metabolites, it was compared with adduct profiles of cells or DNAs exposed to 17beta-estradiol, 4-hydroxy estradiol, 4-hydroxynonenal, or oxidized oat oil. Spot 1 was not detectable in these samples. In addition, Spot 1 did not comigrate with the 1,N(2)-ethenodeoxyguanosine adduct standard. Third, to explore the mechanism of Spot 1 formation, it was compared with adduct profiles detected in DNA or mononucleotides reacted with BPDE, 1-OH-7,8-dihydrodiol of B[a]P, and 3-OH-7,8-dihydrodiol of B[a]P as well as in rats orally treated with B[a]P. Spot 1 comigrated with a minor adduct in BPDE-treated DNA during anion exchange rechromatography but these two adducts were separated by partition chromatography. Spot 1 also behaved in a manner that was very similar to that of the polar B[a]P adducts detected in rat liver, but the two adducts were separated by HPLC. Fourth, Spot 1 was compared with CD1 mice exposed to 7H-benzo[c]fluorene (B[c]F). Spot 1 from some patients comigrated with a major adduct induced by B[c]F. Finally, we found that the presence of Spot 1 in human breast tissues was not related to smoking status but, rather, with CYP1A1 MspI polymorphism. The CYP1A1 mutant carriers had a significantly higher frequency of this adduct than did the wild-type genotypes. Furthermore, individuals with Spot 1 had a significantly higher staining intensity for BPDE-PAH adducts in their tissue sections than those without it. These results demonstrate that this major bulky DNA adduct detected in human breast tissues is related to PAH exposure.
Li
Donghui
D
Department of Gastrointestinal Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030, USA. dli@mdanderson.org
Wang
Mianying
M
Firozi
Pervez Firoz
PF
Chang
Ping
P
Zhang
Weiqing
W
Baer-Dubowska
Wanda
W
Moorthy
Bhagavatula
B
Vulimiri
Suryanarayana V
SV
Goth-Goldstein
Regine
R
Weyand
Eric H
EH
DiGiovanni
John
J
D000818:Animals; D001564:Benzo(a)pyrene / Q000032:analysis; D001940:Breast / Q000737:chemistry* / Q000201:enzymology; D002274:Carcinogens, Environmental / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D018736:DNA Adducts / Q000032:analysis*; D004260:DNA Repair; D004847:Epithelial Cells / Q000737:chemistry; D005260:Female; D006801:Humans; D051379:Mice; D008895:Milk, Human / Q000166:cytology; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology; D011084:Polycyclic Aromatic Hydrocarbons / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D002274:Carcinogens, Environmental; D018736:DNA Adducts; D011084:Polycyclic Aromatic Hydrocarbons; C056612:benzo(a)pyrene-DNA adduct; C095911:polycyclic aromatic hydrocarbons-DNA adduct; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1