Identification and quantification of the depurinating DNA adducts formed in mouse skin treated with dibenzo[a,l]pyrene (DB[a,l]P) or its metabolites and in rat mammary gland treated with DB[a,l]P.
Dibenzo[a,l]pyrene (DB[a,l]P) is the most potent carcinogenic polycyclic aromatic hydrocarbon and has been identified in the environment. Comparative tumorigenicity studies in mouse skin and rat mammary gland indicate that DB[a,l]P is slightly more potent than DB[a,l]P-11,12-dihydrodiol and much more potent than (+/-)-syn-DB[a,l]P-11,12-dihydrodiol-13,14-epoxide {(+/-)-syn-DB[a,l]PDE} and (+/-)-anti-DB[a,l]PDE. We report here the identification and quantification of the depurinating adducts formed in mouse skin treated with DB[a,l]P, DB[a,l]P-11,12-dihydrodiol, (+/-)-syn-DB[a,l]PDE, or (+/-)-anti-DB[a,l]PDE and rat mammary gland treated with DB[a,l]P. The biologically formed adducts were compared with standard adducts by their retention times on HPLC and their spectra obtained by fluorescence line-narrowing spectroscopy at low temperature. In mouse skin treated with DB[a,l]P, depurinating adducts comprised 99% of the total adducts. Most of the depurinating adducts were formed by one-electron oxidation, with 63% at Ade and 12% at Gua. The remainder were formed by the diol epoxide, with 18% at Ade and 6% at Gua. When mouse skin was treated with DB[a,l]P-11,12-dihydrodiol, depurinating adducts comprised 80% of the total, and the predominant one was with Ade (69%). Treatment of skin with (+/-)-syn-DB[a,l]PDE resulted in 32% depurinating adducts, primarily at Ade (25%), whereas treatment with (+/-)-anti-DB[a,l]PDE produced 97% stable adducts. The formation of depurinating adducts following treatment of rat mammary gland with DB[a,l]P resulted in approximately 98% depurinating adducts, with the major adducts formed by one-electron oxidation. Only one depurinating diol epoxide adduct was formed. Tumorigenicity, mutations, and DNA adduct data suggest that depurinating Ade adducts play a major role in the initiation of tumors by DB[a,l]P.
Cavalieri
Ercole L
EL
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA. ecavalie@unmc.edu
Rogan
Eleanor G
EG
Li
Kai-Ming
KM
Todorovic
Rosa
R
Ariese
Freek
F
Jankowiak
Ryszard
R
Grubor
Nenad
N
Small
Gerald J
GJ
D000818:Animals; D001080:Apurinic Acid / Q000737:chemistry / Q000378:metabolism*; D001580:Benzopyrenes / Q000378:metabolism / Q000633:toxicity*; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts / Q000032:analysis / Q000378:metabolism*; D005260:Female; D008321:Mammary Glands, Animal / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism
D001580:Benzopyrenes; D002273:Carcinogens; D018736:DNA Adducts; D001080:Apurinic Acid; D004247:DNA; C041517:dibenzo(a,l)pyrene