Carcinogenesis, Vol. 20, No. 10, 1885-1891,
October 1999
© 1999 Oxford University Press
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Cancer initiation by polycyclic aromatic hydrocarbons results from formation of stable DNA adducts rather than apurinic sites
1 Department of Environmental & Molecular Toxicology and Biochemistry & Biophysics, ALS, Oregon State University, Corvallis, OR 97331, USA,
2 Institute of Toxicology and Environmental Hygiene, Technical University of Munich, 80636 Munich, Germany and
3 Institute of Toxicology, University of Mainz, 55131 Mainz, Germany
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants with high carcinogenic potencies that have been linked to the etiology of human cancers through their presence in cigarette smoke and environmental mixtures. They are metabolically activated in cells by cytochrome P450 enzymes and/or peroxidases to reactive intermediates that damage DNA. One pathway of activation forms dihydrodiol epoxides that covalently bind to exocyclic amino groups of purines in DNA to form stable adducts. Another pathway involves formation of radical cations that bind to the N7 or C8 of purines to form unstable adducts that depurinate to leave apurinic (AP) sites in DNA. In the present study the proportions of stable DNA adducts and AP sites formed by the carcinogenic PAHs dibenzo[a,l]-pyrene (DB[a,l]P), 7,12-dimethylbenz[a]anthracene (DMBA), and benzo[a]pyrene (B[a]P) have been investigated in a target tissue for carcinogenesis, mouse epidermis. After topical application of the PAHs on the skin of female SENCAR mice epidermal DNA was isolated and the formation of stable DNA adducts was measured by 33P-postlabeling and HPLC analysis. AP sites in DNA were measured with an aldehyde reactive probe in a slot-blot assay. At both 4 and 24 h after exposure, DB[a,l]P formed significantly higher amounts of stable DNA adducts than DMBA, and B[a]P exhibited the lowest level of binding. In contrast, the number of AP sites present in mice treated with these PAHs was in the order: DMBA > B[a]P >> DB[a,l]P. The level of AP sites was significantly lower than the level of stable adducts for each PAH. The most potent carcinogen, DB[a,l]P, induced the highest level of stable adducts and the lowest level of AP sites in epidermal DNA. These results indicate that stable DNA adducts rather than AP sites are responsible for tumor initiation by carcinogenic PAHs.
Abbreviations: AP, apurinic; ARP, aldehyde reactive probe; B[a]P, benzo[a]pyrene; B[a]PDE, benzo[a]pyrene-7,8-dihydrodiol 9,10-epoxide; dA, deoxyadenosine; DB[a,l]P, dibenzo[a,l]pyrene; DB[a,l]PDE, dibenzo[a,l]pyrene-11,12-dihydrodiol 13,14-epoxide; dG, deoxyguanosine; DMBA, 7,12-dimethylbenz[a]anthracene; DMBADE, 7,12-dimethylbenz[a]anthracene-3,4-dihydrodiol 1,2-epoxide; DMS, dimethyl sulfate; PAH(s), polycyclic aromatic hydrocarbon(s).
4 Present address: Chemistry of Carcinogenesis Laboratory, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA
5 To whom correspondence should be addressed Email: william.baird{at}orst.edu
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