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BENZO[ A ]PYRENE-7,8-QUINONE FORMS COVALENT-DNA ADDUCTS IN VITRO BUT NONE WERE DETECTED IN THE LUNGS OR LIVERS OF STRAIN A/J MICE IN VIVO
Citation:
NESNOW, S., W. PADGETT, N. BALU, G. B. NELSON, W. M. WINNIK, G. LAMBERT, M. H. GEORGE, AND J. A. ROSS. BENZO[ A ]PYRENE-7,8-QUINONE FORMS COVALENT-DNA ADDUCTS IN VITRO BUT NONE WERE DETECTED IN THE LUNGS OR LIVERS OF STRAIN A/J MICE IN VIVO . Presented at 21st International Symposium for Polycyclic Aromatic Compounds (ISPAC), Trondheim, NORWAY, August 05 - 10, 2007.
Description:
Benzo[a]pyrene (B[a]P) is a potent human and rodent lung carcinogen. This activity has been ascribed in part to the formation of B[a]P-7,8-diol-9,10-epoxide (BPDE)-DNA adducts. Other carcinogenic mechanisms have been proposed: 1.] The induction of apurinic sites from radical cation processes, and 2.] The metabolic formation of B[a]P-7,8-quinone (BPQ) which can form covalent DNA adducts or reactive oxygen species. The studies presented here seek to examine the role of BPQ-DNA adducts in B[a]P-induced mouse lung tumorigenesis. We first synthesized and characterized a series of BPQ-nucleoside and BPQ-nucleotide-3'-phosphate adduct standards of deoxyguanosine, deoxyadenosine, and deoxycytosine. Then, we examined the reaction products from the incubation of calf thymus DNA with BPQ by 32P-postlabeling analysis and found 18 BPQ-DNA adducts of which 8 were identified.1,2 For the in vivo studies, male strain A/J mice were injected intraperitoneally once with BPQ or B[a]P-7,8-diol at 30, 10, 3, or 0 mg/kg. Lungs and livers were harvested after 24 hr, the DNA extracted and subjected to 32P-postlabeling analysis. Additional groups of mice were dosed once with BPQ or B[a]P-7,8-diol at 30 mg/kg and tissues harvested 48 and 72 hr later or B[a]P (50 mg/kg, a tumorigenic dose) and tissues harvested 24 hr later. Current analyses indicate that no BPQ or any other DNA adducts were observed in lung or liver tissues 24, 48, or 72 hr after the BPQ 30 mg/kg treatment. B[a]P-7,8-diol gave BPDE-DNA adducts at all time points in both tissues and B[a]P treatment gave BPDE-DNA adducts in the lung. In each case, no BPQ-DNA adducts were detected. Mouse body weights significantly decreased over time after BPQ treatment suggesting BPQ-induced systemic toxicity, while no body weight changes were observed after B[a]P-7,8-diol treatment. We are exploring the fate of BPQ in these tissues in terms of chemical transformation and covalent protein adduct formation. We conclude that under the treatment conditions BPQ does not form stable covalent DNA adducts in the lungs or livers of strain A/J mice, suggesting that stable BPQ-covalent adducts are not a part of the complex of mechanisms involved in B[a]P-induced mouse lung tumorigenesis.