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Lack of contribution of covalent benzo[a]pyrene-7,8-quinone-DNA adducts in benzo[a]pyrene-induced mouse lung tumorigenesis
Citation:
NESNOW, S., G. B. NELSON, W. Padgett, M. George, T. Moore, L. C. King, L. D. ADAMS, AND J. A. ROSS. Lack of contribution of covalent benzo[a]pyrene-7,8-quinone-DNA adducts in benzo[a]pyrene-induced mouse lung tumorigenesis. CHEMICO-BIOLOGICAL INTERACTIONS. Elsevier Science Ltd, New York, NY, 186(2):157-165, (2010).
Impact/Purpose:
The studies presented here sought to examine the role of stable BPQ-DNA adducts in B[a]P-induced mouse lung tumorigenesis.
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 anti-trans-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) that can form covalent DNA adducts or reactive oxygen species which can damage DNA. The studies presented here sought to examine the role of stable BPQ-DNA adducts in B[a]P-induced mouse lung tumorigenesis. Male strain All 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 each at 30 mglkg and tissues harvested 48 and 72 hr later, or with B[a]P (50 mg/kg, a tumorigenic dose) and tissues harvested 72 hr later. No BPQ or any other DNA adducts were observed in lung or liver tissues 24, 48, or 72 hr after the treatment with 30 mg/kg BPQ. 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. Model studies with BPQ and N-acetylcysteine suggested that BPQ is rapidly inactivated by sulfhydryl-containing compounds and not available for DNA adduction. We conclude that under these treatment conditions BPQ does not form stable covalent DNA adducts in the lungs or livers of strain All 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.
