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REACTIONS OF BENZO[A]PYRENE-7,8-QUINONE WITH DEOXYGUANOSINE AND DEOXYADENOSINE AT PHYSIOLOGICAL pH: IDENTIFICATION AND CHARACTERIZATION OF STABLE ADDUCTS
Citation:
Balu, N, W. T. Padgett, G. R. Lambert, A E. Swank, A M. Richard, AND S. C. Nesnow. REACTIONS OF BENZO[A]PYRENE-7,8-QUINONE WITH DEOXYGUANOSINE AND DEOXYADENOSINE AT PHYSIOLOGICAL pH: IDENTIFICATION AND CHARACTERIZATION OF STABLE ADDUCTS. Presented at AACR, Orlando, Fl, March 27-31, 2004.
Description:
Reactions of Benzo[a]pyrene-7,8-quinone with Deoxyguanosine and Deoxyadenosine at Physiological pH: Identification and Characterization of Stable Adducts
Narayanan Balu, William T. Padgett, Guy Lambert, Adam E. Swank,
Ann M. Richard, and Stephen Nesnow
Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, Office of the Research and Development, U.S. Environmental
Protection Agency, B143-06, Research Triangle Park, North Carolina 27711
Benzo[a]pyrene (B[a]P), an archetypal member of the family of polycyclic aromatic hydrocarbons (PAHs), is a widely distributed environmental pollutant. B[a]P and its complex mixtures are known to induce pronounced carcinogenic effects in animals and humans through metabolic activation to reactive intermediates that damage DNA. The DNA modification by B[a]P metabolites is a complex phenomenon that involves the formation of both stable and unstable (depurinating) adducts. One pathway by which B[a]P can mediate genotoxicity is through the enzymatic formation of B[a]P7,8-quinone (BPQ) formed by the oxidation of B[a]P-7,8-diol by members of the aldoketo reductase family. Once formed, like other 1,2-quinones, BPQ can act as a reactive Michael acceptor which alkylates various cellular nucleophiles. The earlier reports on the reaction of BPQ with DNA and nucleosides provided stable and depurinating adducts respectively at specific pH conditions. In the present study the reactivity of BPQ towards deoxyguanosine (dGuo) and deoxyadenosine (dAdo) nucleosides under physiological pH conditions is examined. Thus six novel BPQ-nucleoside adducts were identified and characterized from the reaction of BPQ and dGuo or dAdo in a solvent mixture of sodium
phosphate buffer and DMF. Most interestingly, addition of water to the C9-C10 double bond is evident in all the products obtained from the BPQ-nucleoside reactions. The reaction of BPQ with dGuo afforded four unique diastereomeric Michael addition products: two diastereomers each for N2-[9-(9,10-dihydro-10-hydroxybenzo[a]pyrene7,8-quinonyl)]-2'-deoxyguanosine (BPQ-9-dGuo-10-OH) and for N2-[10-(9,10-dihydro9-hydroxybenzo[a]pyrene-7,8-quinonyl)]-2'-deoxyguanosine (BPQ-10-dGuo-9-OH), representing covalent modifications at C9 and C10 positions of BPQ by the adducting nucleoside. Under similar but extended reaction conditions the reaction of BPQ with dAdo produced only one diastereomeric pair of adducts identified as BPQ-9-OH-10dAdo. All of the adducts were isolated by reverse-phase HPLC and characterized by UV, MS and NMR spectroscopy studies. Computational methods were employed in an attempt to assign the relative stereochemistry (cis or trans) to each diastereomer of each adduct. As considerable efforts have been placed in documenting the genotoxic effects of BPQ, this first report on the identification and spectroscopic characterization of the stable adducts of BPQ formed under physiological pH conditions is expected to have a significant impact on the area of BPQ-mediated genotoxicity and carcinogenesis. This abstract does not reflect EPA policy or views.