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STUDIES ON THE METABOLISM OF 6-NITROCHRYSENE AND THE FORMATION OF DNA ADDUCTS IN THE LIVER, LUNG AND BLADDER OF A/J MICE
Citation:
McDaniel, M., L D. Adams, J. D. Allison, M H. George, D. Desai, S. Amin, G. Lambert, W. Padgett, S Nesnow, AND L C. King. STUDIES ON THE METABOLISM OF 6-NITROCHRYSENE AND THE FORMATION OF DNA ADDUCTS IN THE LIVER, LUNG AND BLADDER OF A/J MICE. Presented at 18th International Symposium on Polycyclic Aromatic Compounds, University of Cincinnati, Ohio, Sept 9-13, 2001.
Description:
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Studies On The Metabolism of 6-Nitrochrysene and The Formation of DNA Adducts in the Liver, Lung and Bladder ofAJJ Mice
Moses McDaniel*, Linda Adamst, Joycelyn Allisont, Michael George"l", Dhimant Desai+, 5hantu Amin+, Guy Lambertt, William Padgettt, Stephen Nesnowt and Leon C. Kingt
*North Carolina Central University, Department of Biology, Durham, NC 27704; "lU.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Environmental Carcinogenesis Division, MD-68, Research Triangle Park, NC 27711 U5A; + American Health Foundation, One Dana Road,
Valhalla, New York 10595
6-Nitrochrysene (6-NC) is a potent liver and lung carcinogen following i.p. administration to preweanling mice. In this study, we have investigated the aerobic in vitro metabolism of 6-NC by Aroclor-1254-induced rat liver 59 (59), and the anaerobic xanthine oxidase-mediated metabolism of 6-NC. The in vitro covalent binding of 6-NC and the primary metabolites of 6- NC to calf thymus DNA using the described activation systems was then examined in an attempt to identify the DNA adducts in the liver, lung and bladder of AJJ mice treated with 6-NC. Anaerobic metabolism of 6-NC produced one major metabolite, identified as 6-aminochrysene by NMR and MS. Aerobic 59-mediated metabolism of 6-NC produced a major metabolite, identified as trans-1,2-dihydroxy-1,2-dihydro-6-NC (6-NC-1,2-diol) by NMR and Ms. Also present were minor amounts of trans-9,10-dihydroxy-9,10-dihydro-6-NC (6-NC-9,10-diol) and 6-am'inochrysene. DNA adduct analyses were performed using the 32p-postlabeling assay and reverse-phase HPLC. Three major XO-derived calf thymus DNA adducts of 6-NC were
detected: two were identified as reaction products of with 2'-deoxyguanosine and one with 2'- deoxyadenosine. Aerobic 59 activation of 6-NC with calf thymus DNA produced three adducts. Based on their chromatographic mobilities, two were identified as reaction products of 6-NC
with 2'-deoxyguanosine and one with 2'-deoxyadenosine. Anaerobic XO-catalyzed metabolism of 6-NC-1 ,2-diol produced a similar DNA adduct as observed with 6-NC activated anaerobically with xanthine oxidase or aerobically with 59. Single doses of 6-NC induced a time-dependent increase in DNA adduct levels. The maximum extent of DNA adduct formation was observed at 7 days in the following order; liver>bladder>lung. One major and two minor adducts were isolated in all tissues examined. The major adduct detected in tissues was chromatographically similar to one of the major DNA adduct detected in calf thymus DNA following either anaerobic or aerobic metabolism. These results provide additional information that the major adduct formed in the liver, lung and bladder of mice treated with 6-NC is an amino-derivative of the ultimate carcinogenic metabolite, 6-NC-1 ,2-diol.
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