Copper ion-mediated modification of bases in DNA in vitro by benzoyl peroxide |
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Authors: | Akman, Steven A. Kensler, Thomas W. Doroshow, James H. Dizdaroglu, Miral |
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Affiliation: | Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center Duarte, CA 91010 1Division of Toxicological Sciences, Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health Baltimore, MD 21205 2Chemical Science and Technology Laboratory, National Institute of Standards and Technology Gaithersburg, MD 20899, USA |
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Abstract: | The mouse skin tumor promoter benzoyl peroxide (BzPO), in conjunctionwith Cu(I), causes promutagenic damage in DNA. Because freeradical intermediates are produced by the reaction of BzPO withCu(I), we sought to determine whether BzPO plus Cu(I) causedDNA base damage typical of that caused by the hydroxyl radical.A broad range of modified DNA bases were measured by GC-MS withselected-ion monitoring after exposure of purified plasmid pCMVßgalDNA to BzPO ± Cu(I). Exposure to BzPO/Cu(I) caused upto 20-fold increases in the levels of adenine-derived modifiedbases, and only a <2-fold increase in thymine-derived modifiedbases. The guanine-derived modified base 8-hydroxyguanine waselevated to the highest net amount, 160 molecules/105 DNA bases.Exposure to BzPO alone or Cu(I) alone induced only minor (<<2-fold) DNA base modification. Also, benzoic acid, the majornon-radical metabolite of BzPO, or BzPO plus Fe(II) were ineffectiveat inducing DNA base modification. The hydroxyl radical scavengerdimethyl sulfoxide inhibited BzPO/Cu(I)-induced base modificationby 1050%. These data suggest that the reaction of BzPOwith Cu(I) generates hydroxyl radical or a similarly reactiveintermediate which causes DNA base damage. This damage may beresponsible for BzPO/Cu(I) mediated mutagenesis. |
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