Role of the benzoyloxyl radical in DNA damage mediated by benzoyl peroxide

• Published in: Chemical research in toxicology 1991-03, Vol.4 (2), p.223-228
• Main Authors: Swauger, James E, Dolan, Patrick M, Zweier, Jay L, Kuppusamy, Periannan, Kensler, Thomas W
• Format: Article
• Language: English
• Subjects: Benzoyl Peroxide - adverse effects; Benzoyl Peroxide - metabolism; Benzoyl Peroxide - pharmacokinetics; Biological and medical sciences; Biotransformation; Carcinogenesis, carcinogens and anticarcinogens; Chemical agents; Copper - pharmacology; DNA Damage; DNA, Circular - drug effects; DNA, Circular - metabolism; DNA, Superhelical - drug effects; DNA, Superhelical - metabolism; Dose-Response Relationship, Drug; Free Radicals - adverse effects; Free Radicals - metabolism; Medical sciences; Plasmids; Tumors
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx00020a016

Benzoyl peroxide (BzPO) is both a tumor promoter and progressor in mouse skin; however, BzPO is neither an initiator nor a complete carcinogen in this tissue. Although not mutagenic, BzPO has been observed to produce strand breaks in DNA of exposed cells. These actions are presumed to be mediated by free-radical derivatives of BzPO. Previous studies suggested that the metabolism of BzPO in keratinocytes proceeds via the initial cleavage of the peroxide bond, yielding benzoyloxy radicals which, in turn, can either fragment to form phenyl radicals and carbon dioxide or abstract H atoms from biomolecules to yield benzoic acid. Benzoic acid is the major stable metabolite of BzPO produced by keratinocytes. In the present study we have investigated the role of BzPO and its metabolites in the generation of strand scissions in a cell-free system using phi X-174 plasmid DNA. In this system BzPO produced DNA damage that was dose-dependent over a concentration range of 0.1-1 mM and required the presence of copper but not other transition metals. By contrast, benoic acid did not produce DNA damage in this system, either in the presence or in the absence of copper. The inclusion of spin trapping agents, such as N-tert-butyl-alpha-phenylnitrone (PBN), 3,5-dibromo-4-nitrosobenzenesulfonate, and nitrosobenzene, in incubations was found to significantly reduce the extent of DNA damage generated via the copper-mediated activation of BzPO. Electron paramagnetic resonance spectroscopy studies suggested that the primary radical trapped by PBN following copper-mediated decomposition of BzPO was the benzoyloxy radical.