Ambident reactivity of phenoxyl radicals in DNA adduction

Abstract

Phenols are a class of compounds that can create beneficial effects in vivo owing to their antioxidant properties (through radical scavenging), or they can display hazardous effects owing to their pro-oxidant properties. The mechanism by which phenols act as pro-oxidants stems from their one-electron oxidation into reactive phenoxyl radicals by peroxidase enzymes or redox-active transition metals. In the presence of thiols and molecular oxygen, these reactive phenoxyl radicals stimulate an oxidative stress and cause oxidative damage to biomolecules, which is proposed to contribute to the occurrence of cancer in peroxidase rich tissues. Recent results from our laboratory show that certain phenoxyl radicals can also react directly with the C-8 site of deoxyguanosine to afford oxygen and carbon bonded adducts. This reactivity is consistent with the ambident (oxygen vs. C attachment) electrophilicity of phenoxyl radicals coupled with the susceptibility of the C-8 site of deoxyguanosine to radical attachment. Given that formation of covalent DNA adducts is regarded as the initiation event in the carcinogenic process, C-8 deoxyguanosine adducts of phenolic toxins are expected to contribute greatly to peroxidase driven toxic effects of phenolic xenobiotics. The focus of this review is the role of phenoxyl radicals in direct reactions with DNA and the use of Brown σ+ values to predict their reactivity.Key words: DNA adduction, phenoxyl radicals, chlorophenols, ochratoxin A, deoxyguanosine.