ABSTRACT
1. Over the last two decades, the prevalent view in chemical carcinogenesis has been that most free radicals do not bind to DNA. Recent studies, however, are demonstrating formation of adducts between DNA and free radicals such as hydroxyl radicals and aromatic cation radicals. 2. Within this context, we discuss the recent work from our group demonstrating DNA alkylation by carbon-centered radicals formed during biotransformation of genotoxic hydrazine derivatives both in vitro and in vivo. 3. The mutagenic potential of the identified methyl radical adduct, C8-methylguanine, is discussed, and other possible biological sources of carbon-centered radicals are presented
Subject(s)
Animals , Carbon/metabolism , DNA/metabolism , Alkylation , Biotransformation , Free Radicals/metabolism , Genes/drug effects , Hydrazines/pharmacokinetics , Hydrazines/toxicity , Oxidation-ReductionABSTRACT
Spin-trapping experiments demonstrate that oxidation of 1,2-dimethylhydrazine and 2-phenylethylgydrazine generates a comparable yield of carbon-centered radicals when catalyzed by horseradish peroxidase-H2O2. Using oxyhemoglobin as the catalyst, 2-phenylethylgydrazine oxidation generates ten times carbon-centered radicals than 1,2-dimethylhidrazine oxidation. This results is in agreement with oxygen consumption studies from which the apparent KM values of 8.0 mM and 72 mM were calculated for the oxyhemoglobin-catalyzed oxidation of 2-phenylethylhydrazine and 1,2-dimethylhydrazine, respectively. These differences in metabolic activation of mono- and disubstituted hydrazines may be of importance regarding the carcinogenic properties of these derivatives