Malignant transformation by hydrazine derivatives: a role for carbon-centered radicals?

RESUMO

There are several hydrazine derivatives with pharmacological activity, all of which have carcinogenic properties in experimental animals. Several mono- and disubstituted derivatives have been shown to produce carbon-centered radicals upon oxidation by enzymatic systems such as HbO2' Cytochrome P-450, monoamine oxidases, horseradish peroxidase and myeloperoxidase. Proposed mechanisms of hydrazine metabolism leading to alkylating species are discussed. The in vitro induction of DNA alterations by carbon-centered radicals generated in hydrazine metabolism ascertains the possibility of its occurrence in vivo. Our results, discussed herein, established the induction of cytotoxicity, proliferation and transformation of cultured mouse fibroblasts by systems in which hydrazine-derived alkyl radicals are formed. These studies represent another step towards distinguishing the possible involvement of metabolism-generated carbon-centered radicals in the onset of carcinogenic processes, which reinforces the importance of additional experimental approaches in order to consolidate this hypothesis.