Benzene metabolites antagonize etoposide-stabilized cleavable complexes ofDNA topoisomerase II alpha

Chronic exposure to benzene is associated with hematotoxicity and acute mye logenous leukemia. Inhibition of topoisomerase II alpha (topo 11) has been implicated in the development of benzene-induced cytogenetic aberrations. T he purpose of this study was to determine the mechanism of topo 11 inhibiti on by benzene metabolites. In a DNA cleavage/relaxation assay, topo 11 was inhibited by p-benzoquinone and hydroquinone at 10 muM and 10 muM, respecti vely. On peroxidase activation, Inhibition was seen with 4,4'-biphenol, hyd roquinone, and catechol at 10 muM, 10 muM, and 30 muM, respectively. But, I n no case was cleavable complex stabilization observed and the metabolites appeared to act at an earlier step of the enzyme cycle. In support of this conclusion, several metabolites antagonized etoposide-stabilized cleavable complex formation and Inhibited topo R-DNA binding. It is therefore unlikel y that benzene-induced acute myelogenous leukemia stems from events Invoked for leukemogenic topo 11 cleavable complex-stabilizing antitumor agents. ( C) 2001 by The American Society of Hematology.