Affiliation:
1. From Molecular Toxicology and Environmental Health Sciences, School of Pharmacy, Cancer Center, Department of Preventative Medicine, School of Medicine, and Department of Pathology, School of Medicine, University of Colorado Health Sciences Center, Denver, CO.
Abstract
Abstract
Chronic exposure to benzene is associated with hematotoxicity and acute myelogenous leukemia. Inhibition of topoisomerase IIα (topo II) has been implicated in the development of benzene-induced cytogenetic aberrations. The purpose of this study was to determine the mechanism of topo II inhibition by benzene metabolites. In a DNA cleavage/relaxation assay, topo II was inhibited byp-benzoquinone and hydroquinone at 10 μM and 10 mM, respectively. On peroxidase activation, inhibition was seen with 4,4′-biphenol, hydroquinone, and catechol at 10 μM, 10 μM, and 30 μM, respectively. But, in 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 II–DNA binding. It is therefore unlikely that benzene-induced acute myelogenous leukemia stems from events invoked for leukemogenic topo II cleavable complex-stabilizing antitumor agents.
Publisher
American Society of Hematology
Subject
Cell Biology,Hematology,Immunology,Biochemistry
Reference27 articles.
1. Structure and function of type II DNA topoisomerases.;Watt;Biochem J.,1994
2. Secondary leukemias induced by topoisomerase-targeted drugs.;Felix;Biochim Biophys Acta.,1998
3. Hematotoxicity in humans.;Goldstein;J Toxicol Environ Health.,2000
4. Leukemias and myelodysplastic syndromes secondary to drug, radiation, and environmental exposure.;Levine;Semin Oncol.,1992
5. Partial hepatectomy reduces both metabolism and toxicity of benzene.;Sammett;J Toxicol Environ Health.,1979
Cited by
30 articles.
订阅此论文施引文献
订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献