Benzene metabolites antagonize etoposide-stabilized cleavable complexes of DNA topoisomerase IIalpha.
Chronic exposure to benzene is associated with hematotoxicity and acute myelogenous leukemia. Inhibition of topoisomerase IIalpha (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 by p-benzoquinone and hydroquinone at 10 microM and 10 mM, respectively. On peroxidase activation, inhibition was seen with 4,4'-biphenol, hydroquinone, and catechol at 10 microM, 10 microM, and 30 microM, 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. (Blood. 2001;98:830-833)
Baker
R K
RK
Molecular Toxicology and Environmental Health Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO, USA.
Kurz
E U
EU
Pyatt
D W
DW
Irons
R D
RD
Kroll
D J
DJ
D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001554:Benzene / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins; D004336:Drug Antagonism; D004355:Drug Stability; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D007938:Leukemia / Q000139:chemically induced / Q000201:enzymology / Q000209:etiology; D011485:Protein Binding / Q000187:drug effects; D059005:Topoisomerase II Inhibitors
D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic; D002273:Carcinogens; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004247:DNA; D004250:DNA Topoisomerases, Type II; D001554:Benzene