Inhibition of human topoisomerase II in vitro by bioactive benzene metabolites.
Benzene is a clastogenic and carcinogenic agent that induces acute myelogenous leukemia in humans and multiple of tumors in animals. Previous research has indicated that benzene must first be metabolized to one or more bioactive species to exert its myelotoxic and genotoxic effects. To better understand the possible role of individual benzene metabolites in the leukemogenic process, as well as to further investigate inhibition of topoisomerase II by benzene metabolites, a series of known and putative benzene metabolites, phenol, 4,4'-biphenol, 2,2'-biphenol, hydroquinone, catechol, 1,2,4-benzenetriol, 1,4-benzoquinone, and trans-trans-muconaldehyde were tested for inhibitory effects in vitro on the human topoisomerase II enzyme. With minor modifications of the standard assay conditions, 1,4-benzoquinone and trans-trans-muconaldehyde were shown to be directly inhibitory, whereas all of the phenolic metabolites were shown to inhibit enzymatic activity following bioactivation using a peroxidase activation system. The majority of compounds tested inhibited topoisomerase II at concentrations at or below 10 microM. These results confirm and expand upon previous findings from our laboratory and indicate that many of the metabolites of benzene could potentially interfere with topoisomerase II. Since other inhibitors of topoisomerase II have been shown to induce leukemia in humans, inhibition of this enzyme by benzene metabolites may also play a role in the carcinogenic effects of benzene.
Frantz
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Department of Entomology, University of California, Riverside 92521, USA.
Chen
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Eastmond
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D000818:Animals; D001554:Benzene / Q000378:metabolism* / Q000633:toxicity*; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity; D002869:Chromosome Aberrations; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D015470:Leukemia, Myeloid, Acute / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D009195:Peroxidase / Q000378:metabolism; D059005:Topoisomerase II Inhibitors
D002273:Carcinogens; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D009195:Peroxidase; D001554:Benzene