Topoisomerase II inhibition by myeloperoxidase-activated hydroquinone: a potential mechanism underlying the genotoxic and carcinogenic effects of benzene.
Benzene is an established human and animal carcinogen. While many of the key mechanisms underlying its carcinogenic effects remain unknown, there is increasing evidence that chromosomal alterations play an important role in the development of the induced leukemias. Inhibition of enzymes involved in DNA replication and maintenance such as topoisomerases by benzene metabolites represents a potential mechanism by which benzene may induce its chromosome-altering effects. Previous work from our laboratory and others has demonstrated that bioactivated benzene metabolites are capable of inhibiting topoisomerase II (topo II) in isolated enzyme and cell systems as well as in mice administered benzene in vivo. The current studies were designed to build upon this hypothesis, and show that in the presence of human myeloperoxidase and H2O2, hydroquinone can be activated to a potent topo II inhibitor. In the absence of dithiothreitol, partial inhibition can be seen at hydroquinone concentrations as low as 50 nM. The potential role of topo II inhibition in the development of benzene-induced leukemia is also discussed in the context of other known leukemia-inducing agents. Current evidence indicates that multiple mechanisms are likely to contribute to benzene-induced leukemias, and that inhibition of topo II could represent an important step in the development of certain leukemia subtypes.
Eastmond
David A
DA
Environmental Toxicology Graduate Program, 5429 Boyce Hall, University of California, Riverside, CA 92521, USA. david.eastmond@ucr.edu
Mondrala
Scott T
ST
Hasegawa
Leslie
L
D001554:Benzene / Q000378:metabolism / Q000633:toxicity*; D016227:Benzoquinones / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D018105:DNA, Kinetoplast; D004229:Dithiothreitol / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006873:Hydroquinones / Q000378:metabolism / Q000633:toxicity*; D007938:Leukemia / Q000139:chemically induced / Q000201:enzymology*; D009195:Peroxidase / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
D016227:Benzoquinones; D002273:Carcinogens; D018105:DNA, Kinetoplast; D006873:Hydroquinones; D059005:Topoisomerase II Inhibitors; C004532:quinone; D006861:Hydrogen Peroxide; D009195:Peroxidase; D004250:DNA Topoisomerases, Type II; D001554:Benzene; D004229:Dithiothreitol; C031927:hydroquinone