Stimulation of topoisomerase II-mediated DNA cleavage by benzene metabolites.
Benzene is a human carcinogen that induces hematopoietic malignancies. It is believed that benzene does not initiate leukemias directly, but rather generates DNA damage through a series of phenolic and quinone-based metabolites, especially 1,4-benzoquinone. Since the DNA damage induced by 1,4-benzoquinone is consistent with that of topoisomerase II-targeted drugs, it has been proposed that the compound initiates specific types of leukemia by acting as a topoisomerase II poison. This hypothesis, however, was not supported by initial in vitro studies. While 1,4-benzoquinone inhibited topoisomerase II catalysis, increases in enzyme-mediated DNA cleavage were not observed. Because of the potential involvement of topoisomerase II in benzene-induced leukemias, we re-examined the effects of benzene metabolites (including 1,4-benzoquinone, 1,4-hydroquinone, catechol, 1,2,4-benzenetriol, 2,2'-biphenol, and 4,4'-biphenol) on DNA cleavage mediated by human topoisomerase IIalpha. In contrast to previous reports, we found that 1,4-benzoquinone was a strong topoisomerase II poison and was more potent in vitro than the anticancer drug etoposide. Other metabolites displayed considerably less activity. DNA cleavage enhancement by 1,4-benzoquinone was unseen in previous studies due to the presence of reducing agents and the incubation of 1,4-benzoquinone with the enzyme prior to the addition of DNA. Unlike anticancer drugs such as etoposide that interact with topoisomerase IIalpha in a noncovalent manner, the actions of 1,4-benzoquinone appear to involve a covalent attachment to the enzyme. Finally, 1,4-benzoquinone stimulated DNA cleavage by topoisomerase IIalpha in cultured human cells. These findings are consistent with the hypothesis that topoisomerase IIalpha plays a role in the initiation of some benzene-induced leukemias.
Lindsey
R Hunter
RH
Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, TN 37232-0146, USA.
Bender
Ryan P
RP
Osheroff
Neil
N
D000951:Antigens, Neoplasm / Q000378:metabolism; D001554:Benzene / Q000378:metabolism / Q000633:toxicity; D016227:Benzoquinones / Q000633:toxicity*; D019457:Chromosome Breakage; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D016227:Benzoquinones; D004268:DNA-Binding Proteins; D059005:Topoisomerase II Inhibitors; C004532:quinone; D004250:DNA Topoisomerases, Type II; D001554:Benzene