Inhibition of human DNA topoisomerase II by hydroquinone and p-benzoquinone, reactive metabolites of benzene
- Thomas Jefferson Univ., Philadelphia, PA (United States)
Chronic exposure of humans to benzene (BZ) causes acute myeloid leukemia (AML). Both BZ and therapy-related secondary AML are characterized by chromosomal translocations that may occur by inappropriate recombinational events. DNA topoisomerase 11 (topo 11) is an essential sulfhydryl (SH)-dependent endonuclease required for replication, recombination, chromosome segregation, and chromosome structure. Topo 11 cleaves DNA at purine(R)/pyrimidine(Y) repeat sequences that have been shown to be highly recombinogenic in vivo. Certain antineoplastic drugs stabilize topo 11-DNA cleavage complexes at RY repeat sequences, which leads to translocations of the type observed in leukemia. Hydroquinone (HQ) is metabolized to p-benzoquinone (BQ) in a peroxidase-mediated reaction in myeloid progenitor cells. BO interacts with SH groups of SH-dependent enzymes. Consequently, the aims of this research were to determine whether HQ and BO are topo 11 inhibitors. The ability of the compounds to inhibit the activity of topo, 11 was tested using an assay system that depends on the conversion, by homogeneous human topo 11, of catenated kinetoplast DNA into open and/or nicked open circular DNA that can be separated from the catenated DNA by electrophoresis in a 1% agarose-ethidium bromide gel. We provide preliminary data that indicate that both HQ and BO cause a time and concentration (pM)-dependent inhibition of topo 11 activity. 32 refs., 5 figs.
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 472170
- Report Number(s):
- CONF-9506288-; ISSN 0091-6765; TRN: 97:001626-0022
- Journal Information:
- Environmental Health Perspectives, Vol. 104, Issue Suppl.6; Conference: Benzene `95: international conference on benzene toxicity, carcinogenesis, and epidemiology, Piscataway, NJ (United States), 17-20 Jun 1995; Other Information: PBD: Dec 1996
- Country of Publication:
- United States
- Language:
- English
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