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Effects of Benzene Metabolites on DNA Cleavage Mediated by Human Topoisomerase IIα: 1,4-Hydroquinone Is a Topoisomerase II Poison
- Source :
- Chemical Research in Toxicology; April 2005, Vol. 18 Issue: 4 p761-770, 10p
- Publication Year :
- 2005
-
Abstract
- Although benzene induces leukemias in humans, the compound is not believed to generate chromosomal damage directly. Rather, benzene is thought to act through a series of phenolic- and quinone-based metabolites, especially 1,4-benzoquinone. A recent study found that 1,4-benzoquinone is a potent topoisomerase II poison in vitro and in cultured human cells [Lindsey et al. (2004) Biochemistry 43, 7363−7374]. Because benzene is metabolized to multiple compounds in addition to 1,4-benzoquinone, we determined the effects of several phenolic metabolites, including catechol, 1,2,4-benzenetriol, 1,4-hydroquinone, 2,2-biphenol, and 4,4-biphenol, on the DNA cleavage activity of human topoisomerase IIα. Only 1,4-hydroquinone generated substantial levels of topoisomerase II-mediated DNA scission. DNA cleavage with this compound approached levels observed with 1,4-benzoquinone (~5- vs 8-fold) but required a considerably higher concentration (~250 vs 25 μM). 1,4-Hydroquinone is a precursor to 1,4-benzoquinone in the body and can be activated to the quinone by redox cycling. It is not known whether the effects of 1,4-hydroquinone on human topoisomerase IIα reflect a lower reactivity of the hydroquinone or a low level of activation to the quinone. The high concentration of 1,4-hydroquinone required to increase enzyme-mediated DNA cleavage is consistent with either explanation. 1,4-Hydroquinone displayed attributes against topoisomerase IIα, including DNA cleavage specificity, that were similar to those of 1,4-benzoquinone. However, 1,4-hydroquinone consistently inhibited DNA ligation to a greater extent than 1,4-benzoquinone. This latter result implies that the hydroquinone may display (at least in part) independent activity against topoisomerase IIα. The present findings are consistent with the hypothesis that topoisomerase IIα plays a role in the initiation of specific types of leukemia that are induced by benzene and its metabolites.
Details
- Language :
- English
- ISSN :
- 0893228X and 15205010
- Volume :
- 18
- Issue :
- 4
- Database :
- Supplemental Index
- Journal :
- Chemical Research in Toxicology
- Publication Type :
- Periodical
- Accession number :
- ejs7310205