|Schiestl, Robert - UCLA|
Submitted to: Mutation Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: June 6, 2005
Publication Date: March 1, 2006
Citation: Sommers, C.H., Schiestl, R. 2006. Effect of benzene and its closed ring metabolites on intrachromosomal recombination in saccharomyces cerevisiae. Mutation Research. 593:1-8. Interpretive Summary: Benzene and its metabolites are carcinogens that cause the breakage and rearrangement of chromosomes in human, animal, and yeast cells. However, the mechanism as to how benzene and its metabolites cause chromosome breakage and cancer is not entirely certain. Using a novel yeast-based assay that specifically measures the breakage of chromosomes it was determined that one of the metabolites of benzene called p-benzoquinone, which inhibits the chromosome repair enzyme topoisomerase II, was most active in causing chromosomal rearrangements in yeast cells. This work offers insight as to the mechanism by which benzene and its closed ring metabolites damage chromosomes and cause cancer in humans and animals.
Technical Abstract: Genome rearrangements, such as DNA deletions, translocations and duplications, are associated with cancer in rodents and humans, and clastogens are capable of inducing such genomic rearrangements. The clastogen benzene and several of its toxic metabolites have been shown to cause cancer in animals. Benzene is associated with leukemia and other blood related disorders in humans. Benzene and metabolites tested negative in short-term bacterial mutation assays such as the Salmonella Mutagenicity Test and the E. coli Tryptophan Reversion Assay. These assays, while reliable for the detection of point-mutagenic carcinogens, are incapable of detecting DNA strand break inducing xenobiotics. The yeast DEL assay is based on intrachromosomal recombination events resulting in deletions and is very sensitive in detecting DNA strand breaks. In previous results the DEL assay detected 17 Salmonella positive as well as 25 Salmonella negative carcinogens (Bishop and Schiestl, 2000, Human Molec. Genet. 9:2427-2434). The carcinogen benzene and its metabolites including phenol, catechol, p-benzoquinone and hydroquinone induced DEL recombination. The benzene metabolite 1,2,4 benzenetriol was negative. Interestingly, p-benzoquinone induced DEL recombination at a dose 300 fold lower than any of the other metabolites, suggesting that it might be responsible for much of benzene’s genotoxicity. In addition, an excision repair deficient strain was used, but no difference was detected compared to the wildtype, indicating that DNA adducts subject to excision repair were not formed by benzene or its metabolites.