ToxSci Advance Access originally published online on February 18, 2003
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Toxicological Sciences 72, 143-149 (2003)
Copyright © 2003 by the Society of Toxicology
MOLECULAR AND GENETIC TOXICOLOGY |
Homologous Recombination Initiated by Benzene Metabolites: A Potential Role of Oxidative Stress
Department of Pharmacology and Toxicology and School of Environmental Studies, Queen’s University, Kingston K7L 3N6, Ontario, Canada
Benzene is a ubiquitous pollutant and known human leukemogen. Benzene can be enzymatically bioactivated to reactive intermediates that can lead to increased formation of reactive oxygen species (ROS). ROS formation can directly induce DNA double-strand breaks, and also oxidize nucleotides that are subsequently converted to double-strand breaks during DNA replication that can be repaired through homologous recombination, which is not error-free. Therefore increased DNA double-strand-break levels may induce hyper-recombination, which can lead to deleterious genetic changes. To test the hypothesis that benzene and its metabolites can initiate hyper-recombination and to investigate the potential role of ROS, a Chinese hamster ovary (CHO) cell line containing a neo direct repeat recombination substrate (CHO 3–6), was used to determine whether benzene or its metabolites phenol, hydroquinone, catechol, or benzoquinone initiated increased homologous recombination and whether this increase could be diminished by the coincubation of cells with the antioxidative enzyme catalase. Results demonstrated that cells exposed to benzene (1, 10, 30, or 100 µM) for 24 h did not exhibit increased homologous recombination. Increased recombination occurred with exposure to phenol (1.8-, 2.6-, or 2.9-fold), catechol (1.9-, 2-, 5-, or 3.2-fold), or benzoquinone (2.7-, 5.5-, or 6.9-fold) at 1, 10, and 30-µM concentrations, respectively, and with exposure to hydroquinone at 10 and 30 µM concentrations (1.5–1.9-fold; p < 0.05). Studies investigating the effects of catalase demonstrated that increased homologous recombination due to exposure to phenol, hydroquinone, catechol, or benzoquinone (10 µM) could be completely abolished by the addition of catalase. These data support the hypothesis that increased homologous recombination mediates benzene-initiated toxicity and supports a role for oxidative stress in this mechanism.
Key Words: benzene; reactive oxygen species; oxidative stress; homologous recombination.
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