Carcinogenesis Advance Access published online on April 29, 2004
Carcinogenesis, doi:10.1093/carcin/bgh174
© 2004 by Oxford University Press
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1 Department of Environmental Science and Engineering, School of Public Health, University of North Carolina, Chapel Hill, NC 27599-7431
* To whom correspondence should be addressed. E-mail: ynakamur{at}email.unc.edu.
There is increasing concern that compounds formed during the chemical or biological transformation of pollutants in the environment may be more detrimental to human and environmental health than the original pollutant. In this study, two bacterial transformation products of polycyclic aromatic hydrocarbons (PAHs), pyrene-4,5-quinone (P45Q) and fluoranthene-2,3-quinone (F23Q) were evaluated for mutagenicity by measuring aldehydic DNA lesions (ADL) in calf thymus DNA and HeLa S3 cells. Both quinones caused oxidative DNA damage in vitro through a copper-mediated redox cycle and subsequent production of reactive oxygen species (ROS). Hydrogen peroxide and copper were essential for causing oxidative DNA damage and glutathione prevented DNA damage from F23Q better than from P45Q. In experiments using HeLa cells, F23Q decreased cell viability, but did not produce measurable levels of ADL or base oxidation. To test the hypothesis that DNA damage was being prevented by conjugation of F23Q with glutathione, GSH-depleted cells were treated with both quinones. GSH depletion did not increase the toxicity of F23Q or cause it to oxidize DNA. Treatment to HeLa cells with metal chelators did not decrease F23Q toxicity. It is therefore possible that F23Q affected cell viability through a ROS-independent mechanism, either by conjugation with essential cellular proteins or through cellular or mitochondrial membrane damage, which precluded oxidation of DNA. In contrast, P45Q caused both ADL and base oxidation in cells. Neocuproine reduced the amount of ADL caused by P45Q, indicating that copper was still important for the intracellular generation of damaging oxidants. P45Q is a novel metabolite and its effects on DNA have not previously been investigated. This study exemplifies the importance of considering not only primary environmental pollutants, but also their biologically or chemically-generated transformation products. Key Words:
Oxidative stress, DNA damage, PAH quinones, Redox cycling
Revised April 14, 2004
Accepted April 20, 2004
CARCINOGENESIS
Aldehydic DNA lesions in calf thymus DNA and HeLa S3 cells produced by bacterial quinone metabolites of fluoranthene and pyrene
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