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Generation of reactive oxygen species may participate in the clastogenic and mutagenic activity of trans-beta-nitrostvrene

 
: Ziemann, C.; Rahmer, H.; Leyhausen, G; Steinfelder, H.J.; Volk, J.

Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie -DGPT-:
48th Spring Meeting 2007. Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie. Abstracts : 13 - 15 March 2007, Mainz, Germany
Berlin: Springer, 2007 (Naunyn-Schmiedeberg's Archives of Pharmacology 375.2007, Suppl. 1)
pp.87
Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie (Spring Meeting) <48, 2007, Mainz>
English
Conference Paper, Journal Article
Fraunhofer ITEM ()
clastogenic activity; mutagenic activity; DNA damage; nitroaromatic compound

Abstract
Beta-Nitrostyrene (Beta-NS) is used as chain terminator in styrene type polymerization reactions for plastics, rubber, and resins production. Additionally, Beta-NS possesses antifungal, antibacterial, and insecticidal activities and displays a promising anti-tumour potential. Unfortunately, there exist only scarce, inconsistent data on genotoxicity. By using the comet assay, we already demonstrated strong clastogenic potential of Beta-NS (5-25µM) in different cell types, which requires the nitro group and the conjugated C=C bond. In the present study, Beta-NS, without metabolic activation (S9-mix), induced chromosomal aberrations (breaks and exchanges) in V79 cells and concentration-dependently enhanced mutant frequencies in the mouse lymphoma tk assay, with a significant increase at 7.5µM. Interestingly, in all genotoxicity assays, DNA-damage was significantly lower in the presence of S9-mix. Due to induction of DNA-double strand breaks, whose formation was prevented by aclarubicin (inhibitor of topoisomerase-II -binding to DNA), we have previously postulated that topoisomerase-II inhibition might be one mechanism of Beta-NS-mediated genotoxicity. This was supported by the fact that clastogenicity was strongly dependent on cell proliferation. As the antioxidant N-acetylcysteine was shown to decrease the pro-apoptotic effect of Beta-NS, we further speculated whether generation of reactive oxygen species (ROS) might also participate in Beta-NS-mediated DNA-damage. In the present study, Beta-NS indeed concentration-dependently induced ROS generation in L5178YTK+/- mouselymphoma cells (assessed by 2´,7´-dichlorodihydrofluorescein diacetate fluorescence) and mediated reduction in intracellular glutathione (measured by monobromobimane assay). Both effects were efficiently counteracted by N-acetylcysteine. Interestingly, N-acetylcysteine and reduced glutathione also inhibited DNA-damage, whereas pre-incubation of cells for 24h with Lbuthionine-[S,R]-sulfoximine, which depletes intracellular glutathione, significantly increasedthe clastogenic potential of Beta-NS. Comet assays with human 8-hydroxyguanine DNA-glycosylase 1 are now necessary to further investigate hypothesised oxidative DNA-damage due to Beta-NS treatment. In conclusion, Beta-NS exhibits clastogenic and mutagenic potential in vitro, which might be in part due to ROS generation, a mechanism also known for nitroaromatic compounds.

: http://publica.fraunhofer.de/documents/N-59326.html