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Complex clastogenic activity of trans-ß-nitrostyrene in vitro is related to cellular glutathione content

 
: Ziemann, C.; Kaap, S.; Kleemann, I.; Steinfelder, H.J.

Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie -DGPT-:
46th Spring Meeting 2006, Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie. Abstracts : 15 - 17 March 2005, Mainz, Germany
Berlin: Springer, 2005 (Naunyn-Schmiedeberg's Archives of Pharmacology 371.2005, Suppl.1)
Abstract 475
Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie (Spring Meeting) <46, 2005, Mainz>
English
Conference Paper, Journal Article
Fraunhofer ITEM ()

Abstract
Beta-Nitrostyrene (NS) is used as chain stopper in styrene type polymerization reactions for plastics, rubber, and resins production. In addition, NS possesses antifungal, antibacterial and insecticidal activities. NS also displays a promising anti-tumour potential, due to its profound pro-apoptotic properties, but there exist only limited and conflicting data on genotoxicity. In the present study, we demonstrated concentration-dependent DNA-damage in HL60-leukaemia and L5178YTK+/- mouse-lymphoma cells by NS treatment (5-25µM) in the alkaline comet-assay. L5178YTK+/- cells were more and human lymphocytes less sensitive to NS treatment than HL60-cells. Increase in mean tail moment (over 10-fold at 25µM in HL60-cells) was already maximal after 30 min and correlated well with cytotoxicity and the pro-apoptotic effect of NS. To further investigate mechanisms involved in NS-triggered DNA-damage, we performed neutral comet-assays, indicating the involvement of double strand breaks. Interestingly, the NS derivative 2-dinitrostyrene displayed a more pronounced potency for both DNA-damage and apoptosis induction. This was perhaps due to a more pronounced generation of reactive nitrogen species, measured in GH3 cells by dihydrorhodamine 123 oxidation and nitrite generation. Furthermore, cells incubated with NS and aphidicolin as nucleotide excision repair inhibitor, exhibited increased mean tail moments compared to cells exposed to NS without aphidicolin. Thus, NS also seemed to possess alkylating properties, leading to repair-dependent strand break detection in the comet-assay. L5178YTK+/- cells, pre-incubated for 24h with L-buthionine-[S,R]-sulfoximine to deplete glutathione, displayed significantly enhanced DNA-damage in the presence of NS, being in line with a decreased pro-apoptotic effect of NS in N-acetylcysteine pre-incubated GH3 cells. Thus, NS toxicity was dependent on cellular GSH content, suggesting the involvement of reactive oxygen species in NS-caused DNA-damage, a mechanism also known for nitroaromatic compounds. In conclusion, the strong clastogenic potential of NS in isolated cells seemed to involve different mechanisms of DNA-damage, which have to be further investigated.

: http://publica.fraunhofer.de/documents/N-48613.html