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ACTIVATION OF AP-1 IN UROTSA CELLS BY METHYLATED ARSENICALS
Citation:
Drobna, Z., M Styblo, I. Jaspers, AND D J. Thomas. ACTIVATION OF AP-1 IN UROTSA CELLS BY METHYLATED ARSENICALS. Presented at Society of Toxicology, Nashville, TN, March 17-21, 2002.
Description:
ACTIVATION OF AP-1 IN UROTSA CELLS BY METHYLATED TRIVALENT ARSENICALS. Z Drobna1, I Jaspers2, D J Thomas3 and M Styblo1. 1Department of Pediatrics; 2Center for Environmental Medicine and Lung Biology, University of North Carolina at Chapel Hill, NC, USA; 3US EPA, RTP, NC, USA.
Chronic exposures to inorganic arsenicals (iAs) increase risks of various types of cancer in humans. However, mechanisms by which iAs causes cancer are unknown. Biomethylation is the major pathway for iAs metabolism in humans. Both trivalent and pentavalent iAs and methylated arsenicals are intermediates or final products in this pathway: iAsV ? iAsIII? MAsV ? MAsIII ? DMAsV ? DMAsIII. Recent reports have shown trivalent methylated metabolites, methylarsonous acid (MAsIII) and dimethylarsinous acid (DMAsIII), to be more cytotoxic, genotoxic and more potent enzyme inhibitors than either iAsV or iAsIII, indicating that methylation increases toxic and carcinogenic potency of iAs. To further characterize the role of trivalent methylated metabolites in the toxicity and carcinogenicity of iAs, we have examined effects of iAsIII,, MAsIII and DMAsIII on nuclear levels of proto-oncogenes c-jun and c-fos and on the activation of AP-1 in UROtsa cells, an SV-40 immortalized human urothelial cell line. Short-time (0.5 to 2 h) exposures to 0.1 to 5 mM iAsIII,, MAsIII or DMAsIII significantly increased nuclear levels of p-c-jun and DNA-binding activity of AP-1. Western blot and EMSA/supershift analyses indicated that c-fos was not involved in activation of AP-1 by these arsenicals. Notably, MAsIII and DMAsIII were considerably more potent inducers of c-jun phosphorylation and AP-1 activation in UROtsa cells than was iAsIII. Western blot analyses of the MAPK enzyme family in cells exposed to trivalent arsenicals showed a significant increase in p-ERK but not in p-JNK or in p-p38 levels. The increase in p-ERK levels was more profound in cells exposed to MAsIII and DMAsIII and correlated with increased levels of p-c-jun. These results indicate that MAsIII and DMAsIII, toxic intermediates of arsenic metabolism, activate AP-1 in human urothelium, with possible effects on the AP-1-dependent gene transcription.(Supported by an NIH grant ES09941. This abstract does not necessarily represent policy of the U.S. EPA.)