This is an amended proposal from a new investigator now seeking four years of support to examine the relationship between metabolism of iAs and toxicity in cells from liver, skin, urinary bladder and lung. Effects of iAs and trivalent and pentavalent methylated arsenicals on cell viability and proliferation, cellular redox status, induction of oxidative stress, and expression or activation of p53, AP-1 and NF-kB will be examined. The role of antioxidants and antioxidant enzymes in prevention of arsenic-induced effects will be determined. Metabolic conversions of arsenicals will be studied in cultured cells by examining uptake, production of methylated metabolites, interaction of arsenic metabolites with cellular proteins, and efflux of arsenic metabolites from cells. Arsenic metabolites directly responsible for the induction of adverse effects will be identified and critical concentrations determined and linked with expression of oxidative stress-sensitive transcription factors to help identify mechanisms underlying toxic and carcinogenic effects of iAs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES009941-03
Application #
6525297
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Thompson, Claudia L
Project Start
2000-09-18
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2004-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$218,250
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pediatrics
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Walton, Felecia S; Harmon, Anne W; Paul, David S et al. (2004) Inhibition of insulin-dependent glucose uptake by trivalent arsenicals: possible mechanism of arsenic-induced diabetes. Toxicol Appl Pharmacol 198:424-33
Waters, Stephen B; Devesa, Vicenta; Del Razo, Luz Maria et al. (2004) Endogenous reductants support the catalytic function of recombinant rat cyt19, an arsenic methyltransferase. Chem Res Toxicol 17:404-9
Thomas, David J; Waters, Stephen B; Styblo, Miroslav (2004) Elucidating the pathway for arsenic methylation. Toxicol Appl Pharmacol 198:319-26
Drobna, Zuzana; Waters, Stephen B; Walton, Felecia S et al. (2004) Interindividual variation in the metabolism of arsenic in cultured primary human hepatocytes. Toxicol Appl Pharmacol 201:166-77
Walton, Felecia S; Waters, Stephen B; Jolley, Summer L et al. (2003) Selenium compounds modulate the activity of recombinant rat AsIII-methyltransferase and the methylation of arsenite by rat and human hepatocytes. Chem Res Toxicol 16:261-5
Chen, Guo-Qiang; Zhou, Li; Styblo, Miroslav et al. (2003) Methylated metabolites of arsenic trioxide are more potent than arsenic trioxide as apoptotic but not differentiation inducers in leukemia and lymphoma cells. Cancer Res 63:1853-9
Lin, Shan; Shi, Qing; Nix, F Brent et al. (2002) A novel S-adenosyl-L-methionine:arsenic(III) methyltransferase from rat liver cytosol. J Biol Chem 277:10795-803
Styblo, Miroslav; Drobna, Zuzana; Jaspers, Ilona et al. (2002) The role of biomethylation in toxicity and carcinogenicity of arsenic: a research update. Environ Health Perspect 110 Suppl 5:767-71

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