The role of protein binding of trivalent arsenicals in arsenic carcinogenesis and toxicity.
Three of the most plausible biological theories of arsenic carcinogenesis are protein binding, oxidative stress and altered DNA methylation. This review presents the role of trivalent arsenicals binding to proteins in arsenic carcinogenesis. Using vacuum filtration based receptor dissociation binding techniques, the lifetimes of unidentate (<1s), bidentate (1-2min) and tridentate (1-2h) arsenite containing peptide binding complexes were estimated. According to our experimental data some of the protein targets to which arsenite may bind in vivo include tubulin, poly(ADP-ribose)polymerase (PARP-1), thioredoxin reductase, estrogen receptor-alpha, arsenic(+3)methyltransferase and Keap-1. Arsenite binding to tubulin can lead to several of the genetic effects observed after arsenic exposures (aneuploidy, polyploidy and mitotic arrests). Among many other possible arsenite binding sites are rat hemoglobin, the DNA repair enzyme xeroderma pigmentosum protein A (XPA), and other C2H2, C3H and C4 zinc finger proteins including members of the steroid receptor superfamily (e.g. glucocorticoid receptor). Macromolecules to which arsenite does not bind to include calf thymus DNA, mixed Type II-A histones and bovine H3/H4 histone. Although all six tested arsenicals released iron from ferritin, radioactive arsenite did not bind to the protein horse ferritin.
Kitchin
Kirk T
KT
Environmental Carcinogenesis Division, Mail Drop B143-06, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA. kitchin.kirk@epa.gov
Wallace
Kathleen
K
D000818:Animals; D001151:Arsenic / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D008780:Methyltransferases / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000139:chemically induced / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins
D011506:Proteins; D008780:Methyltransferases; D011065:Poly(ADP-ribose) Polymerases; D001151:Arsenic