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THE ROLE OF PROTEIN BINDING OF TRIVALENT ARSENICALS IN ARSENIC CARCINOGENESIS AND TOXICITY
KITCHIN, K. T. AND K. WALLACE. THE ROLE OF PROTEIN BINDING OF TRIVALENT ARSENICALS IN ARSENIC CARCINOGENESIS AND TOXICITY. Journal of Inorganic Biochemistry. Elsevier Science Ltd, New York, NY, 102(3):532-539, (2008).
This review presents the role of trivalent arsenicals binding to proteins in arsenic carcinogenesis.
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 (<1 s), bidentate (1-2 min) and tridentate (1-2 h) arsenite containing peptide binding complexes were estimated. Our experimental data suggest that some of the protein targets to which trivalent arsenicals such as 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 histone. Although several arsenicals release iron from ferritin, radioactive arsenite did not bind to the protein horse ferritin.
What is the study? This is an invited review article based on a 30 minute PowerPoint talk given at a conference on Inorganic Biochemistry. The manuscript summarizes three published EPA journal articles, unpublished EPA binding studies from our group and some important published literature of others that is germane to the issue of how much contribution does protein binding make to the adverse biological properties of arsenic. Why it was done? This is an invited review article taking advantage of an opportunity to better explain some of arsenic's biological properties in a format with possibly less intrusion by journal reviewers and editors. A large motivation in writing this review article is to be able to present some interesting Kd values of peptides (e. g. Keap-1 and tubulin) that by themselves might be insufficient to warrant a journal article. What is the impact on the field and the Agency? The protein binding property of trivalent arsenicals is one of the three better theories of arsenic carcinogenesis and toxicity. The interactions between arsenicals such as arsenite and enzymes have long been a favorite theory of arsenic's toxicity. This review article makes the case for this scientific position of protein binding participating in carcinogeniesis and toxicity by using the best available evidence currently available. The article attempts to be easy enough for risk assessors to be able to understand without undue difficulty and also to encourage risk assessors to use the presented information in their risk assessments and extrapolations.
URLs/Downloads:THE ROLE OF PROTEIN BINDING OF TRIVALENT ARSENICALS IN ARSENIC CARCINOGENESIS AND TOXICITY Exit
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
ENVIRONMENTAL CARCINOGENESIS DIVISION
CANCER BIOLOGY BRANCH