An Overview of Arsenic Metabolism and Toxicity

Zuzana Drobna1, Miroslav Styblo2, David J. Thomas3

1 Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 2 Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 3 Pharmacokinetics Branch, Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina
Publication Name:  Current Protocols in Toxicology
Unit Number:  Unit 4.31
DOI:  10.1002/0471140856.tx0431s42
Online Posting Date:  November, 2009
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Abstract

It is likely that at least some of the toxic and carcinogenic effects associated with exposure to inorganic arsenic are, in fact, due to actions of its methylated metabolites. Here, we provide an overview of current models for the biological methylation of arsenicals. This information provides a context for understanding the chemical, biochemical, and genetic approaches to elucidation of the formation and function of methylated arsenicals, which are presented in the following units in this chapter. Curr. Protoc. Toxicol. 42:4.31.1‐4.31.6. © 2009 by John Wiley & Sons, Inc.

Keywords: inorganic arsenic; methylated arsenic metabolites; As; methyltransferase

     
 
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Table of Contents

  • Introduction
  • Nomenclature
  • General Aspects of Arsenic Methylation
  • Linkage of Arsenic Methylation and Toxicity
  • Enzymatic Basis of Arsenic Methylation in the Context of Cellular Metabolism
  • Identifying the Products of Arsenic Metabolism
  • Disclaimer
  • Literature Cited
  • Figures
     
 
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Materials

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Literature Cited

Literature Cited
   Adair, B.M., Moore, T., Conklin, S.D., Creed, J.T., Wolf, D.C., and Thomas, D.J. 2007. Tissue distribution and urinary excretion of dimethylated arsenic and its metabolites in dimethylarsinic acid‐ or arsenate‐treated rats. Toxicol. Appl. Pharmacol. 222:235‐242.
   Aposhian, H.V., Gurzau, E.S., Le, X.C., Gurzau, A., Healy, S.M., Lu, X., Ma, M., Yip, L., Zakharyan, R.A., Maiorino, R.M., Dart, R.C., Tircus, M.G., Gonzalez‐Ramirez, D., Morgan, D.L., Avram, D., and Aposhian, M.M. 2000. Occurrence of monomethylarsonous acid in urine of humans exposed to inorganic arsenic. Chem. Res. Toxicol. 13:693‐697.
   Bhattacharjee, Y. 2007. A sluggish response to humanity's biggest mass poisoning. Science 315:1659‐1661.
   Buchanan, W.D. 1962. Toxicity of Arsenic Compounds. Elsevier, Amsterdam.
   Challenger, F. 1945. Biological methylation. Chem. Rev. 36:315‐361.
   Challenger, F., 1951. Biological methylation. Adv. Enzymol. Relat. Subj. Biochem. 12:432‐491.
   Chen, C.J., Wang, S.L., Chiou, J.M., Tseng, C.H., Chiou, H.Y., Hsueh, Y.M., Chen, S.Y., Wu, M., and Lai, M.S. 2007. Arsenic and diabetes and hypertension in human populations: A review. Toxicol. Appl. Pharmacol. 222:298‐304.
   Crecelius, E.A. 1977. Changes in the chemical speciation of arsenic following ingestion by man. Environ. Health Perspect. 19:147‐150.
   Cullen, W.R. 2008. Is Arsenic an Aphrodisiac?: The Sociochemistry of an Element. RSC Publishing, Cambridge.
   Cullen, W.R., McBride, B.C., and Reglinski, J. 1984a. The reduction of trimethylarsine oxide to trimethylarsine by thiols: A mechanistic model for the biological reduction of arsenicals. J. Inorg. Biochem. 21:45‐60.
   Cullen, W.R., McBride, B.C., and Reglinski, J. 1984b. The reaction of methylarsenicals with thiols: Some biological implications. J. Inorg. Biochem. 21:179‐194.
   Del Razo, L.M., Styblo, M., Cullen, W.R., and Thomas, D.J. 2001. Determination of trivalent methylated arsenicals in biological matrices. Toxicol. Appl. Pharmacol. 174:282‐293.
   Douer, D. and Tallman, M.S. 2005. Arsenic trioxide: New clinical experience with an old medication in hematologic malignancies. J. Clin. Oncol. 23:2396‐2410.
   Enterline, P.E., Day, R., and Marsh, G.M. 1995. Cancers related to exposure to arsenic at a copper smelter. Occup. Environ. Med. 52:28‐32.
   Hayakawa, T., Kobayashi, Y., Cui, X., and Hirano, S. 2005. A new metabolic pathway of arsenite: Arsenic‐glutathione complexes are substrates for human arsenic methyltransferase Cyt19. Arch. Toxicol. 79:183‐191.
   Jolliffe, D.M. 1993. A history of the use of arsenicals in man. J. Royal Soc. Med. 86:287‐289.
   Le, X.C., Ma, M., Cullen, W.R., Aposhian, H.V., Lu, X., and Zheng, B. 2000. Determination of monomethylarsonous acid, a key arsenic methylation intermediate, in human urine. Environ. Health Perspect. 108:1015‐1018.
   Lin, S., Cullen, W.R., and Thomas, D.J. 1999. Methylarsenicals and arsinothiols are potent inhibitors of mouse liver thioredoxin reductase. Chem. Res. Toxicol. 12:924‐930.
   Lin, S., Del Razo, L.M., Styblo, M., Wang, C., Cullen, W.R., and Thomas, D.J. 2001. Arsenicals inhibit thioredoxin reductase in cultured rat hepatocytes. Chem. Res. Toxicol. 14:305‐311.
   Lubin, J.H., Pottern, L.M., Stone, B.J., and Fraumeni, J.F. Jr. 2000. Respiratory cancer in a cohort of copper smelter workers: Results from more than 50 years of follow‐up. Am. J. Epidemiol. 151:554‐565.
   Murai, T., Iwata, H., Otoshi, T., Endo, G., Horiguchi, S., and Fukushima, S. 1993. Renal lesions induced in F344/DuCrj rats by 4 weeks oral administration of dimethylarsenic acid. Toxicol. Lett. 66:53‐61.
   Naranmandura, H., Suzuki, N., and Suzuki, K.T. 2006. Trivalent arsenicals are bound to proteins during reductive methylation. Chem. Res. Toxicol. 19:1010‐1018.
   Naranmandura, H., Suzuki, N., Iwata, K., Hirano, S., and Suzuki, K.T. 2007. Arsenic metabolism and thioarsenicals in hamsters and rats. Chem. Res. Toxicol. 20:616‐624.
   Navas‐Acien, A., Sharrett, A.R., Silbergeld, E.K., Schwartz, B.S., Nachman, K.E., Burke, T.A., and Guallar, E. 2005. Arsenic exposure and cardiovascular disease: A systematic review of the epidemiologic evidence. Am. J. Epidemiol. 162:1037‐1049.
   Navas‐Acien, A., Silbergeld, E.K., Pastor‐Barriuso, R., and Guallar, E. 2008. Arsenic exposure and prevalence of type 2 diabetes in U.S. adults. JAMA 300:814‐822.
   Raml, R., Rumpler, A., Goessler, W., Vahter, M., Li, L., Ochi, T., and Francesconi, K.A. 2007. Thio‐dimethylarsinate is a common metabolite in urine samples from arsenic‐exposed women in Bangladesh. Toxicol. Appl. Pharmacol. 222:374‐380.
   Rogers, E.H., Chernoff, N., and Kavlock, R.J. 1981. The teratogenic potential of cacodylic acid in the rat and mouse. Drug Chem. Toxicol. 4:49‐61.
   Schwarz, R.S. 2004. Paul Ehrlich's magic bullets. New Engl. J. Med. 350:1079‐1080.
   Smith, A.H., Hopenhayn‐Rich, C., Bates, M.N., Goeden, H.M., Hertz‐Picciotto, I., Duggan, H.M., Wood, R., Kosnett, M.J., and Smith, M.T. 1992. Cancer risks from arsenic in drinking water. Environ. Health Perspect. 97:259‐267.
   Smith, A.H., Lingas, E.O., and Rahman, M. 2000. Contamination of drinking‐water by arsenic in Bangladesh: A public health emergency. Bull. World Health Organ. 78:1093‐1103.
   Thomas, D.J., Styblo, M., and Lin, S. 2001. The cellular metabolism and systemic toxicity of arsenic. Toxicol. Appl. Pharmacol. 176:127‐144.
   Thomas, D.J., Li, J., Waters, S.B., Xing, W., Adair, B.M., Drobna, Z., Devesa, V., and Styblo, M. 2007. Arsenic (+3 oxidation state) methyltransferase and the methylation of arsenicals. Exp. Biol. Med. 232:3‐13.
   Tseng, W.P. 1977. Effects and dose‐response relationships of skin cancer and blackfoot disease with arsenic. Environ. Health Perspect. 19:109‐119.
   Tseng, W.P, Chu, H.M., How, S.W., Fong, J.M., Lin, C.S., and Yeh, S. 1968. Prevalence of skin cancer in an endemic area of chronic arsenicism in Taiwan. J. Natl. Cancer Inst. 40:453‐463.
   Wang, C.H., Hsiao, C.K., Chen, C.L., Hsu, L.I., Chiou, H.Y., Chen, S.Y., Hsueh, Y.M., Wu, M.M., and Chen, C.J. 2007. A review of the epidemiologic literature on the role of environmental arsenic exposure and cardiovascular diseases. Toxicol. Appl. Pharmacol. 222:315‐326.
   Waters, S.B., Devesa, V., Del Razo, L.M., Styblo, M., and Thomas, D.J. 2004a. Endogenous reductants support the catalytic function of recombinant rat cyt19, an arsenic methyltransferase. Chem. Res. Toxicol. 17:404‐409.
   Waters, S.B., Devesa, V., Fricke, M., Creed, J., Styblo, M., and Thomas, D.J. 2004b. Glutathione modulates recombinant rat arsenic (+3 oxidation state) methyltransferase‐catalyzed formation of trimethylarsine oxide and trimethylarsine. Chem. Res. Toxicol. 17:1621‐1629.
   Wei, M., Wanibuchi, H., Yamamoto, S., Li, W., and Fukushima, S. 1999. Urinary bladder carcinogenicity of dimethylarsinic acid in male F344 rats. Carcinogenesis 20:1873‐1876.
   Wright, M.W. and Bruford, E.A. 2006. Human and orthologous gene nomenclature. Gene 369:1‐6.
   Yamamoto, S., Konishi, Y., Matsuda, T., Murai, T., Shibata, M.A., Matsui‐Yuasa, I., Otani, S., Kuroda, K., Endo, G., and Fukushima, S. 1995. Cancer induction by an organic arsenic compound, dimethylarsinic acid (cacodylic acid), in F344/DuCrj rats after pretreatment with five carcinogens. Cancer Res. 55:1271‐1276.
   Yamauchi, H. and Fowler, B.A. 1994. Toxicity and metabolism of inorganic and methylated arsenicals. In Arsenic in the Environment, Part II: Human Health and Ecosystem Effects (J.O. Nriagu, ed.) pp. 35‐43. John Wiley & Sons, New York.
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