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. 2002 Oct;110(Suppl 5):767–771. doi: 10.1289/ehp.110-1241242

The role of biomethylation in toxicity and carcinogenicity of arsenic: a research update.

Miroslav Stýblo 1, Zuzana Drobná 1, Ilona Jaspers 1, Shan Lin 1, David J Thomas 1
PMCID: PMC1241242  PMID: 12426129

Abstract

Recent research of the metabolism and biological effects of arsenic has profoundly changed our understanding of the role of metabolism in modulation of toxicity and carcinogenicity of this metalloid. Historically, the enzymatic conversion of inorganic arsenic to mono- and dimethylated species has been considered a major mechanism for detoxification of inorganic arsenic. However, compelling experimental evidence obtained from several laboratories suggests that biomethylation, particularly the production of methylated metabolites that contain trivalent arsenic, is a process that activates arsenic as a toxin and a carcinogen. This article summarizes this evidence and provides new data on a) the toxicity of methylated trivalent arsenicals in mammalian cells, b) the effects of methylated trivalent arsenicals on gene transcription, and c) the mechanisms involved in arsenic methylation in animal and human tissues.

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Selected References

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  1. 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. Occurrence of monomethylarsonous acid in urine of humans exposed to inorganic arsenic. Chem Res Toxicol. 2000 Aug;13(8):693–697. doi: 10.1021/tx000114o. [DOI] [PubMed] [Google Scholar]
  2. Barchowsky A., Dudek E. J., Treadwell M. D., Wetterhahn K. E. Arsenic induces oxidant stress and NF-kappa B activation in cultured aortic endothelial cells. Free Radic Biol Med. 1996;21(6):783–790. doi: 10.1016/0891-5849(96)00174-8. [DOI] [PubMed] [Google Scholar]
  3. Bates M. N., Smith A. H., Hopenhayn-Rich C. Arsenic ingestion and internal cancers: a review. Am J Epidemiol. 1992 Mar 1;135(5):462–476. doi: 10.1093/oxfordjournals.aje.a116313. [DOI] [PubMed] [Google Scholar]
  4. Buchet J. P., Lauwerys R. Study of inorganic arsenic methylation by rat liver in vitro: relevance for the interpretation of observations in man. Arch Toxicol. 1985 Jun;57(2):125–129. doi: 10.1007/BF00343122. [DOI] [PubMed] [Google Scholar]
  5. Burleson F. G., Simeonova P. P., Germolec D. R., Luster M. I. Dermatotoxic chemical stimulate of c-jun and c-fos transcription and AP-1 DNA binding in human keratinocytes. Res Commun Mol Pathol Pharmacol. 1996 Aug;93(2):131–148. [PubMed] [Google Scholar]
  6. Cavigelli M., Li W. W., Lin A., Su B., Yoshioka K., Karin M. The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase. EMBO J. 1996 Nov 15;15(22):6269–6279. [PMC free article] [PubMed] [Google Scholar]
  7. Del Razo L. M., Styblo M., Cullen W. R., Thomas D. J. Determination of trivalent methylated arsenicals in biological matrices. Toxicol Appl Pharmacol. 2001 Aug 1;174(3):282–293. doi: 10.1006/taap.2001.9226. [DOI] [PubMed] [Google Scholar]
  8. Delnomdedieu M., Basti M. M., Otvos J. D., Thomas D. J. Reduction and binding of arsenate and dimethylarsinate by glutathione: a magnetic resonance study. Chem Biol Interact. 1994 Feb;90(2):139–155. doi: 10.1016/0009-2797(94)90099-x. [DOI] [PubMed] [Google Scholar]
  9. Guo H. R., Chiang H. S., Hu H., Lipsitz S. R., Monson R. R. Arsenic in drinking water and incidence of urinary cancers. Epidemiology. 1997 Sep;8(5):545–550. doi: 10.1097/00001648-199709000-00012. [DOI] [PubMed] [Google Scholar]
  10. Holmgren A. Thioredoxin and glutaredoxin systems. J Biol Chem. 1989 Aug 25;264(24):13963–13966. [PubMed] [Google Scholar]
  11. Holmgren A. Thioredoxin structure and mechanism: conformational changes on oxidation of the active-site sulfhydryls to a disulfide. Structure. 1995 Mar 15;3(3):239–243. doi: 10.1016/s0969-2126(01)00153-8. [DOI] [PubMed] [Google Scholar]
  12. Kitchin K. T. Recent advances in arsenic carcinogenesis: modes of action, animal model systems, and methylated arsenic metabolites. Toxicol Appl Pharmacol. 2001 May 1;172(3):249–261. doi: 10.1006/taap.2001.9157. [DOI] [PubMed] [Google Scholar]
  13. Le X. C., Lu X., Ma M., Cullen W. R., Aposhian H. V., Zheng B. Speciation of key arsenic metabolic intermediates in human urine. Anal Chem. 2000 Nov 1;72(21):5172–5177. doi: 10.1021/ac000527u. [DOI] [PubMed] [Google Scholar]
  14. Le X. C., Ma M., Cullen W. R., Aposhian H. V., Lu X., Zheng B. Determination of monomethylarsonous acid, a key arsenic methylation intermediate, in human urine. Environ Health Perspect. 2000 Nov;108(11):1015–1018. doi: 10.1289/ehp.001081015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lin S., Cullen W. R., Thomas D. J. Methylarsenicals and arsinothiols are potent inhibitors of mouse liver thioredoxin reductase. Chem Res Toxicol. 1999 Oct;12(10):924–930. doi: 10.1021/tx9900775. [DOI] [PubMed] [Google Scholar]
  16. Lin Shan, Shi Qing, Nix F. Brent, Styblo Miroslav, Beck Melinda A., Herbin-Davis Karen M., Hall Larry L., Simeonsson Josef B., Thomas David J. A novel S-adenosyl-L-methionine:arsenic(III) methyltransferase from rat liver cytosol. J Biol Chem. 2002 Jan 14;277(13):10795–10803. doi: 10.1074/jbc.M110246200. [DOI] [PubMed] [Google Scholar]
  17. Mandal B. K., Ogra Y., Suzuki K. T. Identification of dimethylarsinous and monomethylarsonous acids in human urine of the arsenic-affected areas in West Bengal, India. Chem Res Toxicol. 2001 Apr;14(4):371–378. doi: 10.1021/tx000246h. [DOI] [PubMed] [Google Scholar]
  18. Mass M. J., Tennant A., Roop B. C., Cullen W. R., Styblo M., Thomas D. J., Kligerman A. D. Methylated trivalent arsenic species are genotoxic. Chem Res Toxicol. 2001 Apr;14(4):355–361. doi: 10.1021/tx000251l. [DOI] [PubMed] [Google Scholar]
  19. Morris R. D. Drinking water and cancer. Environ Health Perspect. 1995 Nov;103 (Suppl 8):225–231. doi: 10.1289/ehp.95103s8225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Petrick J. S., Ayala-Fierro F., Cullen W. R., Carter D. E., Vasken Aposhian H. Monomethylarsonous acid (MMA(III)) is more toxic than arsenite in Chang human hepatocytes. Toxicol Appl Pharmacol. 2000 Mar 1;163(2):203–207. doi: 10.1006/taap.1999.8872. [DOI] [PubMed] [Google Scholar]
  21. Petrick J. S., Jagadish B., Mash E. A., Aposhian H. V. Monomethylarsonous acid (MMA(III)) and arsenite: LD(50) in hamsters and in vitro inhibition of pyruvate dehydrogenase. Chem Res Toxicol. 2001 Jun;14(6):651–656. doi: 10.1021/tx000264z. [DOI] [PubMed] [Google Scholar]
  22. Radabaugh T. R., Aposhian H. V. Enzymatic reduction of arsenic compounds in mammalian systems: reduction of arsenate to arsenite by human liver arsenate reductase. Chem Res Toxicol. 2000 Jan;13(1):26–30. doi: 10.1021/tx990115k. [DOI] [PubMed] [Google Scholar]
  23. Salazar A. M., Ostrosky-Wegman P., Menéndez D., Miranda E., García-Carrancá A., Rojas E. Induction of p53 protein expression by sodium arsenite. Mutat Res. 1997 Nov 28;381(2):259–265. doi: 10.1016/s0027-5107(97)00207-8. [DOI] [PubMed] [Google Scholar]
  24. Scott N., Hatlelid K. M., MacKenzie N. E., Carter D. E. Reactions of arsenic(III) and arsenic(V) species with glutathione. Chem Res Toxicol. 1993 Jan-Feb;6(1):102–106. doi: 10.1021/tx00031a016. [DOI] [PubMed] [Google Scholar]
  25. Simeonova P. P., Luster M. I. Mechanisms of arsenic carcinogenicity: genetic or epigenetic mechanisms? J Environ Pathol Toxicol Oncol. 2000;19(3):281–286. [PubMed] [Google Scholar]
  26. Simeonova P. P., Wang S., Toriuma W., Kommineni V., Matheson J., Unimye N., Kayama F., Harki D., Ding M., Vallyathan V. Arsenic mediates cell proliferation and gene expression in the bladder epithelium: association with activating protein-1 transactivation. Cancer Res. 2000 Jul 1;60(13):3445–3453. [PubMed] [Google Scholar]
  27. Styblo M., Del Razo L. M., Vega L., Germolec D. R., LeCluyse E. L., Hamilton G. A., Reed W., Wang C., Cullen W. R., Thomas D. J. Comparative toxicity of trivalent and pentavalent inorganic and methylated arsenicals in rat and human cells. Arch Toxicol. 2000 Aug;74(6):289–299. doi: 10.1007/s002040000134. [DOI] [PubMed] [Google Scholar]
  28. Styblo M., Delnomdedieu M., Thomas D. J. Mono- and dimethylation of arsenic in rat liver cytosol in vitro. Chem Biol Interact. 1996 Jan 5;99(1-3):147–164. doi: 10.1016/0009-2797(95)03666-0. [DOI] [PubMed] [Google Scholar]
  29. Styblo M., Serves S. V., Cullen W. R., Thomas D. J. Comparative inhibition of yeast glutathione reductase by arsenicals and arsenothiols. Chem Res Toxicol. 1997 Jan;10(1):27–33. doi: 10.1021/tx960139g. [DOI] [PubMed] [Google Scholar]
  30. Thomas D. J., Styblo M., Lin S. The cellular metabolism and systemic toxicity of arsenic. Toxicol Appl Pharmacol. 2001 Oct 15;176(2):127–144. doi: 10.1006/taap.2001.9258. [DOI] [PubMed] [Google Scholar]
  31. Vega L., Styblo M., Patterson R., Cullen W., Wang C., Germolec D. Differential effects of trivalent and pentavalent arsenicals on cell proliferation and cytokine secretion in normal human epidermal keratinocytes. Toxicol Appl Pharmacol. 2001 May 1;172(3):225–232. doi: 10.1006/taap.2001.9152. [DOI] [PubMed] [Google Scholar]
  32. Zakharyan R. A., Aposhian H. V. Enzymatic reduction of arsenic compounds in mammalian systems: the rate-limiting enzyme of rabbit liver arsenic biotransformation is MMA(V) reductase. Chem Res Toxicol. 1999 Dec;12(12):1278–1283. doi: 10.1021/tx9901231. [DOI] [PubMed] [Google Scholar]
  33. Zakharyan R. A., Sampayo-Reyes A., Healy S. M., Tsaprailis G., Board P. G., Liebler D. C., Aposhian H. V. Human monomethylarsonic acid (MMA(V)) reductase is a member of the glutathione-S-transferase superfamily. Chem Res Toxicol. 2001 Aug;14(8):1051–1057. doi: 10.1021/tx010052h. [DOI] [PubMed] [Google Scholar]
  34. Zakharyan R., Wu Y., Bogdan G. M., Aposhian H. V. Enzymatic methylation of arsenic compounds: assay, partial purification, and properties of arsenite methyltransferase and monomethylarsonic acid methyltransferase of rabbit liver. Chem Res Toxicol. 1995 Dec;8(8):1029–1038. doi: 10.1021/tx00050a006. [DOI] [PubMed] [Google Scholar]

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