Metabolism of arsenic and its toxicological relevance
Arsenic is a worldwide environmental pollutant and a human carcinogen. It is well recognized that the toxicity of arsenicals largely depends on the oxidoreduction states (trivalent or pentavalent) and methylation levels (monomethyl, dimethyl, and trimethyl) that are present during the process of metabolism in mammals. However, presently, the specifics of the metabolic pathway of inorganic arsenicals have yet to be confirmed. In mammals, there are two possible mechanisms that have been proposed for the metabolic pathway of inorganic arsenicals, oxidative methylation, and glutathione conjugation. Oxidative methylation, which was originally proposed in fungi, is based on findings that arsenite (iAsIII) is sequentially converted to monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) in both humans and in laboratory animals such as mice and rats. However, recent in vitro observations have demonstrated that arsenic is only methylated in the presence of glutathione (GSH) or other thiol compounds, which strongly suggests that arsenic is methylated in trivalent forms. The glutathione conjugation mechanism is supported by findings that have shown that most intracellular arsenicals are trivalent and excreted from cells as GSH conjugates. Since non-conjugated trivalent arsenicals are highly reactive with thiol compounds and are easily converted to less toxic corresponding pentavalent arsenicals, the arsenic–glutathione conjugate stability may be the most important factor for determining the toxicity of arsenicals. In addition, “being a non-anionic form” also appears to be a determinant of the toxicity of oxo-arsenicals or thioarsenicals. The present review discusses both the metabolism of arsenic and the toxicity of arsenic metabolites.
KeywordsArsenic (+3 oxidation state) methyltransferase Glutathione Multidrug resistance-associated protein Thioarsenical Oxidoreduction
This work was partially supported by Grant-in-Aid from Ministry of Education, Culture, Sports, Science, and Technology (23390167-002).
Conflict of interest
The authors declare no conflict of interest.
- Chiou HY, Hsueh YM, Hsieh LL, Hsu LI, Hsu YH, Hsieh FI, Wei ML, Chen HC, Yang HT, Leu LC, Chu TH, ChenWu C, Yang MH, Chen CJ (1997) Arsenic methylation capacity, body retention, and null genotypes of glutathione S-transferase M1 and T1 among current arsenic-exposed residents in Taiwan. Mutat Res, Rev Mutat Res 386(3):197–207CrossRefGoogle Scholar
- Diaz-Bone RA, Hollmann M, Wuerfel O, Pieper D (2009) Analysis of volatile arsenic compounds formed by intestinal microorganisms: rapid identification of new metabolic products by use of simultaneous EI-MS and ICP-MS detection after gas chromatographic separation. J Anal At Spectrom 24(6):808–814CrossRefGoogle Scholar
- Drobna Z, Naranmandura H, Kubachka KM, Edwards BC, Herbin-Davis K, Styblo M, Le Chris X, Creed JT, Maeda N, Hughes MF, Thomas DJ (2009) Disruption of the arsenic (+3 oxidation state) methyltransferase gene in the mouse alters the phenotype for methylation of arsenic and affects distribution and retention of orally administered arsenate. Chem Res Toxicol 22(10):1713–1720PubMedCrossRefGoogle Scholar
- Hansen HR, Raab A, Jaspars M, Milne BF, Feldmann J (2004) Sulfur-containing arsenical mistaken for dimethylarsinous acid [DMA(III)] and identified as a natural metabolite in urine: major implications for studies on arsenic metabolism and toxicity. Chem Res Toxicol 17(8):1086–1091PubMedCrossRefGoogle Scholar
- International-Council-on-Mining-and-Metals (2007) Gastrointestinal uptake and absorption, and catalogue of toxicokinetic models. Health risk assessment guidance for metals. Fact sheet 04. http://www.icmm.com/page/1213/health-risk-assessment-guidance-for-metals-herag
- IPCS (2001) Arsenic and arsenic compounds, vol 224. World Health Organization, GenevaGoogle Scholar
- Komissarova EV, Li P, Uddin AN, Chen X, Nadas A, Rossman TG (2008) Gene expression levels in normal human lymphoblasts with variable sensitivities to arsenite: identification of GGT1 and NFKBIE expression levels as possible biomarkers of susceptibility. Toxicol Appl Pharmacol 226(2):199–205PubMedCrossRefGoogle Scholar
- Marnell LL, Garcia-Vargas GG, Chowdhury UK, Zakharyan RA, Walsh B, Avram MD, Kopplin MJ, Cebrian ME, Silbergeld EK, Aposhian HV (2003) Polymorphisms in the human monomethylarsonic acid (MMA V) reductase/hGSTO1 gene and changes in urinary arsenic profiles. Chem Res Toxicol 16(12):1507–1513PubMedCrossRefGoogle Scholar
- Percy AJ, Gailer J (2008) Methylated trivalent arsenic-glutathione complexes are more stable than their arsenite analog. Bioinorg Chem Appl 539082Google Scholar
- Raml R, Raber G, Rumpler A, Bauernhofer T, Goessler W, Francesconi KA (2009) Individual variability in the human metabolism of an arsenic-containing carbohydrate, 2′,3′-dihydroxypropyl 5-deoxy-5-dimethylarsinoyl-beta-D-riboside, a naturally occurring arsenical in seafood. Chem Res Toxicol 22(9):1534–1540PubMedCrossRefGoogle Scholar
- Suner MA, Devesa V, Munoz O, Velez D, Montoro R (2001) Application of column switching in high-performance liquid chromatography with on-line thermo-oxidation and detection by HG-AAS and HG-AFS for the analysis of organoarsenical species in seafood samples. J Anal At Spectrom 16(4):390–397CrossRefGoogle Scholar
- Yu L, Kalla K, Guthrie E, Vidrine A, Klimecki WT (2003) Genetic variation in genes associated with arsenic metabolism: glutathione s-transferase omega 1–1 and purine nucleoside phosphorylase polymorphisms in European and indigenous americans. Environ Health Perspect 111(11):1421–1427PubMedCrossRefGoogle Scholar
- Zhang XW, Yan XJ, Zhou ZR, Yang FF, Wu ZY, Sun HB, Liang WX, Song AX, Lallemand-Breitenbach V, Jeanne M, Zhang QY, Yang HY, Huang QH, Zhou GB, Tong JH, Zhang Y, Wu JH, Hu HY, de The H, Chen SJ, Chen Z (2010) Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science 328(5975):240–243PubMedCrossRefGoogle Scholar