Arsenic biomethylation

After a long fallow period, other workers have recently begun to extend Challenger s arsenic biomethylation work (1-3). Cox and Alexander have studied this reaction by the mold Candida humicola (59-9/). The overall reaction may be summed up by the reaction shown in Eq. (6). Both cell extracts and whole cells of Methanobacterium strain M.o.H. converted arsenate to dimethylarsine (92). Investigations on C. humicola and other molds determined that the rate of (CH s production follows the growth rate pattern of the mold, and decreases when the mold reaches the resting phase (93). The methylated arsenic intermediates were identified by use of... 

Human volunteers who drank wine containing inorganic arsenic excreted methylarsonic and cacodylic acids in their urine (96). These two compounds also occur in the urine of copper smelters, the elevated arsenic content presumably coming from copper ores (97). Cacodylate ion forms when H34As04 is administered orally to dogs or hamsters (98-100). A Japanese group reported that various small animals will form methylar-sonate and cacodylate from H3ASO4 (101). On the basis of presently available data, it remains uncertain whether arsenic biomethylation occurs from the bodily processes of the mammals themselves or from microflora of the intestinal tract. 

Cullen et al. (1994) have proposed a possible mechanism of arsenic methylation after the study in which arsenite, arsenate, monomethyl-arsonate or dimethylarsinic acid were added to the growth medium in the presence of the unicellular alga Polyphsa peniculus. Evidence of arsenic biomethylation by the micro-organism Apiotrichum humicola in the presence of L-methionine-methyl-d3 has come from the same laboratory (Cullen et al., 1995). Their findings point to the role of S-adenosylmethionine, or a related sulfonium compound as possible methyl donors. Arsenic biomethylation and biotransformation has also been demonstrated in a freshwater environment (Kuroiwa et al., 1994). 

Cullen, W.R., Li, H., Pergantis, S.A., Eigendorf, G.K. and Mosi, A A. (1995) Arsenic biomethylation by the microorganism Apiotrichum humicola in the presence of L-methionine-methyl d3. Appl. Organomet. Chem., 9, 507-515. 

The enzymology of arsenic biomethylation is complicated because of its many oxidation states, its propensity to react with sulfur compounds, and low concentrations of arsenic compounds in biological specimens. The chemical intermediates and reactions in the metabolism of arsenate are similar in microorganisms and animals. However, in microorganisms, the reactions tend to proceed to methylarsines, whereas in mammalian species the major urinary metabolite is generally dimethylarsinate and only a very small amount of it is reduced further. The arsenate reductase and methylarsonate reductase were thought to play an important role in arsenic biomethylation however, with the exception of arsenate reductase most of the enzymatic experiments involved mammalian systems. 

The discovery of arsenic biomethylation goes back some 200 years, when German physicians noted cases of poisoning attributable to arsenic-containing paints such as Scheele s Green (copper arsenite, below) that were widely used on wallpaper at the time ... 

Arsenite is also an intermediate in the fungal biomethylation of arsenic (Bentley and Chasteen 2002) and oxidation to the less toxic arsenate can be accomplished by heterotrophic bacteria including Alcaligenes faecalis. Exceptionally, arsenite can serve as electron donor for chemolithotrophic growth of an organism designated NT-26 (Santini et al. 2000), and both selenate and arsenate can be involved in dissimilation reactions as alternative electron acceptors. 

Biomethylation is the preferred detoxification mechanism for inorganic arsenicals. 

Inorganic arsenicals are oxidized in vivo, biomethylated, and usually excreted rapidly in the urine, but organoarsenicals are usually not subject to similar transformations. 

Antimony does not appear to be an essential ultratrace element and does not appear to undergo metabolic reactions analogous to those of arsenic for example, no biomethylation of antimony has been detected.178 Antimony trioxide is now suspected to be carcinogenic to humans. 

Fig. 7. Challenger mechanism for biomethylation of arsenic. Solid arrows represent pathways proposed originally dashed arrows represent additional pathways proposed by the present authors.

At present, arsenic, mercury, selenium, and tin have been unequivocally established as undergoing biomethylation. There is substantial, though not completely unequivocal, evidence for the biomethylation of lead, tellurium, and thallium, at least under laboratory conditions. Various... 

Biomethylation may also produce more complex alkyl arsenic groups. As(C2H5)(CH3)2 has been found in landfill and sewage gas, and probably also exists in natural gas (Bentley and Chasteen, 2002), 251. As(C2H5)3 may also occur in landfill gases and probably natural gas (Bentley and Chasteen, 2002), 251. Further details on the reduction and methylation biochemistry of arsenic are discussed in Chapter 4. 

Odanaka, Y., Matano, O. and Goto, S. (1980) Biomethylation of inorganic arsenic by the rat and some laboratory animals. Bulletin of Environmental Contamination and Toxicology, 24(3), 452-59. 

Smith, M.S., Jones, P.R. and Shirachi, D.Y. (1992) The biomethylation of sodium arsenate by rat liver cytosol determined by mass spectrometry. Proceedings of the Western Pharmacology Society, 35, 53 -55. 

Kuroiwa, T., Ohki, A., Naka, K. and Maeda, S. (1994) Biomethylation and biotransformation of arsenic in a freshwater food chain green alga (Chlorella vulgaris) — shrimp (Neocaridina denticulata) — Killifish (Oryzias latipes). Appl. Organomet. Chem., 8, 325-333. 

There are two major sources of organoarsenic compounds those produced for commercial applications and those produced from the biomethylation of inorganic arsenic by microorganisms. Many different organoarsenic compounds have been identified. 

M. Styblo, Z. Drobna, I. Jaspers, S. Lin, D. J. Thomas, The role of biomethylation in toxicity and carcinogenicity of arsenic a research update, Environ. Health Persp., 110 (2002), Suppl. 5, 767-771. 

Although trivalent inorganic arsenic, with its propensity for binding to the SH group of enzymes, is acknowledged to be more toxic to humans than pentavalent inorganic arsenic, it must be recognized that As can be converted to As in the human body as part of the reduction/biomethylation pathway of excretion... 

In solution under these conditions the major species is [H2As03] (68). The cycle is completed trough the rereduction of new methylated arsenical by a range of nonspecific rednctants (Scheme 6). The organoarsenicals prodnced dnring biomethylation can be reduced by bacteria with lipoic acid and by mammals with the ubiquitons thiolate glntathione, as has been reported in in vitro stndies. ... 

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