Enzymatic Methylation of Arsenic Species and Other New Approaches to Arsenic Toxicity

Hv, Aposhian

doi:10.1146/annurev.pharmtox.37.1.397

Cited by 384 publications

(216 citation statements)

References 64 publications

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“…The methylation of arsenicals is a common feature of the metabolism of this metalloid in organisms ranging in complexity from microorganisms to humans (35)(36)(37). Although reservations have been expressed concerning the use of the rat in studies of the systemic disposition of arsenic (38), both rat liver cytosol and primary rat hepatocytes have been shown to be efficient methylators of arsenic (33,34,39).…”

Section: Discussionmentioning

confidence: 99%

A Novel S-Adenosyl-l-methionine:Arsenic(III) Methyltransferase from Rat Liver Cytosol

Lin

Shi

Nix

et al. 2002

Journal of Biological Chemistry

318

216

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S-Adenosyl-L-methionine (AdoMet):arsenic(III) methyltransferase, purified from liver cytosol of adult male Fischer 344 rats, catalyzes transfer of a methyl group from AdoMet to trivalent arsenicals producing methylated and dimethylated arsenicals. The kinetics of production of methylated arsenicals in reaction mixtures containing enzyme, AdoMet, dithiothreitol, glutathione (GSH), and arsenite are consistent with a scheme in which monomethylated arsenical produced from arsenite is the substrate for a second methylation reaction that yields dimethylated arsenical. The mRNA for this protein predicts a 369-amino acid residue protein (molecular mass 41056) that contains common methyltransferase sequence motifs. Its sequence is similar to Cyt19, a putative methyltransferase, expressed in human and mouse tissues. Reverse transcription-polymerase chain reaction detects S-adenosyl-L-methionine:arsenic(III) methyltransferase mRNA in rat tissues and in HepG2 cells, a human cell line that methylates arsenite and methylarsonous acid. S-Adenosyl-L-methionine:arsenic-(III) methyltransferase mRNA is not detected in UROtsa cells, an immortalized human urothelial cell line that does not methylate arsenite. Because methylation of arsenic is a critical feature of its metabolism, characterization of this enzyme will improve our understanding of this metalloid's metabolism and its actions as a toxin and a carcinogen.In many species, including humans, exposure to inorganic arsenic results in urinary excretion of methylated and dimethylated arsenicals (1-3). Cullen and co-workers (4) summarized the conversion of inorganic arsenic into these methylated products in a reaction scheme which incorporates oxidative methylation and the cycling of arsenic between the pentavalent (As V ) 1 and trivalent (As III ) oxidation states,Because reduction of arsenic to trivalency is a prerequisite for its oxidative methylation, pentavalent arsenicals are reduced by endogenous thiols such as glutathione (GSH) (5, 6) or by As V reductases (7-9). A protein has been purified from rabbit liver cytosol that catalyzes the methylation of both arsenite and methylarsonous acid (10, 11); however, this protein has not been sequenced. These activities are designated arsenite methyltransferase (EC 2.1.1.137) and methylarsonite methyltransferase (EC 2.1.1.138), respectively. This protein (estimated molecular mass 60 kDa) uses S-adenosyl-L-methionine (AdoMet) as the methyl group donor. The methylation of arsenite by this protein is stimulated by a monothiol (GSH) and the methylation of methylarsonous acid is highly stimulated by a dithiol, dithiothreitol (DTT). The methylation of arsenic has been commonly regarded as a mechanism for its detoxification (12). However, recent research has shown that methylated arsenicals that contain As III are important intermediates in the metabolism of inorganic arsenic. Methylated arsenicals that contain As III are found in the urine of individuals who chronically consume drinking water that contains inorganic arsenic and in cells cu...

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Section: Discussionmentioning

confidence: 99%

A Novel S-Adenosyl-l-methionine:Arsenic(III) Methyltransferase from Rat Liver Cytosol

Lin

Shi

Nix

et al. 2002

Journal of Biological Chemistry

318

216

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“…One of the mechanisms by which arsenicals produce toxic effects is through their interaction with cellular sulfhydryl groups in proteins or elsewhere (45). iAs(III) and iAs(V) have been shown to react with some NPSH to form As-SH complexes in vitro at high concentrations (46,47).…”

Section: Discussionmentioning

confidence: 99%

Evidence for induction of oxidative stress caused by chronic exposure of Chinese residents to arsenic contained in drinking water.

Yamauchi

Kumagai

et al. 2002

Environ Health Perspect

243

140

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Exposure of experimental animals or cultured cells to arsenic induces oxidative stress, but, to date, no examination of this phenomenon in humans has been reported. In this study we conducted a cross-sectional study in Wuyuan, Inner Mongolia, China, to explore the relationship between chronic arsenic exposure from drinking water and oxidative stress in humans. Thirty-three inhabitants who had been drinking tube-well water with high concentrations of inorganic arsenic (mean value = 0.41 mg/L) for about 18 years constituted the high-exposure group, and 10 residents who lived nearby but were exposed to much lower concentrations of arsenic in their drinking water (mean value = 0.02 mg/L) were selected as the low-exposure comparison group. Results of the present study indicated that although the activity for superoxide dismutase (SOD) in blood did not differ significantly between the two groups, the mean serum level of lipid peroxides (LPO) was significantly higher among the high-exposed compared with the low-exposed group. Elevated serum LPO concentrations were correlated with blood levels of inorganic arsenic and its methylated metabolites. In addition, they showed an inverse correlation with nonprotein sulfhydryl (NPSH) levels in whole blood. The subjects in the high-arsenic-exposure group had mean blood NPSH levels 57.6% lower than those in the low-exposure group. Blood NPSH levels were inversely correlated with the concentrations of inorganic arsenic and its methylated metabolites in blood and with the ratio of monomethylarsenic to inorganic arsenic. These results provide evidence that chronic exposure to arsenic from drinking water in humans results in induction of oxidative stress, as indicated by the reduction in NPSH and the increase in LPO. Some possible mechanisms for the arsenic-induced oxidative stress are discussed.

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“…In some species, particularly rats and to lesser extent other rodents, DMA III is further methylated to form trimethylarsine oxide (TMA V O) . TMA V O is only formed in humans when there is very high exposure to inorganic arsenic (Aposhian, 1997;Cohen et al, 2006;Thomas, 2007). These methylated metabolites of iAs exert specific toxicities in animal models.…”

Section: Introductionmentioning

confidence: 99%

Effect of dietary treatment with dimethylarsinous acid (DMAIII) on the urinary bladder epithelium of arsenic (+3 oxidation state) methyltransferase (As3mt) knockout and C57BL/6 wild type female mice

et al. 2013

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Dodmane, Puttappa R.; Arnold, Lora L.; Pennington, Karen L.; Thomas, David J.; and Cohen, Samuel M., "Effect of dietary treatment with dimethylarsinous acid (DMA III ) on the urinary bladder epithelium of arsenic (+3 oxidation state) methyltransferase (As3mt) knockout and C57BL/6 wild type female mice" (2013 Chronic exposure to inorganic arsenic (iAs) is carcinogenic to the human urinary bladder. It produces urothelial cytotoxicity and proliferation in rats and mice. DMA V , a major methylated urinary metabolite of iAs, is a rat bladder carcinogen, but without effects on the mouse urothelium. DMA III was shown to be the likely urinary metabolite of DMA V inducing urothelial changes and is also postulated to be one of the active metabolites of iAs. To evaluate potential DMA III -induced urothelial effects, it was administered to As3mt knockout mice which cannot methylate arsenicals. Female C57BL/6 wild type and As3mt knockout mice (10/group) were administered DMA III , 77.3 ppm in water for four weeks. Urothelial effects were evaluated by light and scanning electron microscopy (EM) and immunohistochemical detection of bromodeoxyuridine (BrdU) incorporation. EM findings were rated 1-5, with higher rating indicating greater extent of cytotoxicity visualized. DMA III significantly increased the BrdU labeling index, a ratio of BrdU labeled cells to non-labeled cells, in the treated knockout group compared to control and wild type treated groups. DMA III induced simple hyperplasia in more knockout mice (4/10) compared to wild type mice (2/10). All treated knockout mice had more and larger intracytoplasmic granules compared to the treated wild type mice. Changes in EM classification were not significant. In conclusion, DMA III induces urothelial toxicity and regenerative hyperplasia in mice and most likely plays a role in inorganic arsenic-induced urothelial changes. However, DMA V does not induce hyperplasia in mice, suggesting that urinary concentrations of DMA III do not reach cytotoxic levels in DMA V -treated mice.

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Enzymatic Methylation of Arsenic Species and Other New Approaches to Arsenic Toxicity

Cited by 384 publications

References 64 publications

A Novel S-Adenosyl-l-methionine:Arsenic(III) Methyltransferase from Rat Liver Cytosol

A Novel S-Adenosyl-l-methionine:Arsenic(III) Methyltransferase from Rat Liver Cytosol

Evidence for induction of oxidative stress caused by chronic exposure of Chinese residents to arsenic contained in drinking water.

Effect of dietary treatment with dimethylarsinous acid (DMAIII) on the urinary bladder epithelium of arsenic (+3 oxidation state) methyltransferase (As3mt) knockout and C57BL/6 wild type female mice

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