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. 2005 Dec;113(12):1683-8.
doi: 10.1289/ehp.8084.

Folate, Homocysteine, and Arsenic Metabolism in Arsenic-Exposed Individuals in Bangladesh

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Folate, Homocysteine, and Arsenic Metabolism in Arsenic-Exposed Individuals in Bangladesh

Mary V Gamble et al. Environ Health Perspect. .
Free PMC article


Chronic exposure to arsenic is occurring throughout South and East Asia due to groundwater contamination of well water. Variability in susceptibility to arsenic toxicity may be related to nutritional status. Arsenic is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) via one-carbon metabolism, a biochemical pathway that is dependent on folate. The majority of one-carbon metabolism methylation reactions are devoted to biosynthesis of creatine, the precursor of creatinine. Our objectives of this cross-sectional study were to characterize the relationships among folate, cobalamin, homocysteine, and arsenic metabolism in Bangladeshi adults. Water arsenic, urinary arsenic, urinary creatinine, plasma folate, cobalamin, and homocysteine were assessed in 1,650 adults; urinary arsenic metabolites were analyzed for a subset of 300 individuals. The percentage of DMA in urine was positively associated with plasma folate (r = 0.14, p = 0.02) and negatively associated with total homocysteine (tHcys; r = -0.14, p = 0.01). Conversely, percent MMA was negatively associated with folate (r = -0.12, p = 0.04) and positively associated with tHcys (r = 0.21, p = 0.0002); percent inorganic arsenic (InAs) was negatively associated with folate (r = -0.12, p = 0.03). Urinary creatinine was positively correlated with percent DMA (r = 0.40 for males, p < 0.0001; 0.25 for females, p = 0.001), and with percent InAs (r = -0.45 for males, p < 0.0001; -0.20 for females, p = 0.01). Collectively, these data suggest that folate, tHcys, and other factors involved in one-carbon metabolism influence arsenic methylation. This may be particularly relevant in Bangladesh, where the prevalence of hyperhomocysteinemia is extremely high.


Figure 1
Figure 1
Arsenic metabolic pathway. Arsenate is reduced to arsenite in a reaction thought to be dependent on GSH or other endogenous reductants. Abbreviations: GSH, glutathione; GSSG, glutathione disulfide; GST, glutathione-S-transferase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; TR, thioredoxin reductase. Arsenite then undergoes an oxidative methylation, with SAM as the methyl donor, forming MMAV and SAH. MMAV is reduced to MMAIII before a subsequent oxidative methylation step yielding DMAV and SAH. Little is known regarding in vivo reduction of DMAV to DMAIII. Enzymes capable of catalyzing the illustrated reactions include Cyt19 (Lin et al. 2002), arsenite methyltransferase and methy-larsonite methyltransferase (two activities of one enzyme) (Zakharyan et al. 1995), and MMAV reductase (also known as GST-Ω) (Zakharyan et al. 2001).
Figure 2
Figure 2
Overview of one-carbon metabolism. 1. Dietary folates are reduced to dihydrofolate (DHF) and tetrahydrofolate (THF) by dihydrofolate reductase. 2. The β-carbon of serine is transferred to THF by serine hydroxymethyltransferase, forming 5,10-methenyl-THF and glycine. 3. At a major branch point between transmethylation reactions and nucleotide biosynthesis, 5,10-methenyl-THF can be reduced to 5,10-methylene-THF and further reduced to 5-methyl-THF by 5,10-methylene-THF reductase. 4. In a reaction catalyzed by the vitamin B12-containing enzyme, methionine synthetase, the methyl group of 5-methyl-THF is transferred to homocysteine, generating methionine and regenerating THF. 5. Methionine adenosyl-transferase activates methionine to form S-adenosylmethionine (SAM). 6. SAM serves as a universal methyl donor for numerous acceptors, including predominantly guanidinoacetate (GAA), but also DNA, arsenic, and others, in reactions that involve a number of methyltransferases. 7. The by-product of these methylation reactions, S-adenosylhomocysteine (SAH), is hydrolyzed to generate homocysteine. SAH is a potent inhibitor of most SAM-dependent methylations. 8. Homocysteine is either used to regenerate methionine or is directed to the transsulfuration pathway through which it is ultimately catabolized. 9. The transsulfuration pathway is also responsible for glutathione (GSH) biosynthesis.
Figure 3
Figure 3
Frequency distribution for As metabolites. Interindividual variability across 300 participants for arsenic metabolites in urine.

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