AS3MT, GSTO, and PNP polymorphisms: Impact on arsenic methylation and implications for disease susceptibility

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• 作者：Ray Antonelli^a ; ¹ ; Kan Shao^a ; ¹ ; David J. Thomas^b ; Reeder Sams II^c ; John Cowden^c ; ^{cowden.john@epa.gov" class="auth_mail}
• 关键词：iAs&mdash ; inorganic arsenic ; MMA&mdash ; monomethylated arsenic ; DMA&mdash ; dimethylated arsenic ; AS3MT&mdash ; arsenic (+3 oxidation state) methyltransferase ; PNP&mdash ; purine nucleoside phosphorylase ; GSTO&mdash ; glutathione-s-transferase omega ; PMI&mdash ; primary methylation index ; SMI-secondary methylation index
• 刊名：Environmental Research
• 出版年：July 2014
• 年：2014
• 卷：132
• 期：Complete
• 页码：156-167
• 全文大小：738 K

文摘

Oral exposure to inorganic arsenic (iAs) is associated with adverse health effects. Epidemiological studies suggest differences in susceptibility to these health effects, possibly due to genotypic variation. Genetic polymorphisms in iAs metabolism could lead to increased susceptibility by altering urinary iAs metabolite concentrations.

Objective

To examine the impact of genotypic polymorphisms on iAs metabolism.

Methods

We screened 360 publications from PubMed and Web of Science for data on urinary mono- and dimethylated arsenic (MMA and DMA) percentages and polymorphic genes encoding proteins that are hypothesized to play roles in arsenic metabolism. The genes we examined were arsenic (+3) methyltransferase (AS3MT), glutathione-s-transferase omega (GSTO), and purine nucleoside phosphorylase (PNP). Relevant data were pooled to determine which polymorphisms are associated across studies with changes in urinary metabolite concentration.

Results

In our review, AS3MT polymorphisms rs3740390, rs11191439, and rs11191453 were associated with statistically significant changes in percent urinary MMA. Studies of GSTO polymorphisms did not indicate statistically significant associations with methylation, and there are insufficient data on PNP polymorphisms to evaluate their impact on metabolism.

Discussion

Collectively, these data support the hypothesis that AS3MT polymorphisms alter in vivo metabolite concentrations. Preliminary evidence suggests that AS3MT genetic polymorphisms may impact disease susceptibility. GSTO polymorphisms were not associated with iAs-associated health outcomes. Additional data are needed to evaluate the association between PNP polymorphisms and iAs-associated health outcomes. Delineation of these relationships may inform iAs mode(s) of action and the approach for evaluating low-dose health effects for iAs.

Conclusions

Genotype impacts urinary iAs metabolite concentrations and may be a potential mechanism for iAs-related disease susceptibility.