Individual variations in inorganic arsenic metabolism associated with AS3MT genetic polymorphisms

Abstract

Individual variations in inorganic arsenic metabolism may influence the toxic effects. Arsenic (+3 oxidation state) methyltransferase (AS3MT) that can catalyze the transfer of a methyl group from S-adenosyl-l-methionine (AdoMet) to trivalent arsenical, may play a role in arsenic metabolism in humans. Since the genetic polymorphisms of AS3MT gene may be associated with the susceptibility to inorganic arsenic toxicity, relationships of several single nucleotide polymorphisms (SNPs) in AS3MT with inorganic arsenic metabolism have been investigated. Here, we summarize our recent findings and other previous studies on the inorganic arsenic metabolism and AS3MT genetic polymorphisms in humans. Results of genotype dependent differences in arsenic metabolism for most of SNPs in AS3MT were Inconsistent throughout the studies. Nevertheless, two SNPs, AS3MT 12390 (rs3740393) and 14458 (rs11191439) were consistently related to arsenic methylation regardless of the populations examined for the analysis. Thus, these SNPs may be useful indicators to predict the arsenic metabolism via methylation pathways.

Keywords: AS3MT; arsenic; genetic polymorphism.

Figure 1.

Proposed pathways of inorganic arsenic metabolism by oxidative and reductive methylation.

Figure 2.

Location of genetic polymorphisms in AS3MT. Dark blue rectangles represent exons. Chromosome positions are also indicated. Arrows show the locations of genetic polymorphisms.

Figure 3.

Frequencies of alleles in AS3MT in various populations reported in our studies [20,65] and the HapMap Project [31]. JP: Japanese, JPT (J): Japanese in Tokyo, Japan, SKR: South Koreans, CH: Chinese, CHB (H): Han Chinese in Beijing, China, CHD (D): Chinese in Metropolitan Denver, Colorado, MN: Mongolians, TIB: Tibetans, NP: Nepalese, VN: Vietnamese, SLT: Sri Lanka-Tamils, SLS: Sri Lanka-Sinhalese, OVA: Ovambos, GH: Ghanaians, LWK (L): Luhya in Webuye, Kenya, MKK (K): Maasai in Kinyawa, Kenya, YRI (Y): Yoruban in Ibadan, Nigeria, ASW (A): African ancestry in Southwest USA, TSI (T): Tuscan in Italy, CEU (C): Utah residents with Northern and Western European ancestry from the CEPH collection, GIH (G): Gujarati Indians in Houston, Texas, MEX (M): Mexican ancestry in Los Angeles, California. 1; Fujihara et al. [65], 2; Agusa et al. [20], 3; HapMap Project [31].

Figure 4.

Suspected universal AS3MT genotype-dependent methylation of arsenic. C carrier of AS3MT 14458 (rs11191439) may have higher first methylation capacity than the T carrier, while C carrier of AS3MT 12390 (rs3740393) may have higher second methylation capacity than the G carrier.