Genetic polymorphism of As3MT and delayed urinary DMA excretion after organic arsenic intake from oyster ingestion

Abstract

Organic arsenic intake from seafood is one of the major arsenic exposure routes among the general population. However, organic arsenic metabolism in the human body is not yet clear. The goal of this study was to explore the effects of genetic polymorphisms of human PNP, As3MT and GSTO1 on organic arsenic metabolism among study subjects after oyster ingestion. During the one-week dietary controlled study, fifty study subjects were provided all their daily meals without seafood, except for two designated amounts of oyster given on the fourth day. First morning voided urine samples were provided by the study subjects for 7 consecutive days and analyzed with HPLC-ICP-MS for As(3+), As(5+), monomethylarsonic acid, and dimethylarsinic acid (DMA). Blood samples were collected later for genetic polymorphisms analysis of PNP, As3MT and GSTO1. Study subjects were categorized into "fast-" (n = 32), "medium-" (n = 13) and "slow-metabolizing" (n = 5) groups based on the number of days after ingestion needed for each subject's urinary DMA level reaching peak. Allele frequencies of single nucleotide polymorphisms (SNP) in intron 6 (G/C, p = 0.024) and in intron 10 (T/C, p = 0.039) of As3MT were significantly associated with the urinary DMA excretion. General estimating equation model analysis indicated that the variants of SNP (G>C) in intron 6 and SNP (T > C) in intron 10 of As3MT were respectively associated with higher or lower urinary DMA level by approximately 9 microg L(-1). As3MT was suggested to be one of the major factors affecting the metabolism of dietary organic arsenic in terms of urinary DMA level.

Methylation of arsenic by recombinant human wild-type arsenic (+ 3 oxidation state) methyltransferase and its methionine 287 threonine (M287T) polymorph: Role of glutathione

“…This change arises from a single nucleotide C14458T polymorphism (rs11191439) in the coding region of AS3MT (NM_020682.3: c.860T>C) and occurs in ~10% of Caucasian, African American and Latino populations (Del Razo, et al, 2011; Wood et al, 2006). Individuals with wtAS3MT and AS3MT/M287T genotypes display different urinary profiles of methylated metabolites of iAs, including changes in the DMAs/MAs ratio (Agusa et al, 2009; Chung et al, 2009; Engström et al, 2007, 2011; Fujihara et al, 2009; Hernández et al, 2008a,b; Hwang et al, 2010; Valenzuela et al, 2009), suggesting that AS3MT genotype and As methylation phenotype can be linked. Therefore, we have compared the kinetics of As methylation in reactions catalyzed by recombinant wtAS3MT and AS3MT/M287T using physiological and synthetic reductants and examined the role of GSH as a modulator of catalytic activities of wtAS3MT and AS3MT/M287T.…”

Arsenic in the human food chain, biotransformation and toxicology – Review focusing on seafood arsenic

“…The participants excreted far more DMA than that could have been produced from ingested iAs from the seafood. The enzyme As3MT has also been found to play a major role in the metabolism of organoarsenicals from seafood (oysters) in terms of the urinary DMA excretion [94] following seafood intake, indicating that this enzyme not only takes part in iAs metabolism. It is also possible that the microbiome of the GI-tract can play a role in the (pre-absorptive) metabolism of arsenicals.…”

The relationship between PNP, GSTO-1, AS3MT and ADRB3 gene polymorphisms and urinary arsenic concentration among copper smelter and refinery employers

“…33 A number of factors have been hypothesized to impact As metabolism, including exposed dose, age, gender, race, exposure route, nutritional status, and some environmental circumstances of exposure. 13,34 Taking into account the role of AS3MT, GSTO, and PNP in arsenic biotransformation and metabolism, polymorphisms of genes encoding these enzymes are likely to produce interindividual variations in arsenic metabolism and thus influence susceptibility toward arsenic toxicity, in both in vivo and in vitro studies. 9,12 Glutathione is the most widespread particle with thiol group that can reduce arsenic (5þ) to arsenic (3þ) and create a stable complex.…”

“…However, PNP, GSTO1, and GSTO2 are suggested to be involved in reducing the pentavalent arsenic species, including arsenate (iAs5þ), MMA5þ, and DMA5þ to trivalent arsenicals. [10][11][12][13] Arsenic methylation produces both highly reactive metabolites containing trivalent arsenic (As3þ) and less reactive metabolites containing pentavalent arsenic. 14 Studies on arsenic toxicity yield inconsistent results.…”