Metabolism Of Inorganic Arsenic Research Articles

Analysis of Relationships between Metabolic Changes and Selected Nutrient Intake in Women Environmentally Exposed to Arsenic.

Nutrients involved in the metabolism of inorganic arsenic (iAs) may play a crucial role in mitigating the adverse health effects associated with such exposure. Consequently, the objective of this study was to analyze the association between the intake levels of nutrients involved in iAs metabolism and alterations in the metabolic profile during arsenic exposure. The study cohort comprised environmentally exposed women: WL (lower total urinary arsenic (As), n = 73) and WH (higher As, n = 73). The analysis included urinary untargeted metabolomics (conducted via liquid chromatography-mass spectrometry) and the assessment of nutrient intake involved in iAs metabolism, specifically methionine, vitamins B2, B6, and B12, folate, and zinc (based on 3-day dietary records of food and beverages). In the WL group, the intake of all analyzed nutrients exhibited a negative correlation with 5 metabolites (argininosuccinic acid, 5-hydroxy-L-tryptophan, 11-trans-LTE4, mevalonic acid, aminoadipic acid), while in the WH group, it correlated with 10 metabolites (5-hydroxy-L-tryptophan, dihyroxy-1H-indole glucuronide I, 11-trans-LTE4, isovalerylglucuronide, 18-oxocortisol, 3-hydroxydecanedioic acid, S-3-oxodecanoyl cysteamine, L-arginine, p-cresol glucuronide, thromboxane B2). Furthermore, nutrient intake demonstrated a positive association with 3 metabolites in the WL group (inosine, deoxyuridine, glutamine) and the WH group (inosine, N-acetyl-L-aspartic acid, tetrahydrodeoxycorticosterone). Altering the intake of nutrients involved in iAs metabolism could be a pivotal factor in reducing the negative impact of arsenic exposure on the human body. This study underscores the significance of maintaining adequate nutrient intake, particularly in populations exposed to arsenic.

The research progress of metabolism and occupational biological exposure index metabolism of inorganic arsenic and its compounds

Arsenic is a common metal-like element. Drinking arsenic-containing water and occupational exposure to arsenic are the main ways exposure to arsenic for population. Long-term exposure to arsenic can cause various organs dysfunction and cancer. After entering the body, inorganic arsenic is mainly methylated into monomethyl arsenic and dimethyl arsenic in the liver. Only a small part of inorganic arsenic is metabolized in the kidneys and lungs, and finally the metabolites of arsenic are excreted in the urine. understanding the biological characteristics of arsenic absorption, metabolism, and distribution in the body and formulating biological indicators related to occupational exposure to arsenic and can provide a scientific basis for the prevention and treatment of arsenic-related diseases. This article will review the biological monitoring indicators of occupational exposure to arsenic and the metabolic process of arsenic in the body.

Urinary biomarkers of inorganic arsenic exposure, inorganic arsenic metabolism, and birth weight in Tacna, Peru, 2019

Urinary biomarkers of inorganic arsenic exposure, inorganic arsenic metabolism, and birth weight in Tacna, Peru, 2019

Arsenic Biotransformation: It is a complex process

Arsenic Biotransformation: It is a complex process

Joint effects of genomic markers and urinary methylation capacity associated with inorganic arsenic metabolism on the occurrence of cancers among residents in arseniasis-endemic areas: A cohort subset with average fifteen-year follow-up

BackgroundChronic exposure to inorganic arsenic results in many cancers in susceptible persons. The metabolism of inorganic arsenic and genomic susceptibility are thought to be associated with cancer occurrence. MethodsThis study aims to examine the interaction of genomic susceptibility markers and urinary methylation capacity indicators involved in inorganic arsenic metabolism with all-cancer occurrence. This study conducted a follow-up on 96 residents to determine their urinary inorganic arsenic metabolites and genomic assay from an arseniasis area. Among them, 24 cancer developed. Multivariable Cox proportional hazards model was used to determine and estimate the candidate independent variables for cancer development. ResultsThe residents with high inorganic arsenic exposure, high primary methylation index (PMI; MMA/InAs) (but lower secondary methylation index (SMI)), and non-heterogeneity type of genomic markers, including GSTO1, AS3MT, and MPO, tend to develop cancers. Subjects with higher PMI are at higher risk of developing cancers (HR = 1.66; 95% CI = 1.30–2.12). Cancer occurrence was greater among the CC type of GSTO1 (HR = 3.33; 95% CI = 1.11–10.00), CC type of AS3MT (HR = 19.21; 95% CI = 1.16–318.80), and AA type of MPO (HR = 13.40; 95% CI = 1.26–142.40). After adjusting confounders, a mutually moderating effect was revealed between genomic markers and methylation capacity on cancer occurrence. ConclusionsThis study found the hypermethylation responses to inorganic arsenic exposure and an array of genomic markers may increase the susceptibility of a wide range of organ cancers. The findings indicated a high-risk arsenic-exposed population to develop cancers. The phenotype of arsenic metabolism and genomic polymorphism suggested a potential preventive strategy for arsenic carcinogenesis.

Metabolism of Inorganic Arsenic in Mice Lacking Genes Encoding GST-P, GST-M, and GST-T.

To investigate the role of glutathione transferases (GSTs) in the metabolism of inorganic arsenic (iAs), we compared the disposition of iAs and its metabolites in wild-type mice and mice lacking genes encoding GST-P, -M and -T after exposure to 100 ppb iAs in drinking water. We found no differences between the two genotypes in the concentrations of total arsenic or arsenic species in urine, liver, and kidneys. No genotype-dependent differences were found in proportions of arsenicals in the tissues, and only small differences were observed in the urine. Thus, under these conditions, GST-P, -M and -T did not play a significant role in iAs metabolism in mice.

Differential metabolism of inorganic arsenic in mice from genetically diverse Collaborative Cross strains.

Mice have been frequently used to study the adverse effects of inorganic arsenic (iAs) exposure in laboratory settings. Like humans, mice metabolize iAs to monomethyl-As (MAs) and dimethyl-As (DMAs) metabolites. However, mice metabolize iAs more efficiently than humans, which may explain why some of the effects of iAs reported in humans have been difficult to reproduce in mice. In the present study, we searched for mouse strains in which iAs metabolism resembles that in humans. We examined iAs metabolism in male mice from 12 genetically diverse Collaborative Cross (CC) strains that were exposed to arsenite in drinking water (0.1 or 50ppm) for 2weeks. Concentrations of iAs and its metabolites were measured in urine and livers. Significant differences in total As concentration and in proportions of total As represented by iAs, MAs, and DMAs were observed between the strains. These differences were more pronounced in livers, particularly in mice exposed to 50ppm iAs. In livers, large variations among the strains were found in percentage of iAs (15-48%), MAs (11-29%), and DMAs (29-66%). In contrast, DMAs represented 96-99% of total As in urine in all strains regardless of exposure. Notably, the percentages of As species in urine did not correlate with total As concentration in liver, suggesting that the urinary profiles were not representative of the internal exposure. In livers of mice exposed to 50ppm, but not to 0.1ppm iAs, As3mt expression correlated with percent of iAs and DMAs. No correlations were found between As3mt expression and the proportions of As species in urine regardless of exposure level. Although we did not find yet a CC strain in which proportions of As species in urine would match those reported in humans (typically 10-30% iAs, 10-20% MAs, 60-70% DMAs), CC strains characterized by low %DMAs in livers after exposure to 50ppm iAs (suggesting inefficient iAs methylation) could be better models for studies aiming to reproduce effects of iAs described in humans.

Mendelian randomization of inorganic arsenic metabolism as a risk factor for hypertension- and diabetes-related traits among adults in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort.

Hypertension and diabetes have been associated with inefficient arsenic metabolism, primarily through studies undertaken in populations exposed through drinking water. Recently, rice has been recognized as a source of arsenic exposure, but it remains unclear whether populations with high rice consumption but no known water exposure are at risk for the health problems associated with inefficient arsenic metabolism. The relationships between arsenic metabolism efficiency (% inorganic arsenic, % monomethylarsenate and % dimethylarsinate in urine) and three hypertension- and seven diabetes-related traits were estimated among 12609 participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). A two-sample Mendelian randomization approach incorporated genotype-arsenic metabolism relationships from literature, and genotype-trait relationships from HCHS/SOL, with a mixed-effect linear model. Analyses were stratified by rice consumption and smoking. Among never smokers with high rice consumption, each percentage point increase in was associated with increases of 1.96 mmHg systolic blood pressure (P = 0.034) and 1.85 mmHg inorganic arsenic diastolic blood pressure (P = 0.003). Monomethylarsenate was associated with increased systolic (1.64 mmHg/percentage point increase; P = 0.021) and diastolic (1.33 mmHg/percentage point increase; P = 0.005) blood pressure. Dimethylarsinate, a marker of efficient metabolism, was associated with lower systolic (-0.92 mmHg/percentage point increase; P = 0.025) and diastolic (-0.79 mmHg/percentage point increase; P = 0.004) blood pressure. Among low rice consumers and ever smokers, the results were consistent with no association. Evidence for a relationship with diabetes was equivocal. Less efficient arsenic metabolism was associated with increased blood pressure among never smokers with high rice consumption, suggesting that arsenic exposure through rice may contribute to high blood pressure in the Hispanic/Latino community.

Mendelian randomization of inorganic arsenic metabolism as a risk factor for hypertension- And diabetes-related traits among adults in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort

Mendelian randomization of inorganic arsenic metabolism as a risk factor for hypertension- And diabetes-related traits among adults in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort

Identification of Methylated Dithioarsenicals in the Urine of Rats Fed with Sodium Arsenite.

Biotransformation of inorganic arsenic results in the formation of methylarsenicals of both oxygen and sulfur analogues. Aiming to improve our understanding of metabolism of inorganic arsenic in animals, we conducted an animal feeding study with an emphasis on identifying new arsenic metabolites. Female F344 rats were given 0, 1, 10, 25, 50, and 100 μg/g of arsenite (iAs(III)) in the diet. Arsenic species in rat urine were determined using high performance liquid chromatography (HPLC) separation and inductive coupled plasma mass spectrometry (ICPMS) and electrospray ionization tandem mass spectrometry (ESI MS/MS) detection. Nine arsenic species were detected in the urine of the iAs(III)-dosed rats. Seven of these arsenic species were consistent with previous reports, including iAs(III), arsenate, monomethyarsonic acid, dimethylarsinic acid, trimethylarsine oxide, monomethylmonothioarsonic acid, and dimethylmonothioarsinic acid. Two new methyldithioarsencals, monomethyldithioarsonic acid (MMDTA(V)) and dimethyldithioarsinic acid (DMDTA(V)), were identified for the first time in the urine of rats treated with iAs(III). The concentrations of both MMDTA(V) and DMDTA(V) in rat urine were dependent on the dosage of iAs(III) in diet. The concentration of DMDTA(V) was approximately 5 times higher than that of MMDTA(V). MMDTA(V) has not been identified in any biological samples of animals, and DMDTA(V) has not been reported as a metabolite of inorganic arsenic in the rats. The identification of novel methylated dithioarsenicals as metabolites of inorganic arsenic in the rat urine provided further insights into the understanding of the metabolism of arsenic.

Association of Cardiometabolic Genes with Arsenic Metabolism Biomarkers in American Indian Communities: The Strong Heart Family Study (SHFS).

Background:Metabolism of inorganic arsenic (iAs) is subject to inter-individual variability, which is explained partly by genetic determinants.Objectives:We investigated the association of genetic variants with arsenic species and principal components of arsenic species in the Strong Heart Family Study (SHFS).Methods:We examined variants previously associated with cardiometabolic traits (~ 200,000 from Illumina Cardio MetaboChip) or arsenic metabolism and toxicity (670) among 2,428 American Indian participants in the SHFS. Urine arsenic species were measured by high performance liquid chromatography–inductively coupled plasma mass spectrometry (HPLC-ICP-MS), and percent arsenic species [iAs, monomethylarsonate (MMA), and dimethylarsinate (DMA), divided by their sum × 100] were logit transformed. We created two orthogonal principal components that summarized iAs, MMA, and DMA and were also phenotypes for genetic analyses. Linear regression was performed for each phenotype, dependent on allele dosage of the variant. Models accounted for familial relatedness and were adjusted for age, sex, total arsenic levels, and population stratification. Single nucleotide polymorphism (SNP) associations were stratified by study site and were meta-analyzed. Bonferroni correction was used to account for multiple testing.Results:Variants at 10q24 were statistically significant for all percent arsenic species and principal components of arsenic species. The index SNP for iAs%, MMA%, and DMA% (rs12768205) and for the principal components (rs3740394, rs3740393) were located near AS3MT, whose gene product catalyzes methylation of iAs to MMA and DMA. Among the candidate arsenic variant associations, functional SNPs in AS3MT and 10q24 were most significant (p < 9.33 × 10–5).Conclusions:This hypothesis-driven association study supports the role of common variants in arsenic metabolism, particularly AS3MT and 10q24.Citation:Balakrishnan P, Vaidya D, Franceschini N, Voruganti VS, Gribble MO, Haack K, Laston S, Umans JG, Francesconi KA, Goessler W, North KE, Lee E, Yracheta J, Best LG, MacCluer JW, Kent J Jr., Cole SA, Navas-Acien A. 2017. Association of cardiometabolic genes with arsenic metabolism biomarkers in American Indian communities: the Strong Heart Family Study (SHFS). Environ Health Perspect 125:15–22; http://dx.doi.org/10.1289/EHP251

Analysis of maternal polymorphisms in arsenic (+3 oxidation state)-methyltransferase AS3MT and fetal sex in relation to arsenic metabolism and infant birth outcomes: Implications for risk analysis.

Arsenic (+3 oxidation state) methyltransferase (AS3MT) is the key enzyme in the metabolism of inorganic arsenic (iAs). Polymorphisms of AS3MT influence adverse health effects in adults, but little is known about their role in iAs metabolism in pregnant women and infants. The relationships between seven single nucleotide polymorphisms (SNPs) in AS3MT and urinary concentrations of iAs and its methylated metabolites were assessed in mother-infant pairs of the Biomarkers of Exposure to ARsenic (BEAR) cohort. Maternal alleles for five of the seven SNPs (rs7085104, rs3740400, rs3740393, rs3740390, and rs1046778) were associated with urinary concentrations of iAs metabolites, and alleles for one SNP (rs3740393) were associated with birth outcomes/measures. These associations were strongly dependent upon the male sex of the fetus but independent of fetal genotype for AS3MT. These data highlight a potential sex-dependence of the relationships among maternal genotype, iAs metabolism and infant health outcomes.

983: Hypermethylation biomarkers associated with inorganic arsenic metabolism are predictors to the occurrence of internal organ cancers among arseniasis residents

983: Hypermethylation biomarkers associated with inorganic arsenic metabolism are predictors to the occurrence of internal organ cancers among arseniasis residents

A pilot study: The importance of inter-individual differences in inorganic arsenic metabolism for birth weight outcome

Inorganic arsenic (iAs) exposure is detrimental to birth outcome. We lack information regarding the potential for iAs metabolism to affect fetal growth. Our pilot study evaluated postpartum Romanian women with known birth weight outcome for differences in iAs metabolism. Subjects were chronically exposed to low-to-moderate drinking water iAs. We analyzed well water, arsenic metabolites in urine, and toenail arsenic. Urine iAs and metabolites, toenail iAs, and secondary methylation efficiency increased as an effect of exposure (p<0.001). Urine iAs and metabolites showed a significant interaction effect between exposure and birth weight. Moderately exposed women with low compared to normal birth weight outcome had greater metabolite excretion (p<0.03); 67% with low compared to 10% with normal birth weight outcome presented urine iAs >9μg/L (p=0.019). Metabolic partitioning of iAs toward excretion may impair fetal growth. Prospective studies on iAs excretion before and during pregnancy may provide a biomarker for poor fetal growth risk.

Metabolism of Inorganic Arsenic in Intestinal Epithelial Cell Lines

This study evaluates the metabolism of inorganic arsenic (iAs) [As(III) and As(V)] in human intestinal cells as a function of cell type, differentiation stage, type of support used for cell growth, and exposure time. Additionally, mRNA expression of arsenic (+3 oxidation state) methyltransferase (AS3MT) was evaluated. For this purpose, Caco-2 (absorptive type) and HT29-MTX (goblet type) cells were exposed at various stages of differentiation (5, 15, and 21 days post-seeding) with different concentrations of As(III) and As(V) (1 and 10 μM) and exposure times (24, 48, and 72 h), using multiwell plates or Transwells. The results show that both cell lines express AS3MT at all stages of differentiation and in all culture conditions. Caco-2 cells are capable of metabolizing iAs, As(III) metabolism being greater than that observed for As(V). Metabolism depends on the stage of differentiation, reaching 36% after 48 h of exposure of differentiated cells (15 days post-seeding), with the monomethylated species as the major metabolite. Analysis of the cell interior shows that the metabolites are present predominantly in trivalent form. The type of support is also an important factor, metabolism being greater in multiwell plates than in Transwells (36 ± 6% vs 11 ± 3%). Neither monomethylated arsenic species (MMA) nor dimethylated arsenic species (DMA) are detected in HT29-MTX cells after exposure to iAs, possibly because most of the iAs is retained in the mucus layer and does not internalize. These results show that the intestine is an organ that may take part in presystemic metabolism of iAs. Moreover, the transformation of iAs into more toxic species indicates the need to study the effects of this species on the intestinal epithelium.

Effect of sodium arsenite on the expression of GSTM1, GSTT1 and GSTO2

Epidemiological studies have shown that arsenic exposure is associated with several diseases including cancers. Since glutathione S-transferases (GSTs) are involved in the metabolism of inorganic arsenic, the aim of the present study was to demonstrate the expression level of GSTM1 (a member of GST class mu), GSTT1 (a member of GST class theta) and GSTO2 (a member of GST class omega) genes in HeLa cell line in response to sodium arsenite. In order to determine whether the GSTM1, GSTT1 and GSTO2 mRNA are transcriptionally regulated by sodium arsenite, HeLa cells were treated at a final concentration 2 μM sodium arsenite for 24 h. The expression level of GSTM1, GSTT1 and GSTO2 was determined using quantitative real-time PCR. The results demonstrated that sodium arsenite did not change the expression level of these GST metabolising enzymes.

Relationship of Creatinine and Nutrition with Arsenic Metabolism: Smith et al. Respond

We thank Hall and Gamble for their interest in our findings. In our article (Basu et al. 2011), we cited their earlier results concerning urinary dimethylarsinic acid (DMA) and creatinine concentrations, noting that in 2005 they reported a strong correlation between urinary creatinine and the percentage of DMA (DMA%) (Gamble et al. 2005). We also noted rather similar findings from another group working in Bangladesh (Nermell et al. 2008), so together with our findings in India, there are three separate studies that have reported this association (Basu et al. 2011; Gamble et al 2005; Nermell et al 2008). Our results highlight the strength of the relationship between urinary creatinine and urinary DMA%, which was stronger than the relationship between DMA% and any of the 19 dietary factors and 16 blood micronutrients that we investigated. Gamble and Hall state that they had previously reported (Gamble and Liu 2005) that one implication of the observed association between urinary creatinine and arsenic methylation was that urinary As should not be expressed as per gram creatinine to correct for urine concentrations. This is not quite what they said, although they did point out risks in expressing urinary arsenic per gram of creatinine. However, in that letter (Gamble and Liu 2005) and again in this one, they state that urinary creatinine should be included as a covariate in regression models. We do not agree with this recommendation. Steinmaus et al. (2009) reported a spurious relationship between low-level arsenic concentrations and diabetes in the United States after including urinary creatinine in a regression model. They noted that urinary creatinine concentrations may change as a consequence of diabetes, which is known to affect renal function, and that it is not appropriate to adjust for a factor that is a consequence of the disease being studied. We also do not agree with Gamble and Hall’s criticism of our blood sample handling, which they appear to have raised because our folate findings were different from theirs (e.g., Gamble et al. 2005). For our study (Basu et al. 2011), blood samples were collected in remote villages, and on occasion they had to be stored on ice for up to 24 hr. Gamble and Hall state that “this 24-hr delay can be problematic for some nutrients, especially folate, which is extremely sensitive to oxidative degradation.” In support of this statement they cite Drammeh et al. (2008), who found reductions in serum folate concentrations (about 30%) from whole blood stored for 1 day at 32°C. However, storing blood samples on ice at about 0°C is not the same as storing at 32°C, so this result is not relevant. In addition, Drammeh et al. cited a study that reported stable plasma folate levels during storage of up to 7 days at 4°C (Kubasik et al. 1979). We therefore do not think our findings should be criticized based on sample storage. However, this does not mean we suggest that folate is not related to DMA%. Findings may vary from study to study, and we accept that Gamble et al. have reported several studies suggesting that folate is associated with small increases in arsenic methylation, including a randomized trial with folate supplements (Gamble et al. 2006). In a study of pregnant women in Bangladesh, a small association between folate and arsenic methylation was reported (Gardner et al. 2011; Li et al. 2008); the authors concluded that nutritional status has a marginal influence on the metabolism of arsenic in pregnant women. Although the overall evidence suggests that folate may increase arsenic methylation, the magnitude of the effect is small and in our opinion of little consequence. In their letter Gamble et al. report they are now conducting a randomized trial with creatine. Well-run randomized trials of nutritional supplements with sufficient statistical power typically require a large amount of public health funds and resources. We suggest that randomized trials should be conducted only on people whose exposure to arsenic has ceased. However, it is clear that exposures did not cease in the randomized trial of folate they conducted, but that exposures remained markedly elevated based on urine arsenic concentrations (Gamble et al. 2006). The purpose of a randomized trial of folate or creatine is to determine whether these agents might affect arsenic methylation to help reduce arsenic toxicity and increase excretion. However, the relevance of this goal is questionable because we already know the best and most appropriate way to reduce arsenic toxicity—by reducing exposure. The first priority should be to stop exposure to arsenic. If exposure to arsenic ceased, there would be very little arsenic to methylate and enhancement of methylation with supplements would not be necessary.

Individual Variations in Inorganic Arsenic Metabolism Associated with AS3MT Genetic Polymorphisms

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.

Interspecies differences in metabolism of arsenic by cultured primary hepatocytes

Biomethylation is the major pathway for the metabolism of inorganic arsenic (iAs) in many mammalian species, including the human. However, significant interspecies differences have been reported in the rate of in vivo metabolism of iAs and in yields of iAs metabolites found in urine. Liver is considered the primary site for the methylation of iAs and arsenic (+3 oxidation state) methyltransferase (As3mt) is the key enzyme in this pathway. Thus, the As3mt-catalyzed methylation of iAs in the liver determines in part the rate and the pattern of iAs metabolism in various species. We examined kinetics and concentration–response patterns for iAs methylation by cultured primary hepatocytes derived from human, rat, mice, dog, rabbit, and rhesus monkey. Hepatocytes were exposed to [ 73As]arsenite (iAs III; 0.3, 0.9, 3.0, 9.0 or 30 nmol As/mg protein) for 24 h and radiolabeled metabolites were analyzed in cells and culture media. Hepatocytes from all six species methylated iAs III to methylarsenic (MAs) and dimethylarsenic (DMAs). Notably, dog, rat and monkey hepatocytes were considerably more efficient methylators of iAs III than mouse, rabbit or human hepatocytes. The low efficiency of mouse, rabbit and human hepatocytes to methylate iAs III was associated with inhibition of DMAs production by moderate concentrations of iAs III and with retention of iAs and MAs in cells. No significant correlations were found between the rate of iAs methylation and the thioredoxin reductase activity or glutathione concentration, two factors that modulate the activity of recombinant As3mt. No associations between the rates of iAs methylation and As3mt protein structures were found for the six species examined. Immunoblot analyses indicate that the superior arsenic methylation capacities of dog, rat and monkey hepatocytes examined in this study may be associated with a higher As3mt expression. However, factors other than As3mt expression may also contribute to the interspecies differences in the hepatocyte capacity to methylate iAs.

Metabolism of arsenic in human liver: the role of membrane transporters

Metabolism of inorganic arsenic (iAs) is one of the key factors determining the character of adverse effects associated with exposure to iAs. Results of previous studies indicate that liver plays a primary role in iAs metabolism. This paper reviews these results and presents new data that link the capacity of human hepatocytes to metabolize iAs to the expression of specific membrane transporters. Here, we examined relationship between the expression of potential arsenic transporters (AQP9, GLUT2, P-gp, MRP1, MRP2, and MRP3) and the production and cellular retention of iAs and its methylated metabolites in primary cultures of human hepatocytes exposed for 24 h to subtoxic concentrations of arsenite. Our results show that the retention of iAs and methylarsenic metabolites (MAs) by hepatocytes exposed to sub-micromolar concentrations of arsenite correlates negatively with MRP2 expression. A positive correlation was found between MRP2 expression and the production of dimethylarsenic metabolites (DMAs), specifically, the concentration of DMAs in culture media. After exposures to high micromolar concentrations of arsenite which almost completely inhibited MAs and DMAs production, a positive correlation was found between the expression of GLUT2 and cellular retention of iAs and MAs. MRP3, AQP9, or P-gp expression had no effect on the production or distribution of iAs, MAs, or DMAs, regardless of the exposure level. Hepatocytes from seven donors used in this study did not contain detectable amounts of MRP1 protein. These data suggest that MRP2 plays an important role in the efflux of DMAs, thus, regulating kinetics of the methylation reactions and accumulation of iAs and MAs by human hepatocytes. The membrane transport of iAs by high-capacity GLUT2 transporters is not a rate-limiting step for the metabolism of arsenite at low exposure level, but may play a key role in accumulation of iAs after acute exposures which inhibit iAs methylation.