Mendelian randomization analysis of arsenic metabolism and pulmonary function within the Hispanic Community Health Study/Study of Latinos.

Arsenic exposure has been linked to poor pulmonary function, and inefficient arsenic metabolizers may be at increased risk. Dietary rice has recently been identified as a possible substantial route of exposure to arsenic, and it remains unknown whether it can provide a sufficient level of exposure to affect pulmonary function in inefficient metabolizers. Within 12,609 participants of HCHS/SOL, asthma diagnoses and spirometry-based measures of pulmonary function were assessed, and rice consumption was inferred from grain intake via a food frequency questionnaire. After stratifying by smoking history, the relationship between arsenic metabolism efficiency [percentages of inorganic arsenic (%iAs), monomethylarsenate (%MMA), and dimethylarsinate (%DMA) species in urine] and the measures of pulmonary function were estimated in a two-sample Mendelian randomization approach (genotype information from an Illumina HumanOmni2.5-8v1-1 array), focusing on participants with high inferred rice consumption. Among never-smoking high inferred consumers of rice (n = 1395), inefficient metabolism was associated with past asthma diagnosis and forced vital capacity below the lower limit of normal (LLN) (OR 1.40, p = 0.0212 and OR 1.42, p = 0.0072, respectively, for each percentage-point increase in %iAs; OR 1.26, p = 0.0240 and OR 1.24, p = 0.0193 for %MMA; OR 0.87, p = 0.0209 and OR 0.87, p = 0.0123 for the marker of efficient metabolism, %DMA). Among ever-smoking high inferred consumers of rice (n = 1127), inefficient metabolism was associated with peak expiratory flow below LLN (OR 1.54, p = 0.0108/percentage-point increase in %iAs, OR 1.37, p = 0.0097 for %MMA, and OR 0.83, p = 0.0093 for %DMA). Less efficient arsenic metabolism was associated with indicators of pulmonary dysfunction among those with high inferred rice consumption, suggesting that reductions in dietary arsenic could improve respiratory health.

Determination of arsenicals in mouse tissues after simulated exposure to arsenic from rice for sixteen weeks and the effects on histopathological features.

The accumulation of arsenic in rice has become a worldwide concern. In this study, dose-dependency in tissues (intestine, liver and kidney) and blood distribution of inorganic arsenicals and their methylated metabolites were investigated in male C57BL/6 mice exposed to four arsenic species (arsenite [iAs]III, arsenate [iAs]V, monomethylarsonate [MMA]V, and dimethylarsinate [DMA]V) at four doses (control [C]: 0 µg/g, simulation [S]: 0.91 µg/g, medium [M]: 9.1 µg/g and high [H]: 30 µg/g) according to the arsenical composition in rice for 8 and 16 weeks. No adverse effects were observed, while body weight gain decreased in group H. Increases in total arsenic concentrations (CtAs) and histopathological changes in the tissues occurred in all of the test groups. CtAs presented a tendency of kidney > intestine > liver > blood and were time-/dose-dependent in the liver and kidney in groups M and H. In the intestine and blood, abundant iAs (23%-28% in blood and 36%-49% in intestine) was detected in groups M and H, and CtAs decreased in group H from the 8th week to the 16th week. PMI decreased in the liver and SMI decreased in the kidney. These results indicate that the three tissues are injured through food arsenic. The intestine can also accumulate food arsenic, and the high arsenic dose will cause a deficiency in the absorbing function of the intestine. Thus, long-term exposure to arsenic-contaminated rice should be taken seriously attention.

Metabolism and disposition of arsenic species from controlled dosing with dimethylarsinic acid (DMAV) in adult female CD-1 mice. V. Toxicokinetic studies following oral and intravenous administration.

Arsenic species contaminate food and water, with typical dietary intake below 1 µg/kg bw/d. Exposure to arsenic in heavily contaminated drinking water is associated with human diseases, including cardiovascular and respiratory disorders, diabetes, and cancer. Dietary intake assessments show that rice and seafood are the primary contributors to intake of both inorganic arsenic and dimethylarsinic acid (DMAV) and at similar magnitudes. DMAV plays a central role in the toxicology of arsenic because enzymatic methylation of arsenite produces DMAV as the predominant metabolite, which may promote urinary clearance but also generates reactive intermediates, predominantly DMAIII, that bind extensively to cellular thiols. Both inorganic arsenic and DMAV are carcinogenic in chronically exposed rodents. This study measured pentavalent and trivalent arsenic species in blood and tissues after oral and intravenous administration of DMAV (50 µg As/kg bw). DMAV underwent extensive first-pass metabolism in the intestine and liver, exclusively by reduction to DMAIII, which bound extensively to blood and tissues. The results confirm a role for methylation-independent reductive metabolism in producing fluxes of DMAIII that presumably underlie arsenic toxicity and indicate the need to include all dietary intake of inorganic arsenic and DMAV in risk assessments.

Interspecific differences in the bioaccumulation of arsenic of three Patagonian top predator fish: Organ distribution and arsenic speciation.

Interspecific differences in arsenic bioaccumulation and organ distribution (muscle, liver, kidney and gills) in three predator fish (creole perch, rainbow trout and brown trout) from a Patagonian lake impacted by volcanic eruptions were studied. Arsenic in fish organs were compared analyzing: 1) temporal (before and after volcanic eruption) and spatial (near and far from the volcano) influence of Puyehue-Cordón Caulle volcanic complex activity on arsenic concentrations; 2) the influence of growth (as total length), organ type and their interactions over arsenic accumulation; and 3) arsenic speciation and total arsenic relationship with carbon to nitrogen ratios (C:N), as a proxy of lipid presence, in fish muscle. In general, total arsenic concentrations in creole perch organs were 2-7 times higher than those recorded in the corresponding organs of salmonids. Arsenic was preferentially accumulated in liver and kidney in the three fish species. The influence of the volcanic activity over arsenic concentrations was more evident in creole perch: organs from creole perch captured closest to the volcano exhibited higher arsenic concentrations. Temporal variations were not so consistent. No clear relationship between arsenic and fish length was observed. Positive and linear relationship between arsenic in all pair of organs was found in creole perch, while rainbow trout showed a quadratic relationship between muscle and the remaining organs, indicating different arsenic assimilation-elimination relationships between organs and fish. The arsenic liver:muscle ratio in the three fish species was greater than 1, suggesting some level of arsenic stress. Arsenobetaine (AB) and dimethylarsinic acid (DMA) were the dominant arsenic species in muscle of these fish, having creole perch 3-4 times higher AB than rainbow trout. A positive relationship between C:N ratio and total arsenic concentrations was found, with higher C:N in creole perchs near the volcano. In terms of food safety, no inorganic arsenic compound were detected, therefore arsenic levels in fish from Lake Nahuel Huapi does not represent any health risk to consumers.

Dimethylarsenate (DMA) exposure influences germination rates, arsenic uptake and arsenic species formation in wheat.

The contamination of cereals with arsenic (As) is a global health and agronomic concern. This study compared the physiological response, As uptake and As speciation in the grains and above ground tissues of 20 wheat cultivars exposed to 5 mg As kg-1 soil as either arsenate (AsV) or dimethylarsenate (DMA) under glasshouse conditions. Germination rates for the majority of cultivars exceeded 80% for the majority of cultivars when exposed to AsV, but fell significantly to 20-40% when exposed to DMA. For a number of cultivars, grain yields were 20-50% lower when plants were exposed to DMA compared to AsV. Grain As concentrations were between 0.6 and 1.6 µg As g-1 grain across the twenty cultivars when exposed to AsV, whereas grain As concentrations were much higher (2.2-4.6 µg As g-1 grain) when exposed to DMA. When plants were exposed to AsV, 100% of the As present in the grain was found as inorganic As while in plants exposed to DMA, 70-90% of As was present as DMA with the remainder found as inorganic As. DMA is believed to be incorporated by plants via silica (Si) acid channels and assessment of grain Si concentrations demonstrated that up to 40% less Si was accumulated in grains when plants were exposed to DMA. The decreased germination rates and grain yields in the presence of DMA is similar to the symptoms described for straight head disease in rice, which has been linked to DMA exposure. The results presented here indicate some analogous processes occur in wheat to those described in rice. We hypothesise that exposure to DMA may have inhibited Si-metabolism and translocation which resulted in both developmental impairment and possibly an increased susceptibility to soil pathogens.

Determination and pharmacokinetic properties of arsenic speciation in Xiao-Er-Zhi-Bao-Wan by high-performance liquid chromatography with inductively coupled plasma mass spectrometry.

A method of high performance liquid chromatography with a Hamilton PRP-X100 ion-exchange column (250 × 4.1 mm id, 10 µm) coupled to inductively coupled plasma mass spectrometry was employed to generate a full concentration-time profile of arsenic speciation after oral administration. The results exhibited good linearity and revealed that, in the pills, the average arsenic concentration was 10105.4 ± 380.7 mg/kg, and in the water extraction solution, the inorganic As(III) and As(V) concentrations were 220.1 ± 12.6 and 45.5 ± 2.3 mg/kg, respectively. No trace of monomethyl arsenic acid was detected in any of the plasma samples. We then successfully applied the established methodology to examine the pharmacokinetics of arsenic speciation. The resulting data revealed that, after oral administration in rats, the plasma concentration of each arsenic species reached Cmax shortly after initial dosing, and that the distribution and elimination of As(V) was faster than that of As(III) and dimethyl arsenic acid. Additionally, the t1/2 values of As(V), As(III), and dimethyl arsenic acid were 3.4 ± 1.6, 14.3 ± 4.0, and 19.9 ± 1.6 h, respectively. This study provides references for the determination of arsenic speciation in mineral-containing medicines and could serve as a useful tool in measuring the true toxicity in traditional medicines that contain them.

Toxicological and biochemical responses of the earthworm Eisenia fetida exposed to contaminated soil: Effects of arsenic species.

Arsenic is a pollutant that can be detected in different chemical forms in soil. However, the toxicological effects of different arsenic species on organisms have received little attention. In this study, we exposed earthworms Eisenia fetida to artificial soils contaminated by arsenite [As(III)], arsenate [As(V)], monomethylarsonate (MMA) and dimethylarsinate (DMA) for 28 and 56 days. Three biomarkers including lipid peroxidation (LPO), metallothioneins (MTs) and lysosomal membrane stability (LMS) were analyzed in the organisms. In addition, the contents of total arsenic and arsenic species in earthworms were also determined to investigate the effects of bioaccumulation and biotransformation of arsenic on biomarkers and to evaluate the dose-response relationships. The results showed that the relationship between the three biomarkers and the two inorganic arsenic species were dose dependent, and the correlation levels between the biomarkers and As(III) were higher than that between the biomarkers and As(V). Trivalent arsenic species shows more toxicity than pentavalent arsenic on the earthworms at molecular and subcellular level, including oxidative damage, MTs induction and lysosomal membrane damage. The toxicity of MMA and DMA was lower than inorganic arsenic species. However, the occurrence of demethylation of organic arsenics could lead to the generation of highly toxic inorganic arsenics and induce adverse effects on organisms. The biotransformation of highly toxic inorganic arsenics to the less toxic organic species in the earthworms was also validated in this study. The biomarker responses of the earthworm to different arsenic species found in this study could be helpful in future environment monitoring programs.

Identifiability of PBPK models with applications to dimethylarsinic acid exposure.

Any statistical model should be identifiable in order for estimates and tests using it to be meaningful. We consider statistical analysis of physiologically-based pharmacokinetic (PBPK) models in which parameters cannot be estimated precisely from available data, and discuss different types of identifiability that occur in PBPK models and give reasons why they occur. We particularly focus on how the mathematical structure of a PBPK model and lack of appropriate data can lead to statistical models in which it is impossible to estimate at least some parameters precisely. Methods are reviewed which can determine whether a purely linear PBPK model is globally identifiable. We propose a theorem which determines when identifiability at a set of finite and specific values of the mathematical PBPK model (global discete identifiability) implies identifiability of the statistical model. However, we are unable to establish conditions that imply global discrete identifiability, and conclude that the only safe approach to analysis of PBPK models involves Bayesian analysis with truncated priors. Finally, computational issues regarding posterior simulations of PBPK models are discussed. The methodology is very general and can be applied to numerous PBPK models which can be expressed as linear time-invariant systems. A real data set of a PBPK model for exposure to dimethyl arsinic acid (DMA(V)) is presented to illustrate the proposed methodology.

The distribution in tissues and urine of arsenic metabolites after subchronic exposure to dimethylarsinic acid (DMAV) in rats.

Dimethylarsinic acid (DMA(V)) acted as cancer promoter promoted urinary bladder, liver, and lung carcinogenesis in rats. Understanding of the distribution of arsenicals in critical sites will aid to define the action of DMA(V)-induced toxicity and carcinogenicity. The present experiment was conducted to compare the accumulated levels of arsenicals in the liver, kidney, and bladder of both male and female rats after subchronic exposure to DMA(V). After exposure to DMA(V) in drinking water for 10 weeks, urinary DMA concentrations of 100 and 200 ppm DMA(V)-treated rats increased significantly compared with those of the control rats. Smaller amount of trimethylarsinic acid (TMA) was detected in urine, but not in liver, kidney, and bladder muscle. In the liver and kidney, the levels of DMA in DMA(V)-treated rats significantly increased compared with those of the control group, but there was no difference between 100 and 200 ppm DMA(V)-treated rats. DMA did not accumulate in bladder muscle. There was no difference for DMA concentrations between male and female rats. Our results suggest that the accumulation of DMA in the liver and kidney was saturated above 100 ppm DMA(V) treatment concentration, and DMA(V) was a little partly metabolized to TMA, and TMA was rapidly excreted into urine.

Robust model predictive control for optimal continuous drug administration.

In this paper the model predictive control (MPC) technology is used for tackling the optimal drug administration problem. The important advantage of MPC compared to other control technologies is that it explicitly takes into account the constraints of the system. In particular, for drug treatments of living organisms, MPC can guarantee satisfaction of the minimum toxic concentration (MTC) constraints. A whole-body physiologically-based pharmacokinetic (PBPK) model serves as the dynamic prediction model of the system after it is formulated as a discrete-time state-space model. Only plasma measurements are assumed to be measured on-line. The rest of the states (drug concentrations in other organs and tissues) are estimated in real time by designing an artificial observer. The complete system (observer and MPC controller) is able to drive the drug concentration to the desired levels at the organs of interest, while satisfying the imposed constraints, even in the presence of modelling errors, disturbances and noise. A case study on a PBPK model with 7 compartments, constraints on 5 tissues and a variable drug concentration set-point illustrates the efficiency of the methodology in drug dosing control applications. The proposed methodology is also tested in an uncertain setting and proves successful in presence of modelling errors and inaccurate measurements.

In-vivo evaluation of the permeability of the blood-brain barrier to arsenicals, molybdate, and methylmercury by use of online microdialysis-packed minicolumn-inductively coupled plasma mass spectrometry.

To study the permeability of the blood-brain barrier (BBB) to arsenates, arsenite, monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), molybdate, and methylmercury, and the transfer behavior of these species, we constructed an automatic online analytical system comprising a microdialysis sampling device, a minicolumn packed with nonfunctionalized poly(vinyl chloride) beads, and an inductively coupled plasma mass spectrometer for continuous in-vivo measurement of their dynamic variation in the extracellular space of the brains of living rats. By using ion-polymer interactions as a novel working mechanism for sample pretreatment of volume-limited microdialysate, we simplified the operating procedure of conventional solid-phase extraction and reduced the contribution to the blank of the chemicals used. After optimizing this hyphenated system, we measured its performance by analysis of NIST standard reference materials 1640a (trace elements in natural water) and 2672a (trace elements in human urine) and by in-vivo monitoring of the dynamic variation of the compounds tested in the extracellular fluid (ECF) of rat brain. We found that intraperitoneal administration led to observable BBB permeability of arsenates, arsenite, DMA, MMA, and molybdate. Nevertheless, the limited sensitivity of the system and the size of microdialysis samples meant that detection of MeHg in ECF remained problematic, even when we administered a dose of 20 mg MeHg kg(-1) body weight. On the basis of these practical demonstrations, we suggest that our analytical system could be used not only for dynamic monitoring of the transfer kinetics of the four arsenicals and molybdate in the rat brain but also to describe associated neurotoxicity in terms of exposure to toxic metals and their species.

In vitro toxicological characterization of two arsenosugars and their metabolites.

SCOPE: In their recently published Scientific Opinion on Arsenic in Food, the European Food Safety Authority concluded that a risk assessment for arsenosugars is currently not possible, largely because of the lack of relevant toxicological data. To address this issue, we carried out a toxicological in vitro characterization of two arsenosugars and six arsenosugar metabolites. METHODS AND RESULTS: The highly pure synthesized arsenosugars, DMA(V) -sugar-glycerol and DMA(V) -sugar-sulfate, investigated in this study, as well as four metabolites, oxo-dimethylarsenoacetic acid (oxo-DMAA(V) ), oxo-dimethylarsenoethanol (oxo-DMAE(V) ), thio-DMAA(V) and thio-DMAE(V) , exerted neither cytotoxicity nor genotoxicity up to 500 µM exposure in cultured human bladder cells. However, two arsenosugar metabolites, namely dimethyl-arsinic acid (DMA(V) ) and thio-dimethylarsinic acid (thio-DMA(V) ), were toxic to the cells; thio-DMA(V) was even slightly more cytotoxic than arsenite. Additionally, intestinal bioavailability of the arsenosugars was assessed applying the Caco-2 intestinal barrier model. The observed low, but significant transfer rates of the arsenosugars across the barrier model provide further evidence that arsenosugars are intestinally bioavailable. CONCLUSION: In a cellular system that metabolizes arsenosugars, cellular toxicity likely arises. Thus, in strong contrast to arsenobetaine, arsenosugars cannot be categorized as nontoxic for humans and a risk to human health cannot be excluded.

In vitro study of intestinal transport of arsenite, monomethylarsonous acid, and dimethylarsinous acid by Caco-2 cell line.

Arsenic is a pollutant widely distributed in the environment. There are numerous studies on the toxicity of trivalent arsenic forms As(III), MMA(III), and DMA(III), but few data are available on the processes of digestion and absorption of these arsenic species and the mechanisms involved are unknown. The present study evaluated the processes involved in intestinal absorption of trivalent arsenic species, using the Caco-2 cell model as system. The apparent permeability values obtained for As(III) in apical-basolateral direction (4.6±0.3)×10(-6)cm/s, showing moderate intestinal absorption. Transport of MMA(III) [P(app)=(7.0±0.9)×10(-6)cm/s] and DMA(III) [P(app)=(10.6±1.4)×10(-6)cm/s] is greater than that of As(III). The cellular retention of As(III) (0.9-2.4%) was less than that observed for MMA(III) (30%) and DMA(III) (35%). A substantial paracellular component was observed in transport of As(III) and MMA(III), whereas DMA(III) does not use this pathway for its absorption. For all the trivalent species, transport depends on temperature, with an active transcellular component for MMA(III) and DMA(III). Variations in pH do not affect transport of these species. The presence of GSH and green tea extract significantly alters transport of As(III) across Caco-2 cells.

Distribution and metabolism of four different dimethylated arsenicals in hamsters.

Arsenic toxicity and distribution are highly dependent on animal species and its chemical species. Recently, thioarsenical has been recognized in highly toxic arsenic metabolites, which was commonly found in human and animal urine. In the present study, we revealed the mechanism underlying the distribution and metabolism of non-thiolated and thiolated dimethylarsenic compounds such as dimethylarsinic acid (DMA(V)), dimethylarsinous acid (DMA(III)), dimethylmonothioarsinic acid (DMMTA(V)), and dimethyldithioarsinic acid (DMDTA(V)) after the administration of them into femoral vein of hamsters. DMA(V) and DMDTA(V) distributed in organs and body fluids were in their unmodified form, while DMA(III) and DMMTA(V) were bound to proteins and transformed to DMA(V) in organs. On the other hand, DMA(V) and DMDTA(V) were mostly excreted into urine as their intact form 1 h after post-injection, and more than 70% of the doses were recovered in urine as their intact form. By contrast, less than 8-14% of doses were recovered in urine as DMA(V), while more than 60% of doses were distributed in muscles and target organs (liver, kidney, and lung) of hamsters after the injection of DMMTA(V) and DMA(III). However, in red blood cells (RBCs), only a small amount of the arsenicals was distributed (less than 4% of the doses) after the injection of DMA(III) and DMMTA(V), suggesting that the DMA(III) and DMMTA(V) were hardly accumulated in hamster RBCs. Based on these observations, we suggest that although DMMTA(V) and DMDTA(V) are thioarsenicals, DMMTA(V) is taken up efficiently by organs, in a manner different from that of DMDTA(V). In addition, the distribution and metabolism of DMMTA(V) are like in manner similar to DMA(III) in hamsters, while DMDTA(V) is in a manner similar to DMA(V).

Characterization of the intestinal absorption of arsenate, monomethylarsonic acid, and dimethylarsinic acid using the Caco-2 cell line.

Many toxicological studies have been conducted with arsenic species in target organ cell lines. However, although epithelial gastrointestinal cells constitute the first barrier to the absorption of contaminants, studies using intestinal cells are scarce. The present study examines absorption through the intestinal epithelium of the pentavalent arsenic species most commonly found in foods [arsenate, As(V); monomethylarsonic acid, MMA(V); and dimethylarsinic acid, DMA(V)], using the Caco-2 cell line as a model. Different concentrations (1.3-667.6 microM) and culture conditions (media, pH, addition of phosphates, and treatment with ethylenediaminetetraacetic acid) were evaluated to characterize such transport. The apparent permeabilities indicate that the methylated species show low absorption, whereas As(V) is a compound with moderate absorption. The kinetic study shows only a saturable component for MMA(V) transport in the range of concentrations assayed. The existence of paracellular transport was shown for all of the species, with greater significance in the case of the methylated forms. As(V) absorption was inhibited by 10 mM phosphate, and a phosphate transporter therefore could take part in intestinal absorption. Acidification of the medium (pH 5.5) resulted in a marked increase in As(V) and DMA(V) permeability (4-8 times, respectively) but not in MMA(V) permeability. This makes it necessary to consider the possible existence of absorption in the proximal intestine and even in the stomach, where the environment is acidic; alternatively, an H(+)-dependent transporter may be involved. The results obtained constitute the basis for future research on the mechanisms involved in the intestinal absorption of arsenic and its species, a decisive step in relation to their toxic action.

Evidence for toxicity differences between inorganic arsenite and thioarsenicals in human bladder cancer cells.

Arsenic toxicity is dependent on its chemical species. In humans, the bladder is one of the primary target organs for arsenic-induced carcinogenicity. However, little is known about the mechanisms underlying arsenic-induced carcinogenicity, and what arsenic species are responsible for this carcinogenicity. The present study aimed at comparing the toxic effect of DMMTA(V) with that of inorganic arsenite (iAs(III)) on cell viability, uptake efficiency and production of reactive oxygen species (ROS) toward human bladder cancer EJ-1 cells. The results were compared with those of a previous study using human epidermoid carcinoma A431 cells. Although iAs(III) was known to be toxic to most cells, here we show that iAs(III) (LC(50)=112 microM) was much less cytotoxic than DMMTA(V) (LC(50)=16.7 microM) in human bladder EJ-1 cells. Interestingly, pentavalent sulfur-containing DMMTA(V) generated a high level of intracellular ROS in EJ-1 cells. However, this was not observed in the cells exposed to trivalent inorganic iAs(III) at their respective LC(50) dose. Furthermore, the presence of N-acetyl-cysteine completely inhibited the cytotoxicity of DMMTA(V) but not iAs(III), suggesting that production of ROS was the main cause of cell death from exposure to DMMTA(V), but not iAs(III). Because the cellular uptake of iAs(III) is mediated by aquaporin proteins, and because the resistance of cells to arsenite can be influenced by lower arsenic uptake due to lower expression of aquaporin proteins (AQP 3, 7 and 9), the expression of several members of the aquaporin family was also examined. In human bladder EJ-1 cells, mRNA/proteins of AQP3, 7 and 9 were not detected by reverse transcription polymerase chain reaction (RT-PCR)/western blotting. In A431 cells, only mRNA and protein of AQP3 were detected. The large difference in toxicity between the two cell lines could be related to their differences in uptake of arsenic species.

Time course of arsenic species in the brain and liver of mice after oral administration of arsenate.

The understanding of the biomethylation process of arsenic is essential to uncover the mechanisms of arsenic toxicity. This work analyzes the time course of arsenic species in the brain and liver of adult mice, after a single oral administration of three arsenate doses [2.5, 5.0 and 10 mg As(V)/kg]. Quantification of arsenic species was performed by means of liquid chromatography coupled to atomic fluorescence 2, 5, 8, 12 and 24 h after administration. The results show that 2 h after arsenate administration inorganic arsenic arrives to the liver and its concentration diminishes gradually until becoming non-detectable at 12 h. Arsenic takes longer to appear in the brain and it is present only as dimethyl arsinic acid. Since arsenic concentration decreases in liver while it increases in the brain, this suggests that the arsenic metabolite reaches the brain after formation in the liver. Importantly, the fact that dimethyl arsinic acid is no longer present after 24 h suggests the existence of a mechanism to clear this metabolite from brain tissue.

Arsenite and its metabolites, MMA(III) and DMA(III), modify CYP3A4, PXR and RXR alpha expression in the small intestine of CYP3A4 transgenic mice.

Arsenic is an environmental pollutant that has been associated with an increased risk for the development of cancer and several other diseases through alterations of cellular homeostasis and hepatic function. Cytochrome P450 (P450) modification may be one of the factors contributing to these disorders. Several reports have established that exposure to arsenite modifies P450 expression by decreasing or increasing mRNA and protein levels. Cytochrome P450 3A4 (CYP3A4), the predominant P450 expressed in the human liver and intestines, which is regulated mainly by the Pregnane X Receptor-Retinoid X Receptor alpha (PXR-RXR alpha) heterodimer, contributes to the metabolism of approximately half the drugs in clinical use today. The present study investigates the effect of sodium arsenite and its metabolites monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)) on CYP3A4, PXR, and RXR alpha expression in the small intestine of CYP3A4 transgenic mice. Sodium arsenite treatment increases mRNA, protein and CYP3A4 activity in a dose-dependent manner. However, the increase in protein expression was not as marked as compared to the increase in mRNA levels. Arsenite treatment induces the accumulation of Ub-protein conjugates, indicating that the activation of this mechanism may explain the differences observed between the mRNA and protein expression of CYP3A4 induction. Treatment with 0.05 mg/kg of DMA(III) induces CYP3A4 in a similar way, while treatment with 0.05 mg/kg of MMA(III) increases mostly mRNA, and to a lesser degree, CYP3A4 activity. Sodium arsenite and both its metabolites increase PXR mRNA, while only DMA(III) induces RXR alpha expression. Overall, these results suggest that sodium arsenite and its metabolites induce CYP3A4 expression by increasing PXR expression in the small intestine of CYP3A4 transgenic mice.

A physiologically based pharmacokinetic model for intravenous and ingested dimethylarsinic acid in mice.

A physiologically based pharmacokinetic (PBPK) model for the organoarsenical dimethylarsinic acid (DMA(V)) was developed in mice. The model was calibrated using tissue time course data from multiple tissues in mice administered DMA(V) intravenously. The final model structure was based on diffusion limitation kinetics. In general, PBPK models use the assumption of blood flow-limited transport into tissues. This assumption has historically worked for small lipophilic organic solvents. However, the conditions under which flow-limited kinetics occurs and how to distinguish when flow-limited versus diffusion-limited transport is more appropriate, have been rarely evaluated. One important goal of this modeling effort was to systematically evaluate descriptions of flow-limited compared with diffusion-limited tissue distribution for DMA(V), using the relatively extensive pharmacokinetic data available in mice. The diffusion-limited model consistently provided an improved fit over flow-limited simulations when compared with tissue time course iv experimental data. After model calibration, an independent data set obtained by oral gavage of DMA(V), was used to further test model structure. Sensitivity analysis of the two PBPK model structures showed the importance of early time course data collection, and the impact of diffusion for kidney time course data description. In summary, this modeling effort suggests the importance of availability of organ specific time course data sets necessary for the discernment of PBPK modeling structure, motivated by knowledge of biology, and providing necessary feedback between experimental design and biological modelers.