Redox metabolism of ingested arsenic: Integrated activities of microbiome and host on toxicological outcomes

Roggenbeck, Barbara A.; Leslie, Elaine M.; Walk, Seth T.; Schmidt, Edward E.

doi:10.1016/j.cotox.2018.09.003

Cited by 11 publications

(11 citation statements)

References 85 publications

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“…Lipid-hydroperoxides (ROOH) are relatively large organic electrophiles, yet they are often detoxified by direct enzymatic reduction by GPX4, for which the reducing power comes from GSH (35). Heavy metals (e.g., Au) and metalloids (e.g., As), on the contrary, are often monoatomic oxidants, yet they are more likely to be primarily detoxified by glutathionylation (104). Although both GPX-and GSTdriven detoxification reactions use GSH, each has distinct impacts on the GSH system and on supporting metabolic…”

Section: Impacts Of Stress On S Metabolismmentioning

confidence: 99%

“…Although the overoxidized inorganic S have been irretrievably lost from the pool of metabolites that could contribute S to Met or Cys in the future, in doing so it could have removed up to four molecules of H 2 O 2 from the cell. Such nonrecycling use of S amino acids to reduce H 2 O 2 might seem unfavorable under normal conditions, when the disulfide reductase-fueled GPXs and PRXs are able to remove H 2 O 2 without loss of S. However, under conditions wherein these systems are disrupted or overwhelmed (28,82,98,104), ''sacrificial'' production of H 2 S to support a persulfide-based overoxidation mechanism to eliminate H 2 O 2 , as depicted in Figure 6, could provide a stopgap measure for limiting oxidative damage.…”

Section: Miller and Schmidtmentioning

confidence: 99%

“…4B) (24,45). Some electrophilic drugs or toxins, for example, organoarsenites (As 3+ ) or organomercurial compounds, are glutathionylated yet also covalently bind with high affinity to Cys or Sec residues of GSR, TRXR1, and other critical enzymes, thereby irreversibly disrupting activity of these enzymes (104). Importantly, most of these metals are cytotoxic at low doses, suggesting that consumption of cellular S-stores is not a major determinant of toxicity.…”

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confidence: 99%

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Sulfur Metabolism Under Stress

Miller

Schmidt

2020

Antioxidants & Redox Signaling

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Significance: In humans, imbalances in the reduction-oxidation (redox) status of cells are associated with many pathological states. In addition, many therapeutics and prophylactics used as interventions for diverse pathologies either directly modulate oxidant levels or otherwise influence endogenous cellular redox systems. Recent Advances: The cellular machineries that maintain redox homeostasis or that function within antioxidant defense systems rely heavily on the regulated reactivities of sulfur atoms either within or derived from the amino acids cysteine and methionine. Recent advances have substantially advanced our understanding of the complex and essential chemistry of biological sulfur-containing molecules. Critical Issues: The redox machineries that maintain cellular homeostasis under diverse stresses can consume large amounts of energy to generate reducing power and/or large amounts of sulfur-containing nutrients to replenish or sustain intracellular stores. By understanding the metabolic pathways underlying these responses, one can better predict how to protect cells from specific stresses. Future Directions: Here, we summarize the current state of knowledge about the impacts of different stresses on cellular metabolism of sulfur-containing molecules. This analysis suggests that there remains more to be learned about how cells use sulfur chemistry to respond to stresses, which could in turn lead to advances in therapeutic interventions for some exposures or conditions.

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Section: Impacts Of Stress On S Metabolismmentioning

confidence: 99%

Section: Miller and Schmidtmentioning

confidence: 99%

mentioning

confidence: 99%

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Sulfur Metabolism Under Stress

Miller

Schmidt

2020

Antioxidants & Redox Signaling

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“…Within cells, iAs is transformed by a series of reduction and oxidative methylation steps, and almost exclusively into four methylated products: monomethylarsonic acid (MMA V ), monomethylarsonous acid (MMA III ), dimethylarsinic acid (DMA V ), and dimethylarsinous acid (DMA III ). Methylation is enzymatically catalyzed by arsenic (3+) methyltransferase (AS3MT), utilizing S-adenosylmethionine (SAM) as a methyl group donor in concert with endogenous reducing agents such as thioredoxin (Trx) and glutathione (GSH) [54,55]. Recently, a hypothesis based on evidence from crystallography demonstrated that pentavalent intermediates are likely reduced while still bound to AS3MT, which suggests that more toxic trivalent arsenicals may be the end products of methylation rather than the less toxic pentavalent species [56].…”

Section: Human Arsenic Metabolismmentioning

confidence: 99%

The Human Gut Microbiome’s Influence on Arsenic Toxicity

2019

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Purpose of Review Arsenic exposure is a public health concern of global proportions with a high degree of interindividual variability in pathologic outcomes. Arsenic metabolism is a key factor underlying toxicity, and the primary purpose of this review is to summarize recent discoveries concerning the influence of the human gut microbiome on the metabolism, bioavailability, and toxicity of ingested arsenic. We review and discuss the current state of knowledge along with relevant methodologies for studying these phenomena. Recent Findings Bacteria in the human gut can biochemically transform arsenic-containing compounds (arsenicals). Recent publications utilizing culture-based approaches combined with analytical biochemistry and molecular genetics have helped identify several arsenical transformations by bacteria that are at least possible in the human gut and are likely to mediate arsenic toxicity to the host. Other studies that directly incubate stool samples in vitro also demonstrate the gut microbiome's potential to alter arsenic speciation and bioavailability. In vivo disruption or elimination of the microbiome has been shown to influence toxicity and body burden of arsenic through altered excretion and biotransformation of arsenicals. Currently, few clinical or epidemiological studies have investigated relationships between the gut microbiome and arsenic-related health outcomes in humans, although current evidence provides strong rationale for this research in the future. Summary The human gut microbiome can metabolize arsenic and influence arsenical oxidation state, methylation status, thiolation status, bioavailability, and excretion. We discuss the strength of current evidence and propose that the microbiome be considered in future epidemiologic and toxicologic studies of human arsenic exposure.

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“…3 Food and water contaminated with arsenic was shown to be linked to increased incidence of cancerous (eg, liver, skin, lung, urinary and bladder) and noncancerous conditions (eg, diabetes mellitus, skin lesions, and peripheral vascular disease). 4,5 Oxidative damage that has arisen from reactive oxygen species (ROS) is considered a central mechanism for arsenic pathogenesis. 6 Intracellular accumula-a r t i c l e tion of ROS leads to disruption of mitochondrial membrane potential, release of cytochrome c, activation of the caspase cascades, and ultimately, cell death.…”

Section: Introductionmentioning

confidence: 99%

Subcellular Organelle Toxicity Caused by Arsenic Nanoparticles in Isolated Rat Hepatocytes

Jahangirnejad

Goudarzi

Kalantari‬

et al. 2020

Int J Occup Environ Med

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Background: Arsenic, an environmental pollutant, is a carcinogenic metalloid and also an anticancer agent. Objective: To evaluate the toxicity of arsenic nanoparticles in rat hepatocytes. Methods: Freshly isolated rat hepatocytes were exposed to 0, 20, 40, and 100 µM of arsenic nanoparticles and its bulk counterpart. Their viability, reactive oxygen species level, glutathione depletion, mitochondrial and lysosomal damage, and apoptosis were evaluated. Results: By all concentrations, lysosomal damage and apoptosis were clearly evident in hepatocytes exposed to arsenic nanoparticles. Evaluation of mitochondria and lysosomes revealed that lysosomes were highly damaged. Conclusion: Exposure to arsenic nanoparticles causes apoptosis and organelle impairment. The nanoparticles have potentially higher toxicity than the bulk arsenic. Lysosomes are highly affected. It seems that, instead of mitochondria, lysosomes are the first target organelles involved in the toxicity induced by arsenic nanoparticles.

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Redox metabolism of ingested arsenic: Integrated activities of microbiome and host on toxicological outcomes

Cited by 11 publications

References 85 publications

Sulfur Metabolism Under Stress

Sulfur Metabolism Under Stress

The Human Gut Microbiome’s Influence on Arsenic Toxicity

Subcellular Organelle Toxicity Caused by Arsenic Nanoparticles in Isolated Rat Hepatocytes

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