Novel Lipid-Soluble Thiol-Redox Antioxidant and Heavy Metal Chelator, <i>N</i>,<i>N</i>′-bis(2-Mercaptoethyl)Isophthalamide (NBMI) and Phospholipase D-Specific Inhibitor, 5-Fluoro-2-Indolyl Des-Chlorohalopemide (FIPI) Attenuate Mercury-Induced Lipid Signaling Leading to Protection Against Cytotoxicity in Aortic Endothelial Cells

Secor, Jordan D.; Kotha, Sainath R.; Gurney, Travis O.; Patel, Rishi B.; Kefauver, Nicholas R.; Gupta, Niladri; Morris, Andrew J.; Haley, Boyd E.; Parinandi, Narasimham L.

doi:10.1177/1091581811422413

Cited by 16 publications

(14 citation statements)

References 50 publications

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“…Also, the use of NBMI to study its effects on mercury toxicity on aortic endothelial membranes in culture has shown no toxicity on membrane integrity and to be a very effective prevention of the damage induced by mercury exposure (Secor et al 2011). However, these studies do not eliminate the possible toxic effects that could occur with much longer exposures to ingested NBMI and this will require further long term studies.…”

Section: Discussionmentioning

confidence: 99%

“…The treatment of inhaled mercury vapor (Hg o ) or ingested or injected organic mercury compounds with NBMI may not work as well. However, NBMI has been shown to prevent the toxic effects of methylmercury in cell culture experiments (Secor et al 2011). Based on these results, further studies to characterize the effects of NBMI treatment on chronic, lowdose exposures to inorganic and other Hg species needs to be verified by further studies.…”

Section: Discussionmentioning

confidence: 99%

“…There are other biomarkers that can be used to determine if NBMI would be effective at treating chronic mercury toxicity. First, mercury is known to lower blood glutathione levels and to cause an abnormal urinary porphyrin profile (Woods & Southern, 1989;Geier et al 2011) and the work by others demonstrates that Hg 2+ can either activate or inhibit enzymes thought to be involved in some disease processes (Houston, 2011;Secor, et al 2011) Another mechanism for NBMI protection may be its ability to scavenge any hydroxyl free radicals produced salvaging the GSH levels and preventing GSSG production. GSSG is known to be a molecular precursor of apoptosis and decreasing its cellular level could contribute to cell survival (Franco & Cidlowski, 2009).…”

Section: Discussionmentioning

confidence: 99%

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Amelioration of acute mercury toxicity by a novel, non-toxic lipid soluble chelator N,N′bis-(2-mercaptoethyl)isophthalamide: effect on animal survival, health, mercury excretion, and organ accumulation

Clarke¹,

Buchanan²,

Gupta³

et al. 2012

Toxicological & Environmental Chemistry

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The toxic effects of mercury are known to be complex with specific enzyme inhibitions and subsequent oxidative stress adding to the damaging effects. There are likely other factors involved, such as the development of impaired metal ion homeostasis and depletion of thiol and selenium based metabolites such as cysteine and selenium. Much of the toxicity of mercury occurs at the intracellular level via binding of Hg 2+ to thiol groups in specific proteins. Therefore, amelioration of mercury toxicity by the use of chelation would likely be enhanced by the use of a chelator that could cross the cell membrane and the blood brain barrier. It would be most favorable if this compound was of low toxicity, had appropriate pharmacokinetics, bound and rendered mercury cation non-toxic and had antioxidant properties. Herein we report on such a chelator, N,N′-bis(2-mercaptoethyl)isophthalamide (NBMI), and, using an animal model, show that it prevented the toxic effects associated with acute exposure induced by injected mercury chloride.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Amelioration of acute mercury toxicity by a novel, non-toxic lipid soluble chelator N,N′bis-(2-mercaptoethyl)isophthalamide: effect on animal survival, health, mercury excretion, and organ accumulation

Clarke¹,

Buchanan²,

Gupta³

et al. 2012

Toxicological & Environmental Chemistry

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“…In addition, research on endothelial cell membranes shows that TM, as well as Hg 2+ and Me-Hg compounds, induce breakdown of membrane integrity, leading to leaky membranes. Associated with this breakdown is a major loss of cellular GSH levels [48]. Studies show that the intestinal epithelial membrane is similarly affected by these toxins [49].…”

Section: Research Evidencementioning

confidence: 99%

“…Many studies show that TM decreases GSH availability in human [52] and animal cells [48,53]. James et al [52], for example, showed that TM caused the depletion of intracellular GSH in human neuroblastoma and glioblastoma cell lines, and Agrawal et al [54] found that TM reduces GSH in human dentritic cells.…”

Section: Research Evidencementioning

confidence: 99%

Thimerosal Exposure and the Role of Sulfation Chemistry and Thiol Availability in Autism

Kern

Haley

Geier

et al. 2013

IJERPH

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Autism spectrum disorder (ASD) is a neurological disorder in which a significant number of the children experience a developmental regression characterized by a loss of previously acquired skills and abilities. Typically reported are losses of verbal, nonverbal, and social abilities. Several recent studies suggest that children diagnosed with an ASD have abnormal sulfation chemistry, limited thiol availability, and decreased glutathione (GSH) reserve capacity, resulting in a compromised oxidation/reduction (redox) and detoxification capacity. Research indicates that the availability of thiols, particularly GSH, can influence the effects of thimerosal (TM) and other mercury (Hg) compounds. TM is an organomercurial compound (49.55% Hg by weight) that has been, and continues to be, used as a preservative in many childhood vaccines, particularly in developing countries. Thiol-modulating mechanisms affecting the cytotoxicity of TM have been identified. Importantly, the emergence of ASD symptoms post-6 months of age temporally follows the administration of many childhood vaccines. The purpose of the present critical review is provide mechanistic insight regarding how limited thiol availability, abnormal sulfation chemistry, and decreased GSH reserve capacity in children with an ASD could make them more susceptible to the toxic effects of TM routinely administered as part of mandated childhood immunization schedules.

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Toxicity of ethylmercury (and Thimerosal): a comparison with methylmercury

Dórea

Farina

Rocha

2013

J of Applied Toxicology

109

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Ethylmercury (etHg) is derived from the metabolism of thimerosal (o-carboxyphenyl-thio-ethyl-sodium salt), which is the most widely used form of organic mercury. Because of its application as a vaccine preservative, almost every human and animal (domestic and farmed) that has been immunized with thimerosal-containing vaccines has been exposed to etHg. Although methylmercury (meHg) is considered a hazardous substance that is to be avoided even at small levels when consumed in foods such as seafood and rice (in Asia), the World Health Organization considers small doses of thimerosal safe regardless of multiple/repetitive exposures to vaccines that are predominantly taken during pregnancy or infancy. We have reviewed in vitro and in vivo studies that compare the toxicological parameters among etHg and other forms of mercury (predominantly meHg) to assess their relative toxicities and potential to cause cumulative insults. In vitro studies comparing etHg with meHg demonstrate equivalent measured outcomes for cardiovascular, neural and immune cells. However, under in vivo conditions, evidence indicates a distinct toxicokinetic profile between meHg and etHg, favoring a shorter blood half-life, attendant compartment distribution and the elimination of etHg compared with meHg. EtHg's toxicity profile is different from that of meHg, leading to different exposure and toxicity risks. Therefore, in real-life scenarios, a simultaneous exposure to both etHg and meHg might result in enhanced neurotoxic effects in developing mammals. However, our knowledge on this subject is still incomplete, and studies are required to address the predictability of the additive or synergic toxicological effects of etHg and meHg (or other neurotoxicants).

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Cited by 16 publications

References 50 publications

Amelioration of acute mercury toxicity by a novel, non-toxic lipid soluble chelator N,N′bis-(2-mercaptoethyl)isophthalamide: effect on animal survival, health, mercury excretion, and organ accumulation

Amelioration of acute mercury toxicity by a novel, non-toxic lipid soluble chelator N,N′bis-(2-mercaptoethyl)isophthalamide: effect on animal survival, health, mercury excretion, and organ accumulation

Thimerosal Exposure and the Role of Sulfation Chemistry and Thiol Availability in Autism

Toxicity of ethylmercury (and Thimerosal): a comparison with methylmercury

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