Mercury Binding to the Chelation Therapy Agents DMSA and DMPS and the Rational Design of Custom Chelators for Mercury

George, Graham N.; Prince, Roger C.; Gailer, Jürgen; Buttigieg, Gavin A.; Denton, M. Bonner; Harris, Hugh H.; Pickering, Ingrid J.

doi:10.1021/tx049904e

Cited by 104 publications

(92 citation statements)

References 25 publications

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“…However, several studies have shown that stable DMPS S-and DMSA S-conjugates of Hg 2ϩ are formed by a single mercuric ion bonding to the vicinal thiol groups on a single molecule of DMPS and DMSA, respectively (Rivera et al, 1989;Aposhian and Aposhian, 1990;Maiorino et al, 1991;Aposhian et al, 1995;Ruprecht, 1997). In contrast, George et al (2004) argue that at least two molecules of DMPS or DMSA and two atoms of Hg 2ϩ are required to form respective DMPS S-or DMSA S-conjugates of Hg 2ϩ . Regardless of the exact species of the complexes formed intracellularly, the findings from the current study and those of other studies show clearly that DMPS and DMSA are each capable of effectively reducing the renal and body burden of Hg 2ϩ (Planas-Bohne, 1981;Aposhian, 1983;Aposhian et al, 1992;Zalups et al, 1992;Ruprecht, 1997).…”

Section: Discussionmentioning

confidence: 88%

Multidrug Resistance Proteins and the Renal Elimination of Inorganic Mercury Mediated by 2,3-Dimercaptopropane-1-Sulfonic Acid and Meso-2,3-dimercaptosuccinic Acid

Bridges¹,

Joshee²,

Zalups³

2007

J Pharmacol Exp Ther

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Current therapies for inorganic mercury (Hg 2ϩ ) intoxication include administration of a metal chelator, either 2,3-dimercaptopropane-1-sulfonic acid (DMPS) or meso-2,3-dimercaptosuccinic acid (DMSA). After exposure to either chelator, Hg 2ϩ is rapidly eliminated from the kidneys and excreted in the urine, presumably as an S-conjugate of DMPS or DMSA. The multidrug resistance protein 2 (Mrp2) has been implicated in this process. We hypothesize that Mrp2 mediates the secretion of DMPSor DMSA-S-conjugates of Hg 2ϩ from proximal tubular cells. . Twenty-four and 28 h later, rats were injected with saline, DMPS, or DMSA. Tissues were harvested 48 h after HgCl 2 exposure. The renal and hepatic burden of Hg 2ϩ in the saline-injected TR Ϫ rats was greater than that of controls. In contrast, the amount of Hg 2ϩ excreted in urine and feces of TR Ϫ rats was less than that of controls. DMPS, but not DMSA, significantly reduced the renal and hepatic content of Hg 2ϩ in both groups of rats, with the greatest reduction in controls. A significant increase in urinary and fecal excretion of Hg 2ϩ

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Section: Discussionmentioning

confidence: 88%

Multidrug Resistance Proteins and the Renal Elimination of Inorganic Mercury Mediated by 2,3-Dimercaptopropane-1-Sulfonic Acid and Meso-2,3-dimercaptosuccinic Acid

Bridges¹,

Joshee²,

Zalups³

2007

J Pharmacol Exp Ther

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“…The method is equally applicable to the study of other elements of concern, such as arsenic, selenium, thallium and lead. The technique also provides an ideal tool for investigating drugs such as chelation agents (34) and can be applied to the study of essential metals and other elements of interest during normal development.…”

Section: Resultsmentioning

confidence: 99%

Localizing organomercury uptake and accumulation in zebrafish larvae at the tissue and cellular level

Korbas

Blechinger

Krone

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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125

112

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Using synchrotron x-ray fluorescence mapping, we have examined the uptake and localization of organic mercury in zebrafish larvae. Strikingly, the greatest accumulation of methyl and ethyl mercury compounds was highly localized in the rapidly dividing lens epithelium, with lower levels going to brain, optic nerve, and various other organs. The data suggest that the reported impairment of visual processes by mercury may arise not only from previously reported neurological effects, but also from direct effects on the ocular tissue. This novel approach is a powerful tool for directly investigating the molecular toxicology of heavy metals, and should be equally applicable to the study of a wide range of elements in developing embryos.methylmercury ͉ thimerosal ͉ x-ray fluorescence mapping ͉ eye lens T oxic organic mercury compounds worry many communities worldwide, yet the detailed mechanisms underlying their transport and toxicity remain uncertain (1). These neurotoxic compounds are particularly insidious due to the latency in onset of toxic symptoms and have caused several devastating masspoisonings of humans. Adults are affected, but exposure in utero has resulted in severe consequences such as microcephaly, cerebropalsy, seizures, and mental retardation. Methylmercury (MeHg) compounds are actively transported across cell membranes (2) although not, as originally thought, by molecular mimicry of methionine (3). Beyond this, however, our knowledge of the mechanisms underlying organic mercury (Hg) toxicity is fragmentary. MeHg-induced changes in cellular Ca 2ϩ have been shown to be important (4-7), as has oxidative stress (4), and glutamate metabolism (8). In both yeast and human cells, overexpression of the ubiquitin-targeting enzyme Cdc34 confers protection against the cytotoxic effects of MeHg, which leads to the suggestion that an unknown protein containing a signal for ubiquitination by Cdc34 is involved in the development of the cytotoxic effects of MeHg (9-11).Zebrafish (Danio rerio) are common model organisms for the study of embryonic development, and have found increasing use in vertebrate toxicology (12). While embryonic and larval zebrafish previously have been used to study the toxic effects of MeHg exposure at the whole body (13,14) and at the molecular level (15), there are no available data on MeHg uptake and accumulation with respect to different tissues and organs. Such information is critical to properly integrate information on tissue and cell specific impacts of Hg with uptake and accumulation of the metal at the whole animal level. We present herein a novel approach to the investigation of heavy-metal toxicity using synchrotron x-ray fluorescence imaging (16) to directly image metal localization within zebrafish larvae and to observe remarkable differential accumulation of organic Hg using this technique. Strikingly, we find that both methyl and ethyl Hg derivatives are concentrated to the greatest degree in lens epithelium with lower levels present in the brain, optic nerve, and other organs....

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“…The weaker binding of DMPS and DMSA is due to the fact there is not enough stereo-chemical space between the two thiols located on adjacent carbons to allow for binding a mercury atom. Therefore, DMPS and DMSA are not true chelators as they form "sandwich complexes" with two DMPSs forming single bonds each to a single Hg 2+ (George, et al 2004). Additionally, DMPS and DMSA chelates of Hg 2+ are negatively charged and do not effectively enter cells and are rapidly cleared by the kidney with little mercury exiting through the liver into the feces.…”

Section: Introductionmentioning

confidence: 99%

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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Mercury Binding to the Chelation Therapy Agents DMSA and DMPS and the Rational Design of Custom Chelators for Mercury

Cited by 104 publications

References 25 publications

Multidrug Resistance Proteins and the Renal Elimination of Inorganic Mercury Mediated by 2,3-Dimercaptopropane-1-Sulfonic Acid and Meso-2,3-dimercaptosuccinic Acid

Multidrug Resistance Proteins and the Renal Elimination of Inorganic Mercury Mediated by 2,3-Dimercaptopropane-1-Sulfonic Acid and Meso-2,3-dimercaptosuccinic Acid

Localizing organomercury uptake and accumulation in zebrafish larvae at the tissue and cellular level

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

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