Analysis of Methyl Mercury Binding Sites on Tubulin Subunits and Microtubules

Vogel, D.; Margolis, Robert L.; Mottet, N. Karle

doi:10.1111/j.1600-0773.1989.tb00630.x

Cited by 23 publications

(9 citation statements)

References 20 publications

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“…In this way, any disturbance of these dynamic structures or their polymerization/depolymerization status could compromise cell survival [133, 134]. MeHg has long been known to be a potent inhibitor of microtubule polymerization [135–137]. In vitro studies demonstrated that MeHg has high affinity for tubulin sulphydryl groups (-SH), depolymerizing cerebral microtubules, and directly inhibiting their assembly [135, 137].…”

Section: Mechanisms Of Mehg-induced Developmental Neurotoxicitymentioning

confidence: 99%

Methylmercury and brain development: A review of recent literature

Santos

Hort

Culbreth

et al. 2016

Journal of Trace Elements in Medicine and Biology

144

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Methylmercury (MeHg) is a potent environmental pollutant, which elicits significant toxicity in humans. The central nervous system CNS) is the primary target of toxicity, and is particularly vulnerable during development. Maternal exposure to MeHg via consumption of fish and seafood can have irreversible effects on the neurobehavioral development of children, even in the absence of symptoms in the mother. It is well documented that developmental MeHg exposure may lead to neurological alterations, including cognitive and motor dysfunction. The neurotoxic effects of MeHg on the developing brain have been extensively studied. The mechanism of toxicity, however, is not fully understood. No single process can explain the multitude of effects observed in MeHg-induced neurotoxicity. This review summarizes the most current knowledge on the effects of MeHg during nervous system development considering both, in vitro and in vivo experimental models. Considerable attention was directed towards the role of glutamate and calcium dyshomeostasis, mitochondrial dysfunction, as well as the effects of MeHg on cytoskeletal components/regulators.

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Section: Mechanisms Of Mehg-induced Developmental Neurotoxicitymentioning

confidence: 99%

Methylmercury and brain development: A review of recent literature

Santos

Hort

Culbreth

et al. 2016

Journal of Trace Elements in Medicine and Biology

144

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“…Mercury compounds are known to interact with tubulin and to affect tubulin assembly (Vogel et al 1989;Duhr et al 1993;Liliom et al 2000). Hence, in previous publications (Thier et al 2003;Stoiber et al 2004) we have advanced the theory that the chromosomal genotoxicity of mercury may result, at least in part, from interaction(s) with cytoskeletal proteins.…”

Section: Introductionmentioning

confidence: 95%

Genotoxicity of inorganic mercury salts based on disturbed microtubule function

Bonacker

Stoiber²,

Wang

et al. 2004

Arch Toxicol

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In order to investigate the chromosomal genotoxicity of nitrobenzene and benzonitrile, we studied the induction of micronuclei (MN) by these test compounds in V79 cells, as well as effects on the formation and stability of microtubules and on motor protein functions. No cytotoxicity was seen in V79 cell cultures in terms of Neutral red uptake after 18 h treatment with up to 1 mM nitrobenzene or 1 mM benzonitrile. Subsequently, a concentration range up to 100 micro M was used in the experiments on induction of MN. Both test compounds exhibit a weak, but definitely positive test result compared to the solvent (DMSO) control. Minimal effect concentrations of nitrobenzene and benzonitrile appeared as low as 0.01 micro M, and no-effect-concentrations were between 0.001 and 0.005 micro M. Clearly enhanced MN rates were found at 0.1 micro M and higher. Both, nitrobenzene and benzonitrile, induced mostly kinetochor (CREST)-positive micronuclei, thus characterising the chromosomal effects as aneugenic. In cell-free assays, a slight effect on tubulin assembly was observed at 1 mM nitrobenzene without addition of DMSO. Higher concentrations (5 mM) led to secondary effects. In presence of 1% DMSO, nitrobenzene exerted no detectable effect on tubulin assembly up to the solubility limit in water of about 15 mM. For benzonitrile in presence of DMSO, a clear dose-response of inhibition of tubulin assembly at 37 degrees C was seen above the no-effect-concentration of 2 mM, with an IC(50) of 13 mM and protein denaturation starting above a level of about 20 mM. The nature of the effects of nitrobenzene and benzonitrile on the association of tubulin to form microtubules was confirmed by electron microscopy. Treatment by either 5 mM nitrobenzene or 13 mM benzonitrile plus 1% DMSO left the microtubular structure intact whereas 5 mM nitrobenzene, in absence of DMSO, led to irregular cluster formations. The experiments demonstrate that both nitrobenzene and benzonitrile, in millimolar concentration ranges, may lead to interference with tubulin assembly in a cell-free system. The functionality of the tubulin-kinesin motor protein system was assessed using the microtubule gliding assay. Nitrobenzene affected the gliding velocity in a concentration-dependent manner, starting at about 7.5 micro M and reaching complete inhibition of motility at 30 micro M, whereas benzonitrile up to 200 micro M did not affect the kinesin-driven gliding velocity. The micronucleus assay data demonstrate a chromosomal endpoint of genotoxicity of nitrobenzene and benzonitrile. Aneugenic effects of both compounds occur at remarkably low concentrations, with lowest-effect-concentrations being 0.1 micro M. This points to the relevance of interactions with the cellular spindle apparatus.

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“…MeHg has long been known to be a potent inhibitor of microtubule polymerization, and this effect is presumably caused by the S-mercuration of the microtubules by MeHg (Abe et al, 1975;Sager et al, 1983;Vogel et al, 1985Vogel et al, , 1989. Vogel et al (1989) found that there is a class of binding sites that have high affinities for MeHg on tubulin and that MeHg binds to tubulin stoichiometrically within microtubules. Tubulin has been found to contain thiols with low pKa values (Britto et al, 2002).…”

Section: The Disruption Of Microtubules and S-mercurationmentioning

confidence: 99%

<i>S</i>-Mercuration of cellular proteins by methylmercury and its toxicological implications

2014

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-The accumulation of methylmercury (MeHg) through the daily consumption of large predatory fish poses potential health risks. MeHg has been found to cause Minamata disease, but the full nature of MeHg toxicity remains unclear. Because of its chemical properties, MeHg covalently binds to cellular proteins through their reactive thiols, referred to as S-mercuration, resulting in the formation of protein adducts. In this review, we summarize how the S-mercuration of cellular proteins could be involved in the major mechanisms that have been suggested to underlie MeHg toxicity. Additionally, we introduce our attempts to identify cases of S-mercuration for the research to reveal the true nature of MeHg toxicity.

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Analysis of Methyl Mercury Binding Sites on Tubulin Subunits and Microtubules

Cited by 23 publications

References 20 publications

Methylmercury and brain development: A review of recent literature

Methylmercury and brain development: A review of recent literature

Genotoxicity of inorganic mercury salts based on disturbed microtubule function

<i>S</i>-Mercuration of cellular proteins by methylmercury and its toxicological implications

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