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George
Molecular mimicry in mercury toxicology.Hoffmeyer RE, Singh SP, Doonan CJ, Ross AR, Hughes RJ, Pickering IJ, George GN. Chem Res Toxicol. 2006 Jun;19(6):753-9. [abstract only]
"Molecular mimicry occurs when one molecular entity is "mistaken" for another by cellular or other biological processes, and is thought to arise from structural similarities between the two molecules in question. It has been postulated by others to be important in the mechanism of uptake of toxic metal species into living tissues. A widely accepted example is the transport of methylmercury-cysteine species, which are thought to mimic the amino acid methionine. We have used mass spectrometry and mercury L(III)-edge X-ray absorption spectroscopy to understand the solution structure of complexes between methylmercury and cysteine. With a view to understanding the basis of the suggested molecular mimicry mechanisms, we have used computational chemistry to compare the structure of methionine with that of the dominant solution species L-cysteinato(methyl)mercury(II), and the structure of cystine with that of mercury(II) bis-L-cysteineate. We conclude that the structural similarities between metal compounds and natural products are insufficient to support a mechanism based on molecular mimicry, but instead, mechanisms involving a less-specific mimicry based on similarity with the L(alpha) region of the amino acid part of the molecule."
Mercury binding to the chelation therapy agents DMSA and DMPS and the rational design of custom chelators for mercury.George GN, Prince RC, Gailer J, Buttigieg GA, Denton MB, Harris HH, Pickering IJ. Chem Res Toxicol. 2004 Aug;17(8):999-1006.
"Clinical chelation therapy of mercury poisoning generally uses one or both of two drugs--meso-dimercaptosuccinic acid (DMSA) and dimercaptopropanesulfonic acid (DMPS), commercially sold as Chemet and Dimaval, respectively. We have used a combination of mercury L(III)-edge X-ray absorption spectroscopy and density functional theory calculations to investigate the chemistry of interaction of mercuric ions with each of these chelation therapy drugs. We show that neither DMSA nor DMPS forms a true chelate complex with mercuric ions and that these drugs should be considered suboptimal for their clinical task of binding mercuric ions. We discuss the design criteria for a mercuric specific chelator molecule or "custom chelator", which might form the basis for an improved clinical treatment."
The chemical form of mercury in fish.Harris HH, Pickering IJ, George GN. Science. 2003 Aug 29;301(5637):1203. [citation only]
Structural basis of the antagonism between inorganic mercury and selenium in mammals.Gailer J, George GN, Pickering IJ, Madden S, Prince RC, Yu EY, Denton MB, Younis HS, Aposhian HV. Chem Res Toxicol. 2000 Nov;13(11):1135-42. [abstract only]
"Mercuric chloride toxicity in mammals can be overcome by co-administration of sodium selenite. We report a study of the mutual detoxification product in rabbit plasma, and of a Hg-Se-S-containing species synthesized by addition of equimolar mercuric chloride and sodium selenite to aqueous, buffered glutathione. Chromatographic purification of this Hg-Se-S species and subsequent structural analysis by Se and Hg extended X-ray absorption fine structure (EXAFS) spectroscopy revealed the presence of four-coordinate Se and Hg entities separated by 2.61 A. Hg and Se near-edge X-ray absorption spectroscopy of erythrocytes, plasma, and bile of rabbits that had been injected with solutions of sodium selenite and mercuric chloride showed that Hg and Se in plasma samples exhibited X-ray absorption spectra that were essentially identical to those of the synthetic Hg-Se-S species. Thus, the molecular detoxification product of sodium selenite and mercuric chloride in rabbits exhibits similarities to the synthetic Hg-Se-S species. The underlying molecular mechanism for the formation of the Hg-Se-S species is discussed."
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