Chem. Res. Toxicol. 1993,6, 598-602
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Communications Transfer of Arsenite from Glutathione to Dithiols: A Model of Interaction Marielle Delnomdedieu,*l+JMufeed M. Basti,$ James D. Otvos,f and David J. Thomad Center for Environmental Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-731 0, Pharmacokinetics Branch, Environmental Toxicology Division, Health Effects Research Laboratory, US.Environmental Protection Agency, Research Triangle Park, North Carolina 27711, and Department of Biochemistry, North Carolina State University, Raleigh, North Carolina 27695 Received March 5, 1993
The interactions of arsenate and arsenite with meso-2,3-dimercaptosuccinicacid (DMSA) have been characterized using carbon-13 nuclear magnetic resonance. These studies show that DMSA reduces arsenate to arsenite and complexes arsenite. Monitoring the carbon-13 signals of complexed DMSA and liberated glutathione shows that DMSA readily extracts arsenite from a (glutathione)3-arsenite complex, proving the affinity of arsenite for dithiols is greater than that for monothiols. Competition between DMSA (vicinal thiols) and dithioerythritol (1,4dimercapto-2,3-butanediol) for binding of arsenite indicates that the binding affinity is inversely related to the distance between the two thiol groups. On the basis of these findings, a model for the interaction of arsenic with mono- and dithiol-containing molecules is proposed.
Introduction The role of sulfhydryl-containingmolecules, in both the redox cycle and the biotransformation of arsenic (As), is a central issue in ita biochemistry (I). GSH is the most abundant SH-containingmolecule in cells, present at about 7 mM concentration in hepatocytes (2), and is involved in the reductive metabolism and methylation of arsenic (37). Previous workshowed that GSH produces a 1:2adduct with phenyldichloroarsine (a), and recent structural studies establish that GSH can reduce inorganic arsenate [As(VI] to arsenite [As(III)Iand subsequentlyforma (GS)&(111)complex1(9). Although GSH is an initial molecular target for As in cells, it is likely that As also interacts with a variety of dithiol-containing molecules. For example, As(II1) is complexed by 3 closely spaced cysteines (residues 640,656, and 661) on the rat glucocorticoid receptor (10, l l ) , and the complexation of As(II1) by lipoic acid (6,8thioctic acid) is a well-characterized mechanism for the inhibition of the pyruvate dehydrogenase multienzyme complex (I2,13). From a therapeutic point of view, dithiol molecules such as 2,3-dimercaptopropanol (British anti-Lewisite, BAL): meso-2,3-dimercaptosuccinicacid (DMSA),or 2,3-dimercaptopropanesulfonicacid (DMPS) have been studied from a metabolism viewpoint and have
* Correspondence should be addressed to this author at the Center for Environmental Medicine, US. EPA-HERL MD 74,Research Triangle Park, NC 27711. + University of North Carolina. 8 US. EPA. 8 North Carolina State University. 1M. Delnomdedieu, M. M. Basti, J. D. Otvos, and D. J. Thomas, manuscript submitted. *Abbreviations: DMA(V), dimethylarsinate, cacodylate; BAL, 2,3dimercaptopropanol; DMSA, meeo-2,3-dimercaptoeuccinicacid; DMPS, 2,3-dimercaptopropanesulfonicacid DTE, dithioerythritol; D?T,dithiothreitol.
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